Diamine derivatives

专利摘要:
Formula 1 [Wherein, R 1 and R 2 represent a hydrogen atom, Q 1 represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, Q 2 represents a single bond and Q 3 represents The following flag (Wherein, Q 5 represents an alkylene group having 1 to 8 carbon atoms, etc.), and T 0 and T 1 represent a carbonyl group or the like.], A compound thereof, a salt thereof, a solvate thereof, or an N-oxide thereof . Cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve / joint replacement, thrombus formation and reclosure after thrombosis It is useful as a prophylactic and / or therapeutic agent for syndromes (SIRS), multi-organ failure (MODS), thrombus formation in extracorporeal circulation or blood coagulation in blood collection.
公开号:KR20040029322A
申请号:KR10-2003-7016618
申请日:2002-06-20
公开日:2004-04-06
发明作者:오오타도시하루；고모리야사토시；요시노도시하루；우오토고우이치；나카모토유미；나이토히로유키；모치즈키아키요시；나가타쯔토무；간노히데유키；하기노야노리야스；요시카와겐지；나가모치마사토시；고바야시쇼조；오노마코토
申请人:다이이찌 세이야꾸 가부시기가이샤；
IPC主号:

专利说明:

Diamine derivatives
[2] Unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reclosure after thrombolysis In addition, the thrombus formation during extracorporeal circulation is one of the important factors due to the high coagulation ability, and the dose responsiveness and persistence, the risk of bleeding is low and the side effects are low, and oral administration can provide a sufficient effect immediately. Excellent anticoagulants are required (Thrombosis Research, Vol. 68, pp. 507-512, 1992).
[3] In the study of anticoagulants based on several mechanisms of action, FXa inhibitors are likely to be excellent anticoagulants. The coagulation system is a series of reactions in which a large amount of thrombin is produced through amplification by a multistage enzymatic reaction to produce insoluble fibrin. In the endogenous system, the activation factor VIII and the activation factor IX on the phospholipid membrane in the presence of calcium ion activate the factor X after the multi-step reaction following the activation of the contact factor. In the exogenous system, the activated factor VII activates the factor X in the presence of a tissue factor. In other words, activation of factor X in FXa in the coagulation system is an essential reaction in thrombin generation. Activated X-factor (FXa) in poultry yields thrombin by limited degradation of prothrombin. Thrombin production is further amplified because the thrombin produced activates upstream clotting factors. As mentioned above, since the coagulation system upstream than FXa is divided into endogenous and exogenous, inhibition of coagulation enzymes upstream than FXa does not sufficiently inhibit the production of FXa, resulting in thrombin production. In addition, since the coagulation system is a self-amplifying reaction, it is possible to efficiently suppress the coagulation system by inhibiting FXa located upstream rather than inhibiting the generated thrombin (Thrombosis Research, Vol. 15, pp. 617-629, 1979). year). Another advantage of FXa inhibitors is that there is a large discrepancy between the effective dose in thrombus models and the prolonged bleeding time in experimental bleeding models. From these results, FXa inhibitors are anticoagulants with a low risk of bleeding. I think.
[4] Although several compounds have been reported as FXa inhibitors, antithrombin III and antithrombin III dependent pentasaccharides are generally not known to inhibit the prothrombinase complex which plays a real role in thrombus formation in vivo. (Thrombosis Research, Vol. 68, pp. 507-512, 1992; Journal of Clinical Investigation, pp. 71, 1383-1389, 1983; Mebio, Vol. 14, Aug., 92-97). It does not indicate validity. Tick anticoagulant peptide (TAP) (Science, 248, pp. 593-596, 1990) and antistatin (AST) (Journal of Biological Chemistry, 263) Kwon, pp. 10162-10167, 1988), also inhibited FXa and showed antithrombotic effects from venous thrombosis models to arterial thrombosis models, but these were ineffective by oral administration of the polymer peptide. Thus, development of the orally administrable low molecular weight FXa inhibitor which directly inhibits the coagulation factor in antithrombin III independence has been performed.
[5] Accordingly, an object of the present invention is to provide a novel compound which has a strong FXa inhibitory effect and is rapidly sufficient by oral administration and exhibits a sustained antithrombogenic effect.
[1] The present invention inhibits activated coagulation factor X (hereinafter abbreviated as FXa) and exhibits strong anticoagulant action and is also a novel compound that can be orally administered or prevention of blood coagulation inhibitors, thrombus and embolism containing the same as an active ingredient. And / or therapeutic agents.
[6] Disclosure of the Invention
[7] As a result of examining the synthesis and pharmacological action of novel FXa inhibitors, the inventors have found diamine derivatives, salts thereof, solvates thereof or N-oxides that exhibit strong FXa inhibitory action and strong anticoagulant action. Moreover, since these compounds have immediate effects even in oral administration and continuously inhibit FXa strongly and exhibit potent anticoagulant and antithrombotic effects, they are useful as preventive and therapeutic drugs for various diseases caused by thrombosis and embolism. Discovered to complete the present invention.
[8] That is, the present invention is formula 1
[9]
[10] [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
[11] Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, saturated with or without a substituent Or an unsaturated dicyclic or tricyclic condensed hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
[12] Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, and a substituent A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a divalent saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, and
[13] Q ³ is
[14]
[15] Of (groups, - groups of, Q ⁵ is C 1 -C 8 alkylene group, an Al having a carbon number of 2-8 alkenylene group or a group _{- (CH 2) m -CH 2} -A-CH 2 - (CH 2) n m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-.
[16] R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group which may have an alkyl group and a substituent, an aryl group, an aralkyl group, heteroa Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo Substituted on a 3-6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an alkyl group which may have a nil group, a substituent N, N-dialkylcarbamoylacyl group which may have, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N- which may have a substituent on the alkyl group Alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group, or R ³ and R ⁴ together represent an alkylene group of 1 to 5 carbon atoms, 2 to 5 carbon atoms An alkenylene group, an alkylenedioxy group having 1 to 5 carbon atoms, or a carbonyldioxy group;
[17] Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, heteroaryl with or without a substituent An alkenyl group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
[18] T ⁰ represents a carbonyl group or a thiocarbonyl group;
[19] T ¹ represents a carbonyl group, a sulfonyl group, a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(where R 'is a hydrogen atom , represents a hydroxyl group, alkyl group or alkoxy group), group ^{-C (= O) -A 1 -N} (R ") -. ( group of, a ¹ represents an alkylene group having 1 to 5 carbon atoms which may have a substituent , R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C (= O) -NH-, a group -C (= S) -NH-, a group -C (= O) -NH-NH -, Group -C (= O) -A ² -C (= O)-(wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), and the group -C (= O) -A ³ -C (= O) -NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms), the group -C (= O) -C (= NOR ^a ) -N (R ^b )- R ^a represents a hydrogen atom, an alkyl group, or an alkanoyl group in the group -C (= S) -C (= NOR ^a ) -N (R ^b )-(group, R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or Alkoxy group.), Group -C (= O) -N = N-, group -C (= S) -N = N-, group -C (= NOR ^c ) -C (= O) -N (R ^d) - (of the group, R ^c is a hydrogen , An alkyl group, an alkanoyl represents a group, aryl group or aralkyl, R ^d represents a hydrogen atom, a hydroxyl group, alkyl group or alkoxy group), group ^{-C (= NN (R e)} (R f)) -. C (= O) -N (R ^g )-(In the groups, R ^e and R ^f each independently represent a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl (thiocarbonyl) group, and R ^g represents a hydrogen atom, a hydroxyl group, an alkyl group or Or an thiocarbonyl group.], Salts thereof, solvates thereof or N-oxides thereof.
[20] In addition, the present invention is a compound containing a compound represented by the formula (1), salts thereof, solvates or drugs containing their N-oxides, activating blood coagulation factor X inhibitors, blood coagulation inhibitors, thrombus or embolism prevention and / or Therapeutic agents, further cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after prosthetic valve / joint replacement, thrombus formation and reconstruction after thrombolysis It provides a prophylactic and / or therapeutic agent for occlusion, systemic inflammatory response syndrome (SIRS), multi-organ failure (MODS), thrombogenesis in extracorporeal circulation or blood coagulation in blood collection.
[21] In another aspect, the present invention provides an intermediate for preparing compound (1) represented by the formula (1).
[22] In another aspect, the present invention provides a use of the compound represented by the formula (1), salts thereof, solvates thereof or their N-oxides for the manufacture of pharmaceuticals.
[23] Furthermore, the present invention provides a method for treating thrombus or embolism, comprising administering an effective amount of the compound represented by the formula (1), salts thereof, solvates thereof or N-oxides thereof.
[24] Best Mode for Carrying Out the Invention
[25] The substituent in the diamine derivative of this invention represented by General formula (1) below is demonstrated.
[26] <Group for Q ^4>
[27] The group Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, hetero with or without a substituent It means an arylalkenyl group, a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent.
[28] In the group Q ⁴ aryl group includes an aryl group having 6 to 14 carbon atoms, for example phenyl group, naphthyl group, anthryl group, phenanthryl group and the like. An aryl alkenyl group means group comprised with a C6-C14 aryl group and a C2-C6 alkenylene group, For example, a styryl group etc. are mentioned. As an aryl alkynyl group, it means the group comprised from a C6-C14 aryl group and a C2-C6 alkynylene group, For example, a phenylethynyl group etc. are mentioned.
[29] Heteroaryl group means an aromatic monovalent group having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and has a total of 5 or 6 heteroaryl groups such as pyridyl group, pyridazinyl group, and pyra Genyl group, furyl group, thienyl group, pyrrolyl group, thiazolyl group, oxazolyl group, pyrimidinyl group, tetrazolyl group, etc. are mentioned. Heteroaryl alkenyl group means group comprised by said heteroaryl group and a C2-C6 alkenylene group, For example, a thienyl ethenyl group, a pyridylethenyl group, etc. are mentioned.
[30] A saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group indicates that a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon has become a monovalent group, and its saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon is a homologous or hetero saturation or The bicyclic or tricyclic condensed hydrocarbon formed by condensation of 2-3 unsaturated cyclic hydrocarbons is shown. The saturated or unsaturated 5-6 membered cyclic hydrocarbon in that case is cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, benzene etc. are mentioned, for example. Specific examples of the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group include indenyl group, indanyl group, tetrahydronaphthyl group, naphthyl group and the like. Also, the position of the hydrocarbon group is a condensed saturated or unsaturated, bicyclic or tricyclic, which combined with the T ¹ of the formula (I) is not particularly limited.
[31] A saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group means that a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic ring has become a monovalent group, and the saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group is as follows. ① to ③ are displayed.
[32] ① a bicyclic or tricyclic condensed heterocycle formed by condensation of 2-3 rings of the same or different saturated or unsaturated 5- to 7-membered heterocyclic rings,
[33] ② a bicyclic or tricyclic condensed heterocyclic ring formed by condensation of one saturated or unsaturated 5 to 7 membered heterocycle and 1 to 2 saturated or unsaturated 5 to 6 membered cyclic hydrocarbons;
[34] (3) Tricyclic condensed heterocycle formed by condensation of two saturated or unsaturated 5 to 7 membered heterocycles with one saturated or unsaturated 5 to 6 membered cyclic hydrocarbon.
[35] Position in which the saturated or unsaturated bicyclic or tricyclic condensed heterocyclic bond and T ¹ in the formula 1 is not particularly limited.
[36] Said saturated or unsaturated 5-7 membered heterocycle represents the heterocyclic ring which has at least 1 hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom, and is a furan, a pyrrole, a thiophene, a pyrazole, an imidazole, an oxazole , Oxazolidine, thiazole, thiadiazole, furazane, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine, oxadiazine, morpholine, thiazine, thiazin Diazine, thiomorpholine, tetrazole, triazole, triazine, thiadiazine, oxadiazine, azepine, diazepine, triazepine, thiazepine, oxazinepin, etc. are mentioned as a specific example. In addition, a saturated or unsaturated 5-6 membered cyclic hydrocarbon shows the same thing as the saturated or unsaturated 5-6 membered cyclic hydrocarbon illustrated in description of a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group. Specific examples of the saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group include benzofuryl group, isobenzofuryl group, benzothienyl group, indolyl group, indolinyl group, isoindolinyl group, isoindolinyl group, indazolyl group, Quinolyl group, dihydroxyquinolyl group, 4-oxodihydroquinolyl group (dihydroquinolin-4-one), tetrahydroquinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, chromenyl group, Chromanyl group, isochromenyl group, 4H-4-oxobenzopyranyl group, 3,4-dihydro-4H-4-oxobenzopyranyl group, 4H-quinolininyl group, quinazolinyl group, dihydroquinazolinyl group, tetra Hydroquinazolinyl group, quinoxalinyl group, tetrahydroquinoxalinyl group, cinnaolinyl group, tetrahydrocinnolinyl group, indolinyl group, tetrahydroindolizinyl group, benzothiazolyl group, tetrahydrobenzothiazolyl group, benz Oxazolyl group, benzisothiazolyl group, benzisoxazolyl group, Zimidazolyl group, naphthyridinyl group, tetrahydronaphthyridinyl group, thienopyridyl group, tetrahydrothienopyridyl group, thiazolopyridyl group, tetrahydrothiazolopyridyl group, thiazolopyridazinyl group, tetrahydrothia Zolopyridazinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, tetrahydropyrrolopyridyl group, pyrrolopyrimidinyl group, dihydropyrrolopyrimidinyl group, pyridoquinazolinyl group, dihydropyridoquina Zolinyl group, pyridopyrimidinyl group, tetrahydropyridopyrimidinyl group, pyranothiazolyl group, dihydropyranothiazolyl group, furopyridyl group, tetrahydrofuropyridyl group, oxazolopyridyl group, tetrahydrooxazolo Pyridyl group, oxazolopyridazinyl group, tetrahydrooxazolopyridazinyl group, pyrrolothiazolyl group, dihydropyrrolothiazolyl group, pyrrolooxazolyl group, dihydropy Rooxazolyl group, thienopyrrolyl group, thiazolopyrimidinyl group, 4-oxotetrahydrocinininyl group, 1,2,4-benzothiadiazinyl group, 1,1-dioxy-2H-1,2, 4-benzothiadiazinyl group, 1,2,4-benzoxadiazinyl group, cyclopentapyranyl group, thienofuranyl group, furopyranyl group, pyridoxazinyl group, pyrazole oxazolyl group, imidazothiazolyl group , Imidazopyridyl group, tetrahydroimidazopyridyl group, pyrazinopyridazinyl group, benzisoquinolyl group, furosinolyl group, pyrazolothiazolopyridazinyl group, tetrahydropyrazolothiazolopyridazinyl group Hexahydrothiazolopyridazinopyridazinyl group, imidazotriazinyl group, oxazolopyridyl group, benzoxepinyl group, benzoazinyl group, tetrahydrobenzoazinyl group, benzodiazepinyl group, benzotriazinyl group , Thienoazinyl group, tetrahydrothienoazinyl group, thienodiazepynyl Group, thienotriazinyl group, thiazoloazinyl group, tetrahydrothiazoloazinyl group, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group, 5,6- Trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group etc. are mentioned.
[37] There is no restriction | limiting in particular in the condensation type of the said condensed heterocyclic group, For example, as a naphthyridinyl group, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2, Any of 7-naphthyridinyl group may be sufficient, and a thieno pyridyl group may be a thieno [2,3-b] pyridyl group, a thieno [2,3-c] pyridyl group, and a thieno [3,2-b] group. A pyridyl group, a thieno [3,2-c] pyridyl group, a thieno [3,4-b] pyridyl group, or a thieno [3,4-c] pyridyl group may be sufficient, and a thienopyrrolyl group may be thie; Any of a no [2,3-b] pyrrolyl group and a thieno [2,3-b] pyrrolyl group may be sufficient, and a thiazolo pyridyl group may be a thiazolo [4,5-b] pyridyl group or a thiazolo [4]. , 5-c] pyridyl group, thiazolo [5,4-b] pyridyl group, thiazolo [5,4-c] pyridyl group, thiazolo [3,4-a] pyridyl group, thiazolo [3,2 any of the -a] pyridyl group may be used, and the thiazolopyridazinyl group may be a thiazolo [4,5-c] pyridazinyl group, a thiazolo [4,5-d] pyridazinyl group, or a thiazolo [5 , 4-c] pyridazinyl group, thiazole Any of a ro [3,2-b] pyridazinyl group may be sufficient, and a pyrrolopyridyl group may be a pyrrolo [2,3-b] pyridyl group, a pyrrolo [2,3-c] pyridyl group, a pyrrolo Any of a [3,2-b] pyridyl group, a pyrrolo [3,2-c] pyridyl group, a pyrrolo [3,4-b] pyridyl group, a pyrrolo [3,4-c] pyridyl group, And pyridopyrimidinyl groups include pyrido [2,3-d] pyrimidinyl groups, pyrido [3,2-d] pyrimidinyl groups, pyrido [3,4-d] pyrimidinyl groups, pyrido [ A 4,3-d] pyrimidinyl group, a pyrido [1,2-c] pyrimidinyl group, a pyrido [1,2-a] pyrimidinyl group may be sufficient, and a pyranothiazolyl group may be pyrano [ Any of a 2,3-d] thiazolyl group, a pyrano [4,3-d] thiazolyl group, a pyrano [3,4-d] thiazolyl group, a pyrano [3,2-d] thiazolyl group As the furypyridyl group, a furo [2,3-b] pyridyl group, a furo [2,3-c] pyridyl group, a furo [3,2-b] pyridyl group and a furo [3,2-c] group may be used. A pyridyl group, a furo [3, 4-b] pyridyl group, a furo [3, 4-c] pyridyl group may be sufficient, and an oxa Examples of the ropyridyl group include oxazolo [4,5-b] pyridyl groups, oxazolo [4,5-c] pyridyl groups, oxazolo [5,4-b] pyridyl groups and oxazolo [5,4-c]. A pyridyl group, an oxazolo [3,4-a] pyridyl group, an oxazolo [3,2-a] pyridyl group may be sufficient, and an oxazolo pyridazinyl group is an oxazolo [4,5-c] pyrida. Any of a genyl group, an oxazolo [4,5-d] pyridazinyl group, an oxazolo [5,4-c] pyridazinyl group, an oxazolo [3,4-b] pyridazinyl group, Pyrrolothiazolyl groups include pyrrolo [2,1-b] thiazolyl groups, pyrrolo [1,2-c] thiazolyl groups, pyrrolo [2,3-d] thiazolyl groups, pyrrolo [3, A 2-d] thiazolyl group or a pyrrolo [3,4-d] thiazolyl group may be sufficient, and a pyrrolooxazolyl group may be a pyrrolo [2,1-b] oxazolyl group, a pyrrolo [1, Any of 2-c] oxazolyl group, pyrrolo [2,3-d] oxazolyl group, pyrrolo [3,2-d] oxazolyl group, pyrrolo [3,4-d] oxazolyl group As the benzoazinyl group, 1H-1-benzoazinyl group, 1H-2-benzoa Either a zefinyl group or a 1H-3-benzoazinyl group may be sufficient, and a benzoazinyl group of a dihydro-oxo derivative type like 4,5-dihydro-1-oxo-1H-2-benzoazinyl group The benzodiazepinyl group may be any of 1H-1,3-benzodiazepinyl group, 1H-1,4-benzodiazepinyl group, 1H-1,5-benzodiazepynyl group, and 4, A dihydro-oxo derivative type benzodiazepinyl group may be used, such as a 5-dihydro-4-oxo-1H-1,3-benzodiazepinyl group, and the benzotriazinyl group may be 1H-1,3,4-benzo. Any of the triazinyl group and the 1H-1,3,5-benzotriazinyl group may be sufficient, and also dihydro, such as 4,5-dihydro-5-oxo-1H-1,3,4-benzotriazinyl group A benzotriazinyl group of an oxo derivative type may be sufficient, and a thieno [2,3-b] azinyl group, a thieno [2,3-c] azinyl group, thieno [2,3] may be sufficient as a thienoazinyl group. -d] azinyl, thieno [3,2-c] azinyl, thi Any of the eno [3,2-b] azinyl groups may be used, and a di, like 5,6,7,8-tetrahydro-4-oxo-4H-thieno [3,2-c] azinyl group may be used. The thienoazinyl group of the hydro-oxo derivative type may be sufficient, and any condensation type may be similarly used also in a thienodiazepynyl group and a thienotriazinyl group, and a dihydro-oxo derivative type may be sufficient as a benzothiazepi As a nil group, any of the 1H-1-benzothiazepinyl group, the 1H-2-benzothiazepinyl group, and the 1H-3-benzothiazepinyl group may be sufficient, and 4,5-dihydro-1-oxo-1H-2 may be sufficient as it. A benzothiazepinyl group of a dihydro-oxo derivative type, such as a benzothiazepinyl group, may be used. Examples of the benzoxazepinyl group include a 1H-1-benzoxazepinyl group, a 1H-2-benzoxazepinyl group, and a 1H- group. Any of the 3-benzoxazepinyl group may be used, and dihydro-ox, such as 4,5-dihydro-1-oxo-1H-2-benzoxazepinyl group, may be used. May be a benzoxazole Jaffe group of the induction body, it is further It may be other than those of a condensing type.
[38] Said aryl group, heteroaryl group, aryl alkenyl group, heteroaryl alkenyl group, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group and saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group are each one to three There may be a substituent, and as a substituent, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a halogen atom of iodine atom, a halogen atom alkyl group having 1 to 3 carbon atoms substituted with 1 to 3 halogen atoms, amino group, cyano group, amino Alkyl group, nitro group, hydroxyalkyl group (for example, hydroxymethyl group, 2-hydroxyethyl group etc.), alkoxyalkyl group (for example, methoxymethyl group, 2-methoxyethyl group etc.), carboxyl group, carboxyalkyl group (for example For example, carboxymethyl group, 2-carboxyethyl group, etc.), alkoxycarbonylalkyl group (for example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, etc.), acyl group (for example, formyl group, acetyl group, pro) Alkanoyl groups, such as an oyl group), an amidino group, a hydroxy amidino group, a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, etc.), linear, branched Or an amidino group in which a cyclic alkoxy group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, etc.), a linear, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms is substituted (for example, , Methoxycarbonylamidino groups, ethoxycarbonylamidino groups, etc.), linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms (e.g., vinyl, allyl, etc.), linear Or a branched C2-C6 alkynyl group (for example, ethynyl group, propynyl group, etc.), linear, branched or cyclic C2-C6 alkoxycarbonyl group (for example, methoxycarbonyl group, e.g. Oxycarbonyl group, etc.), carbamoyl group, and a straight chain on a nitrogen atom , Mono or dialkylcarbamoyl groups (eg, methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group, ethylmethylcarbamoyl group, etc.) in which a branched or cyclic alkyl group having 1 to 6 carbon atoms is substituted. , Mono or dialkylamino groups (eg, ethylamino groups, dimethylamino groups, methylethylamino groups) substituted with linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms and nitrogen containing heterocyclic groups of 5 to 6 members (For example, pyrrolidino group, piperidino group, piperazino group, morpholino group, etc.) etc. are mentioned.
[39] Q ⁴ is a group to group, among the 12 kinds of group (a) ~ (l) are preferable. In other words,
[40]
[41] [In the group, R ⁵ and R ⁶ are each independently a hydrogen atom, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, Or a phenyl group which may be substituted with a cyano group, a hydroxyl group, a halogen atom, an alkyl group or an alkoxy group, and R ⁷ and R ⁸ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group or an alkenyl group , Alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, An amidino group or an alkoxycarbonylalkyl group.],
[42]
[43] [In the group, R ⁹ and R ¹⁰ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group. , Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.],
[44]
[45] [In the group, R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group Alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.
[46]
[47] [In the group, X ¹ represents CH ₂ , CH, NH, NOH, N, O or S, and R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, and a halogen Atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcar A barmoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.],
[48]
[49] [Wherein, X ² represents NH, N, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH, and R ¹⁷ and R ¹⁸ are each independently a hydrogen atom , Hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N- An alkyl carbamoyl group, an N, N-dialkyl carbamoyl group, an alkoxycarbonyl group, an amidino group, or an alkoxycarbonylalkyl group is shown. Except that X ³ and X ⁴ are a combination of C and CH and both are C or CH.],
[50]
[51] [In the group, N represents one or two carbon atoms of the ring substituted by R ¹⁹ is substituted with a nitrogen atom, and R ¹⁹ , R ²⁰ and R ²¹ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, Cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N A dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.],
[52]
[53] [Wherein, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, Z ³ represents CH ₂ , CH , S, SO ₂ or C═O, X ⁵ -Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, R ²² and R ²³ are each independently a hydrogen atom, a hydroxyl group, Nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamo A diary, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group, and R ²⁴ represents a hydrogen atom or an alkyl group.],
[54]
[55] [Wherein, X ⁶ represents O or S, and R ²⁵ and R ²⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, Hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group ],
[56]
[57] [In the group, R ²⁷ and R ²⁸ are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group , Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.],
[58]
[59] [In the group, E ¹ and E ² each independently represent N or CH, and R ²⁹ and R ³⁰ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, and an alkoxy group. Nyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino Group or an alkoxycarbonylalkyl group.],
[60]
[61] [In group, Y <^1> represents CH or N, Y <^2> represents -N ( ^R33 )-(in group, ^R33 represents a hydrogen atom or a C1-C6 alkyl group.), O or S, R ³¹ and R ³² are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxy Alkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.],
[62] And the following groups
[63]
[64] [Wherein, the numbers 1 to 8 represent positions, and each N represents any one of 1 to 4 carbon atoms and one of 5 to 8 carbon atoms is substituted with one nitrogen atom, R ³⁴ , R ³⁵ and R ³⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.] Are mentioned as a preferable group. have.
[65] Description is added about these groups below.
[66] In the above group, the halogen atom in the description of R ⁵ to R ³⁶ represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the alkyl group represents a linear, branched or cyclic C 1-6 carbon. The kenyl group represents a straight, branched or cyclic carbon number of 2 to 6, the alkynyl group represents a straight or branched carbon number of 2 to 6, and the hydroxyalkyl group represents a hydroxyl group of the C ₁ -C ₆ alkyl group. indicates that the one is the substituted alkoxy group is linear, branched or represents that the carbon number of 1-6 of the ring-shaped, an alkoxy group is substituted on the above C ₁ -C ₆ alkyl group wherein the dog of the C ₁ -C ₆ alkoxy group 1 The carboxyalkyl group represents that one carboxyl group is substituted with the above C ₁ -C ₆ alkyl group, and the acyl group has an alkanoyl group (including formyl group) having 1 to 6 carbon atoms, a benzoyl group or a naphthoyl group. Or an arylalkanoyl group in which the C ₆ -C ₁₄ aryl group is substituted with the aroyl group or the C ₁ -C ₆ alkanoyl group described above, and the N-alkylcarbamoyl group is the C ₁ -C ₆ alkyl group described above. Represents a carbamoyl group substituted on a nitrogen atom, an N, N-dialkylcarbamoyl group represents a carbamoyl group in which two C ₁ -C ₆ alkyl groups are substituted on a nitrogen atom, and an alkoxycarbonyl group is a C ₁ -C ₆ indicates that the alkoxy group and a carbonyl group, an alkoxycarbonylalkyl group indicates that the dog is C ₁ -C ₆ alkoxycarbonyl group 1 of the the above-mentioned C ₁ -C ₆ alkyl group substituted with halogeno-alkyl groups of the The C ₁ -C ₆ alkyl group is substituted with 1 to 3 halogen atoms. In addition, in said description, a substitution position is not specifically limited.
[67] The following flag
[68]
[69] [In the group, R <^5> , R <^6> , R <^7> and R <^8> represent the same thing as the above, and the numbers of 1-6 show a position. In R <^5> and R <^6> are respectively independently a hydrogen atom and a cyano group , Halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group is preferable. As R ⁵ and R ^{6, a} hydrogen atom or an alkyl group is more preferable, and in the case of an alkyl group, a methyl group is preferable. Furthermore, R ⁷ and R ^{8 are preferably} one of a hydrogen atom and the other of a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, among others, a hydrogen atom, It is especially preferable when it is a halogen atom, an alkyl group, or an alkynyl group. As the halogen atom in this case, a fluorine atom, a chlorine atom and a bromine atom are preferable, a methyl group is preferable as the alkyl group, and an ethynyl group is particularly preferable as the alkynyl group. As a specific group represented by said formula, a chloro styryl group, a fluoro styryl group, a bromostyryl group, an ethynyl styryl group, etc. are mentioned as a preferable example, The halogen atom, alkyl group, or alkynyl group in these groups is substituted. Although it does not specifically limit as a position, The 4th position in the said formula is especially preferable. Specifically, 4-chloro styryl group, 4-fluoro styryl group, 4-bromostyryl group, 4-ethynyl styryl group, etc. are mentioned as a preferable example.
[70] The following flag
[71]
[72] In the group, R ⁹ and R ¹⁰ represent the same as described above, and the numbers 1 to 6 represent positions. In R ⁹ and R ¹⁰ , each independently, a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group is used. desirable. Furthermore, it is preferable that R ⁹ is a hydrogen atom and R ¹⁰ is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. As the halogen atom in this case, a fluorine atom, a chlorine atom and a bromine atom are preferable, a methyl group is preferable as the alkyl group, and an ethynyl group is particularly preferable as the alkynyl group. As a specific group represented by said formula, a chlorophenylethynyl group, a fluorophenylethynyl group, a bromophenylethynyl group, an ethynylphenylethynyl group, etc. are mentioned as a preferable example, The halogen atom in these groups is mentioned. Although it does not specifically limit as a position where an alkyl group or an alkynyl group is substituted, The 4th position in the said formula is especially preferable. Specifically, 4-chlorophenylethynyl group, 4-fluorophenylethynyl group, 4-bromophenylethynyl group, 4-ethynylphenylethynyl group, etc. are mentioned as a preferable example.
[73] The following flag
[74]
[75] [Group of, R ^11, R ¹² and R ¹³ are the same meanings as defined above, represents the number position of 1-8.] The method, R ^11, R ¹² and R ¹³ is a hydrogen atom, cyano group, each independently , Halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group is preferable. As R ¹¹ , a hydrogen atom, an alkyl group, a halogen atom and a hydroxyl group are preferable, and a hydrogen atom is particularly preferable. As R ¹² and R ¹³ , one side is preferably a hydrogen atom and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and the other is a hydrogen atom or a halogen atom. It is especially preferable when it is an alkyl group or an alkynyl group. The halogen atom in that case is preferably a fluorine atom, a chlorine atom and a bromine atom, a methyl group is preferable as the alkyl group, and an ethynyl group is preferable as the alkynyl group. The naphthyl group is preferably 2-naphthyl group than 1-naphthyl group, and in the case of 2-naphthyl group, it is not particularly limited as a position where a halogen atom, an alkyl group or an alkynyl group is substituted, but the 6-position or Position 7 is preferred, and position 6 is most preferred. Furthermore, it is more preferable that chlorine atom, fluorine atom, bromine atom, alkynyl group, etc. are substituted by these naphthyl groups, Furthermore, it is especially preferable that chlorine atom, fluorine atom, bromine atom, alkynyl group etc. were substituted. Specifically, 6-chloro-2-naphthyl group, 6-fluoro-2-naphthyl group, 6-bromo-2-naphthyl group, 6-ethynyl-2-naphthyl group, 7-chloro-2-naphthyl group , 7-fluoro-2-naphthyl group, 7-bromo-2-naphthyl group, 7-ethynyl-2-naphthyl group, etc. are mentioned as a preferable example.
[76] The following flag
[77]
[78] In the group, X ¹ , R ¹⁴ , R ¹⁵ and R ¹⁶ represent the same as described above, and the numbers 4 to 7 represent positions. In the above, X ¹ is preferably NH, NOH, N, O and S. And NH, O, and S are more preferable. R ¹⁴ is preferably a hydrogen atom, a halogen atom, an acyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkyl group, and R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, a cyano group, Preference is given to halogen atoms, alkyl groups, alkenyl groups, alkynyl groups or halogenoalkyl groups. One of R ¹⁵ and R ¹⁶ is a hydrogen atom or a halogen atom, preferably a fluorine atom or a chlorine atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. Especially, especially when the other is a hydrogen atom, a halogen atom, an alkyl group, or an alkynyl group. The halogen atom in that case is preferably a fluorine atom, a chlorine atom and a bromine atom, a methyl group is preferable as the alkyl group, and an ethynyl group is preferable as the alkynyl group. Although it does not specifically limit as a position which a halogen atom, an alkyl group, or an alkynyl group substitutes, The 4th, 5th, or 6th position in the said formula is preferable. Specific groups represented by the above formula include 5-chloroindolyl group, 5-fluoroindolyl group, 5-bromoindolinyl group, 5-ethynylindolyl group, 5-methylindolyl group, 5-chloro-4 -Fluoroindolyl group, 5-chloro-3-fluoroindolyl group, 5-fluoro-3-chloroindolyl group, 5-ethynyl-3-fluoroindolyl group, 5-chloro-3- (N, N-dimethylcarbamoyl) indolyl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indolyl group, 5-chloro-3-formylindolyl group, 5-fluoro- 3-formylindolyl group, 6-chloroindolyl group, 6-fluoroindolyl group, 6-bromoindolyl group, 6-ethynyl indolyl group, 6-methylindolyl group, 5-chlorobenzothier Neyl group, 5-fluorobenzothienyl group, 5-bromobenzothienyl group, 5-ethynylbenzothienyl group, 5-methylbenzothienyl group, 5-chloro-4-fluorobenzothienyl group, 6-chlorobenzothier Neyl group, 6-fluorobenzothienyl group, 6-bromobenzothienyl group, 6-ethynylbenzothienyl group, 6-methyl Jothienyl group, 5-chlorobenzofuryl group, 5-fluorobenzofuryl group, 5-bromobenzofuryl group, 5-ethynylbenzofuryl group, 5-methylbenzofuryl group, 5-chloro-4-fluoro Benzofuryl group, 6-chlorobenzofuryl group, 6-fluorobenzofuryl group, 6-bromobenzofuryl group, 6-ethynylbenzofuryl group, 6-methylbenzofuryl group, etc. are mentioned as a preferable example, position, where these substituents combine with T ¹ is not particularly limited, and the formula (d) is preferably 2-position or 3-position of, and in particular the 5-chloro-indole-2-yl group, 5-fluoro-indole- 2-yl group, 5-bromoindol-2-yl group, 5-ethynylindol-2-yl group, 5-methylindol-2-yl group, 5-chloro-4-fluoroindol-2-yl group, 5-chloro -3-fluoroindol-2-yl group, 3-bromo-5-chloroindol-2-yl group, 3-chloro-5-fluoroindol-2-yl group, 3-bromo-5-fluoroindole- 2-yl group, 5-bromo-3-chloroindol-2-yl group, 5-bromo-3-fluoroindol-2-yl group, 5- Loro-3-formylindol-2-yl group, 5-fluoro-3-formylindol-2-yl group, 5-bromo-3-formylindol-2-yl group, 5-ethynyl-3-form Millindol-2-yl group, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indole-2- Diary, 5-bromo-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 6- Chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chloroindole -3-yl group, 5-fluoroindol-3-yl group, 5-bromoindol-3-yl group, 5-ethynylindol-3-yl group, 5-methylindol-3-yl group, 5-chloro-4- Fluoroindol-3-yl group, 6-chloroindol-3-yl group, 6-fluoroindol-3-yl group, 6-bromoindol-3-yl group, 6-ethynylindol-3-yl group, 6-methyl Indol-3-yl group, 5-chlorobenzothiophen-2-yl group, 5-fluorobenzothiophen-2-yl group, 5-bromobenzothiophen-2-yl group, 5-ethynylbenzo Thiophen-2-yl group, 5-methylbenzothiophen-2-yl group, 5-chloro-4-fluorobenzothiophen-2-yl group, 6-chlorobenzothiophen-2-yl group, 6-fluorobenzo Thiophen-2-yl group, 6-bromobenzothiophen-2-yl group, 6-ethynylbenzothiophen-2-yl group, 6-methylbenzothiophen-2-yl group, 5-chlorobenzothiophen-3 -Group, 5-fluorobenzothiophen-3-yl group, 5-bromobenzothiophen-3-yl group, 5-ethynylbenzothiophen-3-yl group, 5-methylbenzothiophen-3-yl group, 5-chloro-4-fluorobenzothiophen-3-yl group, 6-chlorobenzothiophen-3-yl group, 6-fluorobenzothiophen-3-yl group, 6-bromobenzothiophen-3-yl group , 6-ethynylbenzothiophen-3-yl group, 6-methylbenzothiophen-3-yl group, 5-chlorobenzofuran-2-yl group, 5-fluorobenzofuran-2-yl group, 5-bromobenzo Furan-2-yl group, 5-ethynylbenzofuran-2-yl group, 5-methylbenzofuran-2-yl group, 5-chloro-4-fluorobenzofuran-2-yl group, 6-chlorobenzofuran-2- Diary, 6-fluorobenzofuran-2-yl , 6-bromobenzofuran-2-yl group, 6-ethynylbenzofuran-2-yl group, 6-methylbenzofuran-2-yl group, 5-chlorobenzofuran-3-yl group, 5-fluorobenzofuran- 3-yl group, 5-bromobenzofuran-3-yl group, 5-ethynylbenzofuran-3-yl group, 5-methylbenzofuran-3-yl group, 5-chloro-4-fluorobenzofuran-3-yl group , 6-chlorobenzofuran-3-yl group, 6-fluorobenzofuran-3-yl group, 6-bromobenzofuran-3-yl group, 6-ethynylbenzofuran-3-yl group, 6-methylbenzofuran- 3-yl group etc. are more preferable; 5-chloroindol-2-yl group, 5-fluoroindol-2-yl group, 5-bromoindol-2-yl group, 5-ethynylindol-2-yl group, 5-methylindol-2-yl group, 5- Chloro-4-fluoroindol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl , 6-methylindol-2-yl group, 5-chloro-3-fluoroindol-2-yl group, 3-bromo-5-chloroindol-2-yl group, 3-chloro-5-fluoroindole-2- Diary, 3-bromo-5-fluoroindol-2-yl group, 5-bromo-3-chloroindol-2-yl group, 5-bromo-3-fluoroindol-2-yl group, 5-chloro- 3-formylindol-2-yl group, 5-fluoro-3-formylindol-2-yl group, 5-bromo-3-formylindol-2-yl group, 5-ethynyl-3-formylindole -2-yl group, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-bromo-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-chlorobene Thiophen-2-yl group, 5-fluorobenzothiophen-2-yl group, 5-bromobenzothiophen-2-yl group, 5-ethynyl benzothiophen-2-yl group, 5-methylbenzothiophene- 2-yl group, 5-chloro-4-fluorobenzothiophen-2-yl group, 6-chlorobenzothiophen-2-yl group, 6-fluorobenzothiophen-2-yl group, 6-bromobenzothiophene -2-yl group, 6-ethynylbenzothiophen-2-yl group, 6-methylbenzothiophen-2-yl group, 5-chlorobenzofuran-2-yl group, 5-fluorobenzofuran-2-yl group, 5 -Bromobenzofuran-2-yl group, 5-ethynylbenzofuran-2-yl group, 5-methylbenzofuran-2-yl group, 5-chloro-4-fluorobenzofuran-2-yl group, 6-chlorobenzo In particular, furan-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, and 6-methylbenzofuran-2-yl desirable.
[79] The following flag
[80]
[81] In the group, X ² , X ³ , X ⁴ , R ¹⁷ and R ¹⁸ represent the same as described above, and the numbers 4 to 7 represent positions. In the above, X ² is preferably NH, O or S. In addition, it is preferable that either one of X <^3> and X <^4> is CH or C, and it is especially preferable that one is C. R ¹⁷ and R ¹⁸ each independently represent a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, or a halogenoalkyl group. As R ¹⁷ and R ¹⁸ , one side is preferably a hydrogen atom and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and the other is a hydrogen atom or a halogen atom. It is especially preferable when it is an alkyl group or an alkynyl group. The halogen atom in that case is preferably a fluorine atom, a chlorine atom and a bromine atom, a methyl group is preferable as the alkyl group, and an ethynyl group is preferable as the alkynyl group. Although it does not specifically limit as a position which a halogen atom, an alkyl group, or an alkynyl group substitutes, The 5th position or 6th position in the said formula is preferable. Specific groups represented by the above formula are 5-chloroindazolyl group, 5-fluoroindazolyl group, 5-bromoindazolyl group, 5-ethynylindazolyl group, 6-chloroindazolyl group, 6-fluoro Zolyl group, 6-bromoindazolyl group, 6-ethynylindazolyl group, 5-chlorobenzimidazolyl group, 5-fluorobenzimidazolyl group, 5-bromobenzimidazolyl group, 5-e Tinylbenzimidazolyl group, 6-chlorobenzimidazolyl group, 6-fluorobenzimidazolyl group, 6-bromobenzimidazolyl group, 6-ethynylbenzimidazolyl group, 5-chlorobenzo Thiazolyl group, 5-fluorobenzothiazolyl group, 5-bromobenzothiazolyl group, 5-ethynylbenzothiazolyl group, 6-chlorobenzothiazolyl group, 6-fluorobenzothiazolyl group, 6- Bromobenzothiazolyl group, 6-ethynylbenzothiazolyl group, 5-chlorobenzoxazolyl group, 5-fluorobenzoxazolyl group, 5-bromobenzoxazolyl group, 5-ethynylbenzoxazolyl group Group, 6-chlorobenzoxazolyl group, 6-fluorobenzoxazolyl group, 6-bromobenzoxazolyl group, 6-ethynylbenzoxazolyl group, 5-chlorobenzisothiazolyl group, 5-fluoro Benzisothiazolyl group, 5-bromobenzisothiazolyl group, 5-ethynylbenzisothiazolyl group, 6-chlorobenzisothiazolyl group, 6-fluorobenzisothiazolyl group, 6-bromobenz Isothiazolyl group, 6-ethynylbenzisothiazolyl group, 5-chlorobenzisoxazolyl group, 5-fluorobenzisoxazolyl group, 5-bromobenzisoxazolyl group, 5-ethynylbenzisoxazolyl group, 6-chloro-benjeuyi snapshot pyridazinyl group, a pyridazinyl group benjeuyi snapshot 6-fluoro, 6-bromo benjeuyi snapshot pyridazinyl group, there may be mentioned thiazolyl group, and the like benjeuyi snapshot ethynyl 6 as a preferable example, these substituent T ¹ and The position to be bonded is not particularly limited, but 5-chloroindazol-3-yl group, 5-fluoroindazol-3-yl group, 5-bromoindazol-3-yl group, 5-ethynylindazol-3-yl group, 6-chloroindazol-3-yl group, 6-fluoroindazol-3-yl group, 6-bromoindazol-3-yl group, 6-ethynylindazol-3 -Group, 5-chlorobenzimidazol-2-yl group, 5-fluorobenzimidazol-2-yl group, 5-bromobenzimidazol-2-yl group, 5-ethynylbenzimidazol-2-yl group, 6-chlorobenzimidazol-2-yl group, 6-fluorobenzimidazol-2-yl group, 6-bromobenzimidazol-2-yl group, 6-ethynylbenzimidazol-2-yl group, 5-chloro Benzothiazol-2-yl group, 5-fluorobenzothiazol-2-yl group, 5-bromobenzothiazol-2-yl group, 5-ethynylbenzothiazol-2-yl group, 6-chlorobenzothiazole -2-yl group, 6-fluorobenzothiazol-2-yl group, 6-bromobenzothiazol-2-yl group, 6-ethynylbenzothiazol-2-yl group, 5-chlorobenzoxazole-2- Diary, 5-fluorobenzoxazol-2-yl group, 5-bromobenzoxazol-2-yl group, 5-ethynyl benzoxazol-2-yl group, 6-chlorobenzoxazol-2-yl group, 6 Fluorobenz jade Zol-2-yl group, 6-bromobenzoxazol-2-yl group, 6-ethynyl benzoxazol-2-yl group, 5-chlorobenzisothiazol-3-yl group, 5-fluorobenzisothiazole -3-yl group, 5-bromobenzisothiazol-3-yl group, 5-ethynylbenzisothiazol-3-yl group, 6-chlorobenzisothiazol-3-yl group, 6-fluorobenzisothia Sol-3-yl group, 6-bromobenzisothiazol-3-yl group, 6-ethynylbenzisothiazol-3-yl group, 5-chlorobenzisoxazol-3-yl group, 5-fluorobenzisoxazole -3-yl group, 5-bromobenzisoxazol-3-yl group, 5-ethynylbenzisoxazol-3-yl group, 6-chlorobenzisoxazol-3-yl group, 6-fluorobenzisoxazol-3- A diary, 6-bromobenzisoxazol-3-yl group, 6-ethynylbenzisoxazol-3-yl group is more preferable, 5-chlorobenzimidazol-2-yl group, 5-fluorobenzimidazole-2 -Group, 5-bromobenzimidazol-2-yl group, 5-ethynylbenzimidazol-2-yl group, 6-chlorobenzimidazol-2-yl group, 6-ple Orbenzimidazol-2-yl group, 6-bromobenzimidazol-2-yl group, 6-ethynylbenzimidazol-2-yl group, 5-chlorobenzothiazol-2-yl group, 5-fluorobenzothia Zol-2-yl group, 5-bromobenzothiazol-2-yl group, 5-ethynylbenzothiazol-2-yl group, 6-chlorobenzothiazol-2-yl group, 6-fluorobenzothiazole-2 -Group, 6-bromobenzothiazol-2-yl group, 6-ethynylbenzothiazol-2-yl group, 5-chlorobenzoxazol-2-yl group, 5-fluorobenzoxazol-2-yl group, 5-bromobenzoxazol-2-yl group, 5-ethynylbenzoxazol-2-yl group, 6-chlorobenzoxazol-2-yl group, 6-fluorobenzoxazol-2-yl group, 6-bro Mobenzoxazol-2-yl group, 6-ethynylbenzoxazol-2-yl group are particularly preferred, 5-chlorobenzimidazol-2-yl group, 5-fluorobenzimidazol-2-yl group, 5- The bromobenzimidazol-2-yl group and 5-ethynylbenzimidazol-2-yl group are more preferable among them.
[82] The following flag
[83]
[84] [Wherein, N represents that one or two carbon atoms of the ring in which R ¹⁹ is substituted is substituted with a nitrogen atom, R ¹⁹ , R ²⁰ and R ²¹ represent the same as above, and the numbers 5 to 8 represent positions R ¹⁹ , R ²⁰ and R ²¹ each independently represent a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. R ¹⁹ is particularly preferably a hydrogen atom, and R ²⁰ and R ²¹ are each preferably a hydrogen atom and the other a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. In particular, the other one is particularly preferably a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. The halogen atom in that case is preferably a fluorine atom, a chlorine atom and a bromine atom, a methyl group is preferable as the alkyl group, and an ethynyl group is preferable as the alkynyl group. Although it does not specifically limit as a position which a halogen atom, an alkyl group, or an alkynyl group substitutes, The 6th position or 7th position in the said formula is preferable. Specific examples of the group represented by the above formula include a quinolinyl group, an isoquinolinyl group, and a cynolinyl group, and 6-chloroquinolinyl group, 6-fluoroquinolinyl group, 6-bromoquinolinyl group, and 6- group. Ethynylquinolinyl group, 6-chloroisoquinolinyl group, 6-fluoroisoquinolinyl group, 6-bromoisoquinolinyl group, 6-ethynylisoquinolinyl group, 7-chlorocinnolinyl group, 7-fluoro A cinnaolinyl group, a 7-bromosinolinyl group, a 7-ethynylcinolinyl group is preferable, a 6-chloroquinolin-2-yl group, a 6-fluoroquinolin-2-yl group, a 6-bromoquinolin-2-yl group, 6-ethynylquinolin-2-yl group, 6-chloroquinolin-3-yl group, 6-fluoroquinolin-3-yl group, 6-bromoquinolin-3-yl group, 6-ethynylquinoline-3-yl group, 7 -Chloroquinolin-2-yl group, 7-fluoroquinolin-2-yl group, 7-bromoquinolin-2-yl group, 7-ethynylquinolin-2-yl group, 7-chloroquinolin-3-yl group, 7-fluoro Loquinolin-3-yl group, 7-bromoquinolin-3-yl group, 7- Thynilquinolin-3-yl group, 6-chloroisoquinolin-3-yl group, 6-fluoroisoquinolin-3-yl group, 6-bromoisoquinolin-3-yl group, 6-ethynylisoquinolin-3-yl group, 7-chloroisoquinolin-3-yl group, 7-fluoroisoquinolin-3-yl group, 7-bromoisoquinolin-3-yl group, 7-ethynylisoquinolin-3-yl group, 7-chlorocinnoline-3 -Group, 7-fluorocinnoline-3-yl group, 7-bromosinolin-3-yl group, 7-ethynylcinnoline-3-yl group are particularly preferred, and 6-chloroquinolin-2-yl group, 6-fluoro Loquinolin-2-yl group, 6-bromoquinolin-2-yl group, 6-ethynylquinolin-2-yl group, 7-chloroquinolin-3-yl group, 7-fluoroquinolin-3-yl group, 7-bromo Quinolin-3-yl group, 7-ethynylquinolin-3-yl group, 7-chloroisoquinolin-3-yl group, 7-fluoroisoquinolin-3-yl group, 7-bromoisoquinoline-3-yl group, 7- Ethynylisoquinolin-3-yl, 7-chlorocinnoline-3-yl, 7-fluorocinnoline-3-yl, 7-bromosinolin-3-yl, 7-ethynylcin Among the lean-3-yl group that is more preferred.
[85] The following flag
[86]
[87] [Wherein, numbers from 5 to 8 represent positions, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N Z ³ represents CH ₂ , CH, S, SO ₂ or C═O, X ⁵ -Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, R ²² , R ²³ and R ²⁴ represent the same as the above. In R ²² and R ²³ are each independently hydrogen, cyano, halogen, alkyl, alkenyl, alkynyl or halogenoalkyl. R ²² and R ^{23 preferably} have one of them a hydrogen atom and the other a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and the other is a hydrogen atom or a halogen. It is especially preferable when it is an atom, an alkyl group, or an alkynyl group. The halogen atom in that case is preferably a fluorine atom, a chlorine atom and a bromine atom, a methyl group is preferable as the alkyl group, and an ethynyl group is preferable as the alkynyl group. Although it does not specifically limit as a position which a halogen atom, an alkyl group, or an alkynyl group substitutes, The 6th position or 7th position in the said formula is preferable. As R ^{24, a} hydrogen atom or an alkyl group is preferable, and as the alkyl group, a methyl group is preferable. As R ^{24, a} hydrogen atom is particularly preferable. As a specific group represented by the said formula, 4-oxodihydroquinolinyl group, tetrahydroquinolinyl group, 4-oxodihydroquinazolin-2-yl group, 4-oxo tetrahydrocinnolinyl group, 4-oxobenzopyra A silyl group, a 4-oxobenzothiadiazinyl group, a 1,1-dioxy-4-oxobenzothiadiazinyl group, a benzoxadiazinyl group, etc. are mentioned, As a more specific group, 6-chloro-4- oxodi Hydroquinolinyl group, 6-fluoro-4-oxodihydroquinolinyl group, 6-bromo-4-oxodihydroquinolinyl group, 6-ethynyl-4-oxodihydroquinolinyl group, 7-chloro 4-oxodihydroquinolinyl group, 7-fluoro-4-oxodihydroquinolinyl group, 7-bromo-4-oxodihydroquinolinyl group, 7-ethynyl-4-oxodihydroquinolin A silyl group, 6-chloro-4-oxo-1,4-dihydroquinazolinyl group, 6-fluoro-4-oxo-1,4-dihydroquinazolinyl group, 6-bromo-4-oxo-1, 4-dihydroquinazolinyl group, 6-ethynyl-4 -Oxo-1,4-dihydroquinazolinyl group, 7-chloro-4-oxo-1,4-dihydroquinazolinyl group, 7-fluoro-4-oxo-1,4-dihydroquinazolinyl group, 7-bromo-4-oxo-1,4-dihydroquinazolinyl group, 7-ethynyl-4-oxo-1,4-dihydroquinazoloyl group, 6-chloro-1,2,3,4- Tetrahydroquinolinyl group, 6-fluoro-1,2,3,4-tetrahydroquinolinyl group, 6-bromo-1,2,3,4-tetrahydroquinolinyl group, 6-ethynyl-1 , 2,3,4-tetrahydroquinolinyl group, 7-chloro-1,2,3,4-tetrahydroquinolinyl group, 7-fluoro-1,2,3,4-tetrahydroquinolinyl group, 7-bromo-1,2,3,4-tetrahydroquinolinyl group, 7-ethynyl-1,2,3,4-tetrahydroquinolinyl group, 6-chloro-1,2,3,4- Tetrahydro-4-oxocinnolinyl group, 6-fluoro-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 6-bromo-1,2,3,4-tetrahydro-4 -Oxocinnolinyl group, 6-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 7-chloro-1,2,3,4- Tetrahydro-4-oxocinnolinyl group, 7-fluoro-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 7-bromo-1,2,3,4-tetrahydro-4 Oxocinnolinyl group, 7-ethynyl-1,2,3,4-tetrahydro-4-oxocinnolinyl group, 6-chloro-4H-4-oxobenzopyranyl group, 6-fluoro-4H-4 -Oxobenzopyranyl group, 6-bromo-4H-4-oxobenzopyranyl group, 6-ethynyl-4H-4-oxobenzopyranyl group, 7-chloro-4H-4-oxobenzopyranyl group, 7-fluor Rho-4H-4-oxobenzopyranyl group, 7-bromo-4H-4-oxobenzopyranyl group, 7-ethynyl-4H-4-oxobenzopyranyl group, 6-chloro-1,1-dioxy- 2H-1,2,4-benzothiadiazinyl group, 6-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 6-bromo-1,1-di Oxy-2H-1,2,4-benzothiadiazinyl group, 6-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 7-chloro-1,1- Dioxy-2H-1,2,4-benzothiadiazinyl group, 7-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 7-bromo-1, 1-D Cy-2H-1,2,4-benzothiadiazinyl group, 7-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 6-chloro-2H-1, 2,4-benzoxadiazinyl group, 6-fluoro-2H-1,2,4-benzoxadiazinyl group, 6-bromo-2H-1,2,4-benzoxadiazinyl group, 6- Ethynyl-2H-1,2,4-benzoxadiazinyl group, 7-chloro-2H-1,2,4-benzoxadiazinyl group, 7-fluoro-2H-1,2,4-benzoxa A diazinyl group, a 7-bromo-2H-1,2,4-benzoxadiazinyl group, a 7-ethynyl-2H-1,2,4-benzoxadiazinyl group, etc .; Especially 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-bromo-4-oxo -1,4-dihydroquinolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl group, 7-chloro-4-oxo-1,4-dihydroquinoline- 2-yl group, 7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl group, 7-bromo-4-oxo-1,4-dihydroquinolin-2-yl group, 7-ethynyl -4-oxo-1,4-dihydroquinolin-2-yl group, 6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-fluoro-4-oxo-1,4 -Dihydroquinazolin-2-yl group, 6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinazoline- 2-yl group, 7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl group, 7-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl group, 7-bro Parent-4-oxo-1,4-dihydroquinazolin-2-yl group, 7-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-chloro-1,2,3 , 4-tetrahydroquinol -2-yl group, 6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl group, 6-bromo-1,2,3,4-tetrahydroquinolin-2-yl group, 6-on Tinyl-1,2,3,4-tetrahydroquinolin-2-yl group, 6-chloro-1,2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 6-fluoro-1, 2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 6-bromo-1,2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 6-ethynyl- 1,2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 7-chloro-1,2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 7-fluoro -1,2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 7-bromo-1,2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 7- Ethynyl-1,2,3,4-tetrahydro-4-oxocinnoline-2-yl group, 6-chloro-4H-4-oxobenzopyran-2-yl group, 6-fluoro-4H-4-oxo Benzopyran-2-yl group, 6-bromo-4H-4-oxobenzopyran-2-yl group, 6-ethynyl-4H-4-oxobenzopyran-2-yl group, 7-chloro-4H-4-oxo Benzopyran-2-yl group, 7-fluoro-4H-4-oxobenzopy Lan-2-yl group, 7-bromo-4H-4-oxobenzopyran-2-yl group, 7-ethynyl-4H-4-oxobenzopyran-2-yl group, 6-chloro-1,1-dioxy -2H-1,2,4-benzothiadiazin-3-yl group, 6-fluoro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 6-bro Parent-1,1-dioxy-2H-1,2,4-benzothiadiazine-3-yl group, 6-ethynyl-1,1-dioxy-2H-1,2,4-benzothiadiazine -3-yl group, 7-chloro-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 7-fluoro-1,1-dioxy-2H-1,2 , 4-benzothiadiazin-3-yl group, 7-bromo-1,1-dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 7-ethynyl-1,1- Dioxy-2H-1,2,4-benzothiadiazin-3-yl group, 6-chloro-2H-1,2,4-benzoxadiazin-3-yl group, 6-fluoro-2H-1, 2,4-benzoxadiazin-3-yl group, 6-bromo-2H-1,2,4-benzoxadiazin-3-yl group, 6-ethynyl-2H-1,2,4-benzoxa Diazine-3-yl group, 7-chloro-2H-1,2,4-benzoxadiazin-3-yl group, 7-fluoro-2H-1,2,4-benzoxadiazin-3-yl group, 7-bromo-2H-1,2,4-benz A sadazin-3-yl group, a 7-ethynyl-2H-1,2,4-benzoxadiazin-3-yl group and the like are preferable, and a 6-chloro-4-oxo-1,4-dihydroquinoline-2 -Yl group, 6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-bromo-4-oxo-1,4-dihydroquinolin-2-yl group, 6-ethynyl- 4-oxo-1,4-dihydroquinolin-2-yl group, 6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-fluoro-4-oxo-1,4- Dihydroquinazolin-2-yl group, 6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinazolin-2 The diary is more preferable among them.
[88] The following flag
[89]
[90] In the group, X ⁶ represents O or S, R ²⁵ and R ²⁶ represent the same as described above, and the numbers 5 to 8 represent positions. In X ⁶ , O is preferable, and R ²⁵ and R ²⁶ is each independently a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group. R ²⁵ and R ²⁶ are preferably one of them being a hydrogen atom and the other being a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and the other is a hydrogen atom or a halogen It is especially preferable when it is an atom, an alkyl group, or an alkynyl group. The halogen atom in that case is preferably a fluorine atom, a chlorine atom and a bromine atom, a methyl group is preferable as the alkyl group, and an ethynyl group is preferable as the alkynyl group. Although it does not specifically limit as a position which a halogen atom, an alkyl group, or an alkynyl group substitutes, The 6th position or 7th position in the said formula is preferable. Specific groups include 6-chloro-2H-chromen-3-yl, 6-fluoro-2H-chromen-3-yl, 6-bromo-2H-chromen-3-yl and 6-ethynyl-2H. -Cromen-3-yl group, 7-chloro-2H-chromen-3-yl group, 7-fluoro-2H-chromen-3-yl group, 7-bromo-2H-chromen-3-yl group, 7 -Ethynyl-2H-chromen-3-yl group is mentioned. 7-chloro-2H-chromen-3-yl group, 7-fluoro-2H-chromen-3-yl group, 7-bromo-2H-chromen-3-yl group, 7-ethynyl-2H-chromen The 3-yl group is particularly preferred.
[91] The following flag
[92]
[93] In the group, R ²⁷ and R ²⁸ represent the same as described above, and the numbers 1 to 6 represent positions. In R ²⁷ and R ^28, one side is a hydrogen atom or a halogen atom, and the other side is a hydrogen atom. , A cyano group, a nitro group, an amino group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group or an N, N-dialkylcarbamoyl group is preferable, and among others, a hydrogen atom, a halogen atom, It is especially preferable when it is an alkyl group or an alkynyl group. As the halogen atom in this case, a fluorine atom, a chlorine atom and a bromine atom are preferable, a methyl group is preferable as the alkyl group, and an ethynyl group is particularly preferable as the alkynyl group. As a specific group represented by said formula, a phenyl group, a chlorophenyl group, a fluorophenyl group, a bromophenyl group, an ethynylphenyl group, a chlorofluorophenyl group etc. are mentioned as a preferable example, The halogen atom, alkyl group, or alkynyl group in these groups is mentioned. Although it does not specifically limit as a position substituted, When a substituent is 1, the 3rd position and the 4th position in the said formula are especially preferable, and when there are 2 substituents, the 4th position, the 2nd position, or the 3rd position in the said formula are Is particularly preferred. Specifically, a phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-ethynylphenyl group, 3-chlorophenyl group, 3-fluorophenyl group, 3-bromophenyl group, 3-ethynylphenyl group , 3-chloro-4-fluorophenyl group, 4-chloro-3-fluorophenyl group, 4-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group, 4-bromo-2-fluoro Phenyl group, 2-bromo-4-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dibromophenyl group, 4-chloro-3-methylphenyl group, 4-fluoro Rho-3-methylphenyl group, 4-bromo-3-methylphenyl group, 4-chloro-2-methylphenyl group, 4-fluoro-2-methylphenyl group, 4-bromo-2-methylphenyl group, 3,4- Dichlorophenyl group, 3, 4- difluorophenyl group, 3, 4- dibromophenyl group can be mentioned as a preferable example.
[94]
[95] [In group, E <^1> , E <^2> , R <^29> and R <^30> show the same thing as the above, and the numbers of 1-6 show a position. In R <^29> and R <^30>, one is a hydrogen atom or a halogen atom. It is preferable that the other one is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and particularly the case where the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. Do. As the halogen atom in this case, a fluorine atom, a chlorine atom and a bromine atom are preferable, a methyl group is preferable as the alkyl group, and an ethynyl group is particularly preferable as the alkynyl group. And the like groups possess all Specific examples of the group represented by the formula a pyridyl group, a pyridyl group mi, flutes, a halogen atom in groups them, alkyl group or alkynyl group is not particularly limited that the substitution position, a group T ¹ and When the bond of is at position 2 in the above formula, positions 4 and 5 in the formula are particularly preferable. Specifically, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-chloro-2-pyridyl group, 4-fluoro-2-pyridyl group, 4-bromo-2-pyridyl group, 4-e Tinyl-2-pyridyl group, 4-chloro-3-pyridyl group, 4-fluoro-3-pyridyl group, 4-bromo-3-pyridyl group, 4-ethynyl-3-pyridyl group, 5-chloro- 2-pyridyl group, 5-fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 5 -Chloro-4-fluoro-2-pyridyl group, 5-chloro-3-pyridyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyrid Dyl group, 5-chloro-2-pyrimidyl group, 5-fluoro-2-pyrimidyl group, 5-bromo-2-pyrimidyl group, 5-ethynyl-2-pyrimidyl group, 4-chloro-3 -Pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bromo-3-pyridazinyl group, 4-ethynyl-3-pyridazinyl group, 6-chloro-3-pyrida Genyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 6-ethynyl-3- Preferred examples include a lidazinyl group, and especially 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-chloro-2-pyridyl group, 4-fluoro-2-pyridyl group, 4-bro Mo-2-pyridyl group, 4-ethynyl-2-pyridyl group, 4-chloro-3-pyridyl group, 4-fluoro-3-pyridyl group, 4-bromo-3-pyridyl group, 4-ethynyl 3-pyridyl group, 5-chloro-2-pyridyl group, 5-fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2-pyridyl group, 4-chloro-5 -Fluoro-2-pyridyl group, 5-chloro-4-fluoro-2-pyridyl group, 5-chloro-3-pyridyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyri Dyl group, 5-ethynyl-3-pyridyl group, 6-chloro-3-pyridazinyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 6-e Tinyl-3-pyridazinyl group, 4-chloro-3-pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bromo-3-pyridazinyl group, 4-ethynyl-3 -Pyridazinyl group is preferable, and 2-pyridyl group and 3-pi Dyl group, 4-pyridyl group, 5-chloro-2-pyridyl group, 5-fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2-pyridyl group, 5-chloro- 4-fluoro-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 4-chloro-3-pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bro More preferred are a mo-3-pyridazinyl group and a 4-ethynyl-3-pyridazinyl group.
[96] In addition, the following group
[97]
[98] [In group, Y <^1> , Y <^2> , R <^31> and R <^32> represent the same thing as the above, and the numbers of 1-5 show a position. In R <^31> and R <^32>, one side is a hydrogen atom or a halogen atom. It is preferable that the other one is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and particularly the case where the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. Do. As the halogen atom in this case, a fluorine atom, a chlorine atom and a bromine atom are preferable, a methyl group is preferable as the alkyl group, and an ethynyl group is particularly preferable as the alkynyl group. Specific examples of the group represented by the above formula include a thienyl group, a pyrrolyl group, a furyl group, an oxazolyl group, a thiazolyl group, and the like, and the position where the halogen atom, alkyl group or alkynyl group in these groups is substituted is not particularly limited. , Position 4 and position 5 in the above formula are particularly preferred. Specifically, 4-chloro-2-thienyl group, 4-fluoro-2-thienyl group, 4-bromo-2-thienyl group, 4-ethynyl-2-thienyl group, 4-chloro-2-pyrrolyl group , 4-fluoro-2-pyrrolyl group, 4-bromo-2-pyrrolyl group, 4-ethynyl-2-pyrrolyl group, 4-chloro-2-furyl group, 4-fluoro-2-furyl group, 4-bromo-2-furyl group, 4-ethynyl-2-furyl group, 5-chloro-2-thienyl group, 5-fluoro-2-thienyl group, 5-bromo-2-thienyl group, 5 -Ethynyl-2-thienyl group, 5-chloro-2-thiazolyl group, 5-fluoro-2-thiazolyl group, 5-bromo-2-thiazolyl group, 5-ethynyl-2-thiazolyl Group, 5-chloro-2-oxazolyl group, 5-fluoro-2-oxazolyl group, 5-bromo-2-oxazolyl group, 5-ethynyl-2-oxazolyl group, etc. are mentioned. Especially 5-chloro-2- thiazolyl group, 5-fluoro-2- thiazolyl group, 5-bromo-2- thiazolyl group, and 5-ethynyl-2- thiazolyl group are preferable.
[99] Furthermore, the following flag
[100]
[101] [Wherein, the numbers 1 to 8 represent positions, and each N represents any one of 1 to 4 carbon atoms and one of 5 to 8 carbon atoms is substituted with one nitrogen atom, R ³⁴ to R ³⁶ represent the same as described above. In each position, the position of each nitrogen atom may be any positional relationship, R ³⁴ is preferably a hydrogen atom or a halogen atom, and R ³⁵ and R ³⁶ are one of hydrogen atoms. Or a halogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group, and the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. The case is particularly preferred. As the halogen atom, a fluorine atom, a chlorine atom and a bromine atom are preferable, a methyl group is preferable as the alkyl group, and an ethynyl group is particularly preferable as the alkynyl group. Specific groups represented by 6-chloro-1,5-naphthyridin-2-yl group, 6-fluoro-1,5-naphthyridin-2-yl group, 6-bromo-1,5-naphthyridine-2 -Yl group, 6-ethynyl-1,5-naphthyridin-2-yl group, 7-chloro-1,5-naphthyridin-2-yl group, 7-fluoro-1,5-naphthyridin-2-yl group, 7-bromo-1,5-naphthyridin-2-yl group, 7-ethynyl-1,5-naphthyridin-2-yl group, 6-chloro-1,5-naphthyridin-3-yl group, 6-fluoro Rho-1,5-naphthyridin-3-yl group, 6-bromo-1,5-naphthyridin-3-yl group, 6-ethynyl-1,5-naphthyridin-3-yl group, 7-chloro-1 , 5-naphthyridin-3-yl group, 7-fluoro-1,5-naphthyridin-3-yl group, 7-bromo-1,5-naphthyridine- 3-yl group, 7-ethynyl-1,5-naphthyridin-3-yl group, 6-chloro-1,7-naphthyridin-2-yl group, 6-fluoro-1,7-naphthyridin-2-yl group , 6-bromo-1,7-naphthyridin-2-yl group, 6-ethynyl-1,7-naphthyridin-2-yl group, 6-chloro-1,7-naphthyridin-3-yl group, 6- Fluoro-1,7-naphthyridin-3-yl group, 6-bromo-1,7-naphthyridin-3-yl group, 6-ethynyl-1,7-naphthyridin-3-yl group, 6-chloro- 1,8-naphthyridin-2-yl group, 6-fluoro-1,8-naphthyridin-2-yl group, 6-bromo-1,8-naphthyridin-2-yl group, 6-ethynyl-1, 8-naphthyridin-2-yl group, 7-chloro-1,8-naphthyridin-2-yl group, 7-fluoro-1,8-naphthyridin-2-yl group, 7-bromo-1,8-naphthy Ridin-2-yl group, 7-ethynyl-1,8-naphthyridin-2-yl group, 6-chloro-1,8-naphthyridin-3-yl group, 6-fluoro-1,8-naphthyridine-3 -Group, 6-bromo-1,8-naphthyridin-3-yl group, 6-ethynyl-1,8-naphthyridin-3-yl group, 7-chloro-1,8-naphthyridin-3-yl group, 7-fluoro-1,8-naphthyridin-3-yl group, 7-bro Mo-1,8-naphthyridin-3-yl group, 7-ethynyl-1,8-naphthyridin-3-yl group, 6-chloro-2,5-naphthyridin-3-yl group, 6-fluoro-2 , 5-naphthyridin-3-yl group, 6-bromo-2,5-naphthyridin-3-yl group, 6-ethynyl-2,5-naphthyridin-3-yl group, 7-chloro-2,5- Naphthyridin-3-yl group, 7-fluoro-2,5-naphthyridin-3-yl group, 7-bromo-2,5-naphthyridin-3-yl group, 7-ethynyl-2,5-naphthyridine -3-yl group, 7-chloro-2,6-naphthyridin-3-yl group, 7-fluoro-2,6-naphthyridin-3-yl group, 7-bromo-2,6-naphthyridine-3- Diary, 7-ethynyl-2,6-naphthyridin-3-yl group, 6-chloro-2,8-naphthyridin-3-yl group, 6-fluoro-2,8-naphthyridin-3-yl group, 6 -Bromo-2,8-naphthyridin-3-yl group, 6-ethynyl-2,8-naphthyridin-3-yl group, 7-chloro-2,8-naphthyridin-3-yl group, 7-fluoro -2,8-naphthyridin-3-yl group, 7-bromo-2,8-naphthyridin-3-yl group, 7-ethynyl-2,8-naphthyridin-3-yl group, etc. are mentioned, Especially 7-claw as preferred -2,5-naphthyridin-3-yl group, 7-fluoro-2,5-naphthyridin-3-yl group, 7-bromo-2,5-naphthyridin-3-yl group, 7-ethynyl-2 And a 5-5-naphthyridin-3-yl group.
[102] In addition to the 12 kinds of groups (a) to (l) above, a thienopyrrolyl group having or without a substituent is also preferable. One to three substituents may be used, and examples of the substituent include a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group and a carboxy group. Alkyl groups, acyl groups, carbamoyl groups, N-alkylcarbamoyl groups, N, N-dialkylcarbamoyl groups, alkoxycarbonyl groups, amidino groups and alkoxycarbonylalkyl groups, among which cyano groups, halogen atoms, Alkyl group, alkenyl group, alkynyl group and halogenoalkyl group are preferable. Specifically, 2-chlorothieno [2,3-b] pyrrole-5-yl group, 2-fluorothieno [2,3-b] pyrrole-5-yl group, 2-bromothieno [2,3 -b] pyrrole-5-yl group or 2-ethynylthieno [2,3-b] pyrrole-5-yl group etc. are mentioned as a preferable thing.
[103] <Group for Q ^1>
[104] In the present invention, Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, or with or without a substituent. It means a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent.
[105] As said saturated or unsaturated 5-6 membered cyclic hydrocarbon group, a cyclopentyl group, a cyclopentenyl group, a cyclohexyl group, a cyclohexenyl group, a phenyl group etc. are mentioned, for example, a cyclopentyl group, a cyclohexyl group, A phenyl group is preferable and a phenyl group is more preferable.
[106] A saturated or unsaturated 5 to 7 membered heterocyclic group means that a heterocyclic ring having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom has become a monovalent group. For example, a furyl group, a pyrrolyl group, a thienyl group , Pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidyl, pyri Dazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tria A sleepy group, a triazinyl group, an azepinyl group, a diazepinyl group, and a triazinyl group etc. are mentioned, A thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a thiadiazolyl group, fura Janyl group, pyridyl group, pyrimidyl group, pyrida A silyl group, a pyrrolidinyl group, a piperazinyl group, a piperidinyl group, a morpholinyl group, a thiadiazinyl group and a triazolyl group are preferable, and a thienyl group, thiazolyl group, pyrazolyl group, imidazolyl group, pyridyl group, The pyrimidyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group and piperidinyl group are more preferable. In addition, the nitrogen-containing heterocyclic group in these heterocyclic groups may be N-oxide.
[107] The saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group means the same as the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group described in the description of Q ^{4 in} the general formula (1), and specific examples thereof include indenyl group, indanyl group and naph. A methyl group, a tetrahydronaphthyl group, an anthryl group, a phenanthryl group, etc. are mentioned, An indenyl group, an indanyl group, a naphthyl group, and a tetrahydro naphthyl group are preferable.
[108] Examples of saturated or unsaturated, bicyclic or fused heterocyclic ring of the tricyclic dish means that the same substrate a saturated or unsaturated, bicyclic or fused hydrocarbon group of tricyclic in the description of formula (1) of Q ^4, and specific examples include benzo furyl group, isobutyl benzoin Furyl group, benzothienyl group, indolyl group, indolinyl group, isoindolinyl group, isoindolinyl group, indazolyl group, quinolyl group, dihydroquinolyl group, 4-oxo-dihydroquinolyl group (dihydro Quinolin-4-one), tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, chromaenyl, chromanyl, isochromenyl, 4H-4-oxobenzopyranyl, 3,4-di Hydro-4H-4-oxobenzopyranyl group, 4H-quinolininyl group, quinazolinyl group, dihydroquinazolinyl group, tetrahydroquinazolinyl group, quinoxalinyl group, tetrahydroquinoxalinyl group, cinnaolinyl group, tetrahydro Cynolinyl group, indolinyl group, te Lahydroindolizinyl group, benzothiazolyl group, tetrahydrobenzothiazolyl group, benzoxazolyl group, benzisothiazolyl group, benzisoxazolyl group, benzimidazolyl group, naphthyridinyl group, tetrahydronaphthyridinyl group , Thienopyridyl group, tetrahydrothienopyridyl group, thiazolopyridyl group, tetrahydrothiazolopyridyl group, thiazolopyridazinyl group, tetrahydrothiazolopyridazinyl group, pyrrolopyridyl group, dihydropyrrolo Pyridyl group, tetrahydropyrrolopyridyl group, pyrrolopyrimidinyl group, dihydropyrrolopyrimidinyl group, pyridoquinazolinyl group, dihydropyridoquinazolinyl group, pyridopyrimidinyl group, tetrahydropyridopyrimidi Neyl group, pyranothiazolyl group, dihydropyranothiazolyl group, furopyridyl group, tetrahydrofuropyridyl group, oxazolopyridyl group, tetrahydrooxazolopyridyl group, oxazole Pyridazinyl group, tetrahydrooxazolopyridazinyl group, pyrrolothiazolyl group, dihydropyrrolothiazolyl group, pyrrolooxazolyl group, dihydropyrrolooxazolyl group, thienopyrrolyl group, thiazolopyrrole Midinyl group, dihydrothiazolopyrimidinyl group, 4-oxo-tetrahydrocinnolinyl group, 1,2,4-benzothiadiazinyl group, 1,1-dioxy-2H-1,2,4-benzothia Diazinyl group, 1,2,4-benzoxadiazinyl group, cyclopentapyranyl group, thienofuranyl group, furopyranyl group, pyridoxazinyl group, pyrazole oxazolyl group, imidazothiazolyl group, imidazopyri Dyl group, tetrahydroimidazopyridyl group, pyrazinopyridazinyl group, benzisoquinolyl group, furosinolyl group, pyrazolothiazolopyridazinyl group, tetrahydropyrazolothiazolopyridazinyl group, hexahydrothia Solopyridazinopyridazinyl group, imidazotriazinyl group, oxazolopyridyl group, benzoxe Pinyl group, benzoazinyl group, tetrahydrobenzoazinyl group, benzodiazepinyl group, benzotriazinyl group, thienoazinyl group, tetrahydrothienoazinyl group, thienodiazepinyl group, thienotriazinyl group, thia Zoloazinyl group, tetrahydrothiazoloazinyl group, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group, 5,6-trimethylene-4,5,6, Although 7-tetrahydro thiazolopyridazinyl group etc. are mentioned, A benzothiazolyl group, a tetrahydrobenzothiazolyl group, a thienopyridyl group, a tetrahydro thienopyridyl group, a thienopyrrolyl group, a thiazolopyridyl group, Tetrahydrothiazolopyridyl group, thiazolopyridazinyl group, tetrahydrothiazolopyridazinyl group, pyrrolopyrimidinyl group, dihydropyrrolopyrimidinyl group, pyranothiazolyl group, dihydropyranothiazolyl group , Furypyridyl group, tetrahydrofu Pyridyl group, oxazolopyridyl group, tetrahydrooxazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, tetrahydropyrrolopyridyl group, oxazolopyridazinyl group, tetrahydrooxazolopyridazinyl group, Pyrrolothiazolyl group, dihydropyrrolothiazolyl group, pyrrolooxazolyl group, dihydropyrrolooxazolyl group, thiazolopyrimidinyl group, dihydrothiazolopyrimidinyl group, benzoazinyl group, tetrahydroben Azoazinyl group, thiazoloazinyl group, tetrahydrothiazoloazinyl group, thienoazinyl group, tetrahydrothienoazinyl group, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyri Dazinyl group and 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group are preferable, and especially tetrahydrobenzothiazolyl group, tetrahydrothienopyridyl group, tetrahydrothiazolopyri Dill, te Lahydrothiazolopyridazinyl group, dihydropyrrolopyrimidinyl group, dihydropyranothiazolyl group, tetrahydrooxazolopyridyl group, dihydropyrrolothiazolyl group, 4,5,6,7-tetrahydro Preference is given to -5,6-tetramethylenethiazolopyridazinyl groups and 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups.
[109] There is no restriction | limiting in particular in the condensation type in the said condensed heterocyclic group, For example, thieno pyridine, thieno [2, 3-b] pyridine, thieno [2, 3-c] pyridine, thieno [ 3,2-b] pyridine, thieno [3,2-c] pyridine, thieno [3,4-b] pyridine, thieno [3,4-c] pyridine may be used, but thieno [2 , 3-c] pyridine and thieno [3,2-c] pyridine are preferred. The thienopyrrolyl group may be any of [2,3-b] pyrrolyl and thieno [3,2-b] pyrrolyl group. Thiazolopyridine includes thiazolo [4,5-b] pyridine, thiazolo [4,5-c] pyridine, thiazolo [5,4-b] pyridine, thiazolo [5,4-c] pyridine, thia Solo may be any of solo [3,4-a] pyridine, thiazolo [3,2-a] pyridine, but thiazolo [4,5-c] pyridine and thiazolo [5,4-c] pyridine are preferred. . Thiazolopyridazines include thiazolo [4,5-c] pyridazines, thiazolo [4,5-d] pyridazines, thiazolo [5,4-c] pyridazines, thiazolo [3,2-b] ] Any of pyridazines may be used, but thiazolo [4,5-d] pyridazines are preferable. Pyrrolopyridine includes pyrrolo [2,3-b] pyridine, pyrrolo [2,3-c] pyridine, pyrrolo [3,2-b] pyridine, pyrrolo [3,2-c] pyridine, Any of rolo [3,4-b] pyridine and pyrrolo [3,4-c] pyridine may be used, but pyrrolo [2,3-c] pyridine and pyrrolo [3,2-c] pyridine are preferred. . The pyrrolopyrimidine may be any of pyrrolo [3,4-d] pyrimidine, pyrrolo [3,2-d] pyrimidine, pyrrolo [2,3-d] pyrimidine, but pyrrolo [ 3,4-d] pyrimidine is preferred. Pyridopyrimidines include pyrido [2,3-d] pyrimidines, pyrido [3,2-d] pyrimidines, pyrido [3,4-d] pyrimidines, pyrido [4,3-d ] Pyrimidine, pyrido [1,2-c] pyrimidine, pyrido [1,2-a] pyrimidine may be used, but pyrido [3,4-d] pyrimidine and pyrido [4, 3-d] pyrimidine is preferred. Pyranothiazoles include pyrano [2,3-d] thiazoles, pyrano [4,3-d] thiazoles, pyrano [3,4-d] thiazoles, pyrano [3,2-d] Although either thiazole may be sufficient, pyrano [4,3-d] thiazole and pyrano [3,4-d] thiazole are preferable. Furopyridine includes furo [2,3-b] pyridine, furo [2,3-c] pyridine, furo [3,2-b] pyridine, furo [3,2-c] pyridine, furo [3,4- b] Pyridine, furo [3,4-c] pyridine may be any, but furo [2,3-c] pyridine and furo [3,2-c] pyridine are preferable. Oxazolopyridine includes oxazolo [4,5-b] pyridine, oxazolo [4,5-c] pyridine, oxazolo [5,4-b] pyridine, oxazolo [5,4-c] pyridine, oxa Solo may be any of solo [3,4-a] pyridine and oxazolo [3,2-a] pyridine, with oxazolo [4,5-c] pyridine and oxazolo [5,4-c] pyridine. . Oxazolopyridazines include oxazolo [4,5-c] pyridazine, oxazolo [4,5-d] pyridazine, oxazolo [5,4-c] pyridazine and oxazolo [3,4-b ] Any of pyridazines may be used, but oxazolo [4,5-d] pyridazine is preferable. Pyrrolothiazoles include pyrrolo [2,1-b] thiazoles, pyrrolo [1,2-c] thiazoles, pyrrolo [2,3-d] thiazoles, pyrrolo [3,2-d] Any of thiazole and pyrrolo [3,4-d] thiazole may be sufficient, and pyrrolo [3,4-d] thiazole is preferable. Pyrrolooxazoles include pyrrolo [2,1-b] oxazoles, pyrrolo [1,2-c] oxazoles, pyrrolo [2,3-d] oxazoles, pyrrolo [3,2-d] Although any of oxazole and pyrrolo [3,4-d] oxazole may be sufficient, pyrrolo [3,4-d] oxazole is preferable. As the benzoazepine, any of 1H-1-benzoazepine, 1H-2-benzoazepine and 1H-3-benzoazepine may be used, but 1H-3-benzoazepine is preferable. Thiazolo [4,5-c] azepines include 4H-thiazolo [4,5-c] azepine, 4H-thiazolo [4,5-d] azepine, 4H-thiazolo [5,4- c] Azepine may be any, but [4,5-d] azepine is preferable as 4H-thiazole. The thieno [2,3-c] azepine may be 4H-thieno [2,3-d] azepine or 4H-thieno [3,2-c] azine, but 4H-thieno [2,3-d] azepine is preferred.
[110] In addition, the nitrogen-containing heterocyclic group in these heterocyclic groups may be N-oxide. In addition, the position of the substituent is combined with Q ² is not particularly limited.
[111] Said saturated or unsaturated 5-6 membered cyclic hydrocarbon group, a saturated or unsaturated 5-7 membered heterocyclic group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group, or a saturated or unsaturated bicyclic or tricyclic Condensed heterocyclic groups may each have 1 to 3 substituents, and examples of the substituent include a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a halogen atom of an iodine atom, a halogenoalkyl group containing 1 to 3 halogen atoms, Amino, cyano, amidino, hydroxyamidino, linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms (hereinafter referred to as C ₁ -C ₆ alkyl groups, which are linear, branched and cyclic) Straight chain or branched C ₁ -C ₆ alkyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, 1-methyl, such as methyl group, ethyl group, isopropyl group, tert-butyl group, etc. Cyclopropyl group C ₃ -C ₆ cycloalkyl group), C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group (eg cyclopropylmethyl group, etc.), hydroxy C ₁ -C ₆ alkyl group (eg hydroxyethyl group, 1,1-dimethyl-2-hydroxyethyl group, etc.), C ₁ -C ₆ alkoxy group (for example, methoxy group, ethoxy group, etc.), C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, carboxyl group, C ₂ -C ₆ carboxyalkyl group (e.g., carboxymethyl group, etc.), C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group (e.g., methoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, etc.) , An amidino group substituted with a C ₂ -C ₆ alkoxycarbonyl group, a C ₂ -C ₆ alkenyl group (for example, a vinyl group, an allyl group, etc.), a C ₂ -C ₆ alkynyl group (for example, an ethynyl group, Propynyl groups, etc.), C ₂ -C ₆ alkoxycarbonyl groups (e.g., methoxycarbonyl groups, ethoxycarbonyl groups, tert-butoxycarbonyl groups, etc.), amino C ₁ -C ₆ alkyl groups (e.g., aminomethyl groups, aminoethyl groups Etc) , C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl group (eg, N-methylaminomethyl group, N-ethylaminomethyl group, etc.), di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl group ( for example, N, N- dimethylamino group, N, N- diethylamino group, N- ethyl -N- methylamino group and the like), C ₂ -C ₆ alkoxycarbonylamino C ₁ -C ₆ alkyl group (e.g. for example, methoxycarbonyl amino group, tert- butoxycarbonylamino group and the like), C ₁ -C ₆ alkanoyl group (e.g., formyl group, acetyl group, methylpropionyl group, a cyclopentane group, etc.) , C ₁ -C ₆ alkanoylamino C ₁ -C ₆ alkyl group (eg acetylaminomethyl group, etc.), C ₁ -C ₆ alkylsulfonyl group (eg methanesulfonyl group, etc.), C ₁ -C ₆ alkyl sulfonylamino C ₁ -C ₆ alkyl group (e.g., methanesulfonylamino group, etc.), carbamoyl, C ₁ -C ₆ alkyl carbamoyl group (e.g., methyl carbamoyl group, ethyl carbamoyl group , Isopro A carbamoyl group, tert- butyl carbamoyl group, etc.), N, N- di (C ₁ -C ₆ alkyl) carbamoyl group (for example, dimethyl carbamoyl, diethyl carbamoyl, methyl ethyl carbamoyl group Etc.), a C ₁ -C ₆ alkylamino group (e.g., N-methylamino group, N-ethylamino group, etc.), a di (C ₁ -C ₆ alkyl) amino group (e.g., N, N-dimethylamino group, N , A 5- to 6-membered heterocyclic group containing two nitrogen, oxygen, or sulfur atoms of the same kind or different kinds or a heterocyclic group (e.g., pyrroly, N-diethylamino group, N-ethyl-N-methylamino group, etc.) di group, piperidinyl group, piperazinyl group, morpholinyl group, pyridyl group, pyrimidinyl group, tetrahydropyranyl group and the like), a heterocyclic ring of the 5-6 won tableware -C ₁ -C ₄ alkyl group (e.g. , Morpholinomethyl group, etc.), and the 5- to 6-membered heterocyclic group-amino-C ₁ -C ₄ alkyl group (for example, N- (oxazol-2-yl) aminomethyl group). .
[112] Specific examples of Q ¹ include 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl group, 5-cyclopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5-carboxymethyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5-butyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5- (4-pyridyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 5-methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridin-2-yl group, 6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl group, 5-methyl-4,5, 6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl group, 5-methyl-4,6-dihydro-5H-pyrrolo [3,4-d] thiazol-2-yl group, 5,7-dihydro-6-methylpyrrolo [3,4-d] pyrimidin-2-yl group, 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d ] Pyridazin-2-yl, 5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] py Ridazin-2-yl group, 5-dimethylamino-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl group, 5- (4-pyridyl) -4,5,6,7- Bicyclic heterocyclic groups such as tetrahydrothiazolo [5,4-c] pyridin-2-yl group, 6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl group, 4 -Pyridyl groups such as pyridyl group and 2-pyridyl group, dihydrooxazolyl groups such as 4,5-dihydrooxazol-2-yl group and 4- [N- (4,5-dihydrooxazole-2- Yl) -N-methylaminomethyl] thiophen-2-yl group, 4- [N- (4,5-dihydrooxazol-2-yl) -N-methylaminomethyl] -3-chlorothiophen-2 -Yl group, 5- (N-methylaminomethyl) thiazol-2-yl group, 5- (N-methylaminomethyl) thiophen-2-yl group, 5- (N, N-dimethylaminomethyl) thiazole-2 5- to 6-membered heterocyclic groups such as -group, 5- (N, N-dimethylaminomethyl) thiophen-2-yl group and 5- (N, N-dimethylaminomethyl) pyridin-2-yl group have. However, these examples do not limit at all with respect to Q ^1.
[113] <Group for Q ^2>
[114] Group Q ² is a divalent saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group with or without a single bond, a substituent, a divalent saturated or unsaturated 5- to 7-membered heterocyclic group with or without a substituent, and a substituent. It means a divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without, or a divalent saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent.
[115] Is in a divalent saturated or cyclic hydrocarbon of a saturated or unsaturated 5-6 won described in the cyclic hydrocarbon group refers to the description of formula (I) of the Q ⁴ of the unsaturated 5-6 won the group Q ^2, and means a divalent group, As a specific example, a cyclohexylene group, a cyclohexenylene group, a phenylene group, etc. are mentioned, A cyclohexylene group and a phenylene group are preferable.
[116] The divalent saturated or unsaturated 5- to 7-membered heterocyclic group means that the saturated or unsaturated 5- to 7-membered heterocycle described in the description of Q ^{4 in} the formula (1) is a divalent group, and specific examples thereof include furan, pyrrole, Thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazane, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, pepiridine, oxazine, oxa Diazine, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazole, triazole, triazine, azepine, diazepine, triazepine, etc. are bivalent groups, among which pyrazole, Imidazole, oxazole, thiazole, thiadiazole, furazane, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, triazole, triazine, azepine, diazepine and triazine Preferable examples include those which become bivalent groups.
[117] As the divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group, it means that the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon described in the description of Q ^{4 in} the formula (1) is a divalent group. Specific examples include indene, Indane, naphthalene, tetrahydronaphthalene, anthracene, phenanthrene, etc. are mentioned as bivalent groups, and indan and naphthalene became bivalent groups are mentioned as a preferable example.
[118] Divalent saturated or unsaturated, bicyclic or fused heterocyclic ring of the tricyclic dishes as meaning that the condensed heterocyclic ring in the saturated or unsaturated, bicyclic or tricyclic described in the description of formula (I) of the Q ⁴ a divalent group, and specific examples include Benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, quinazoline, dihydroquinazolin, tetrahydroquinazolin, quinoxaline, tetrahydroquinoxaline, Cinnoline, Tetrahydrocinnoline, Indolizine, Tetrahydroindolizine, Benzothiazole, Tetrahydrobenzothiazole, Naphthyridine, Tetrahydronaphthyridine, Thienopyridine, Tetrahydrothienopyridine, Thiazolopyridine, Tetrahydro Thiazolopyridine, thiazolopyridazine, tetrahydrothiazolopyridazine, pyrrolopyridine, dihydropyrrolopyridine, tetra Dropyrrolopyridine, pyrrolopyrimidine, dihydropyrrolopyrimidine, dihydropyridoquinazolin, pyranothiazole, dihydropyranothiazole, furopyridine, tetrahydrofuropyridine, oxazolopyridine, tetrahydrooxazolo Pyridine, oxazolopyridazine, tetrahydrooxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole, pyrrolooxazole, dihydropyrrolooxazole, benzoazine, etc. are bivalent groups. Benzofuran, benzothiophene, indole, indazole, quinoline, isoquinoline, tetrahydroisoquinoline, benzothiazole, naphthyridine, thienopyridine, thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine, Pyrrolopyridine, tetrahydropyrrolopyridine, pyridopyrimidine, pyranothiazole, dihydropyranothiazole, furopyridine, oxazolopyridine, oxazolopyridazine, pyrrolothia , Dihydro-pyrrolo can be mentioned thiazole, oxazole and pyrrolo-dihydro-pyrrolo oxazole as a preferable example that the group is divalent. There is no restriction | limiting in particular in the condensation type in the said condensed heterocyclic group, For example, naphthyridine is 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2 Or any of 7-naphthyridine, and thienopyridine may be thieno [2,3-b] pyridine, thieno [2,3-c] pyridine, thieno [3,2-b] pyridine or thi Noo [3,2-c] pyridine, thieno [3,4-b] pyridine, thieno [3,4-c] pyridine, or thiazolo [4,5-b] as thiazolopyridine. ] Pyridine, thiazolo [4,5-c] pyridine, thiazolo [5,4-b] pyridine, thiazolo [5,4-c] pyridine, thiazolo [3,4-a] pyridine, thiazolo [ 3,2-a] pyridine may be used, and thiazolopyridazine may be thiazolo [4,5-c] pyridazine, thiazolo [4,5-d] pyridazine, thiazolo [5,4- c] pyridazine or thiazolo [3,2-b] pyridazine may be used, and pyrrolopyridine may be pyrrolo [2,3-b] pyridine, pyrrolo [2,3-c] pyridine, Rolo [3,2-b] pyridine, pyrrolo [3,2-c] pyridine, pyrrolo [3,4-b] pyridine or pyrrolo [3,4-c] pyridine may be used, and pyrrolopyrimidine may be pyrrolo [3,4-d ] Pyrimidine, pyrrolo [3,2-d] pyrimidine, pyrrolo [2,3-d] pyrimidine may be used, and pyridopyrimidine may be pyrido [2,3-d] pyrimidine , Pyrido [3,2-d] pyrimidine, pyrido [3,4-d] pyrimidine may be used, and pyranothiazole may be pyrano [2,3-d] thiazole, pyrano [ 4,3-d] thiazole, pyrano [3,4-d] thiazole, pyrano [3,2-d] thiazole may be used, and as furopyridine, furo [2,3-b] Pyridine, furo [2,3-c] pyridine, furo [3,2-b] pyridine, furo [3,2-c] pyridine, furo [3,4-b] pyridine, furo [3,4-c] Any of pyridine may be used, and oxazolopyridine may be oxazolo [4,5-b] pyridine, oxazolo [4,5-c] pyridine, oxazolo [5,4-b] pyridine or oxazolo [5, 4-c] pyridine, oxazolo [3,4-a] pyridine or oxazolo [3,2-a] pyridine The oxazolopyridazine may be oxazolo [4,5-c] pyridazine, oxazolo [4,5-d] pyridazine, oxazolo [5,4-c] pyridazine, oxazolo [3, 4-b] pyridazine may be used, and pyrrolothiazole may be pyrrolo [2,1-b] thiazole, pyrrolo [1,2-c] thiazole, pyrrolo [3,2-d] Thiazole, pyrrolo [3,4-d] thiazole may be used, and pyrrolooxazole may be pyrrolo [2,1-b] oxazole, pyrrolo [1,2-c] oxazole, Any of rolo [2,3-d] oxazole, pyrrolo [3,2-d] oxazole and pyrrolo [3,4-d] oxazole may be used, or may be other than these condensation types. .
[119] The divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group, divalent saturated or unsaturated 5-7 membered heterocyclic group, divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group and divalent saturated or unsaturated The bicyclic or tricyclic condensed heterocyclic group may have 1 to 3 substituents, respectively, and examples of the substituent include a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a halogen atom of an iodine atom, and one to three halogen atoms. Substituted halogenoalkyl group, amino group, cyano group, aminoalkyl group, amidino group, hydroxyamidino group, linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (e.g., methyl group, ethyl group, etc.), Amidino having a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms (e.g., methoxy group, ethoxy group, etc.), a straight, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms group( For example, a methoxycarbonyl amidino group, an ethoxycarbonyl amidino group, etc.), a linear, branched, or cyclic alkenyl group having 2 to 6 carbon atoms (e.g., vinyl group, allyl group, etc.), Linear or branched C2-C6 alkynyl groups (e.g., ethynyl groups, propynyl groups, etc.), straight-chain, branched or cyclic C2-C6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups , Ethoxycarbonyl group, and the like) and carbamoyl group.
[120] Wherein Q ² a single bond, which may have a substituent divalent saturated or unsaturated 5 to 6-membered cyclic hydrocarbon group, a saturated divalent that may have a substituent or no divalent or unsaturated 5 to 7 round of the heterocyclic group and the substituent of the The divalent saturated or unsaturated dicyclic or tricyclic heterocyclic group which has or does not have is preferable, and a single bond, bivalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group, bivalent saturated or unsaturated 5-7 is especially preferable. Original heterocyclic group is more preferable.
[121] Furthermore, when the group Q ¹ is a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, Q ² is preferably a single bond. Here, the case where Q ² in the above combination is a single bond is represented by the formula (1)
[122] Formula 1
[123]
[124] [Wherein, R ¹ , R ² , Q ¹ , Q ² , Q ³ , Q ⁴ , T ⁰ and T ¹ represent the same as described above.]
[125] Formula 1 '
[126]
[127] [Wherein, Q ¹ represents the bicyclic or tricyclic condensed hydrocarbon group or the bicyclic or tricyclic condensed heterocyclic group, and R ¹ , R ² , Q ³ , Q ⁴ , T ⁰ and T ¹ are Same thing as above.]
[128] It means to be.
[129] More preferably a thienopyridyl group with or without a group Q ¹ , a tetrahydrothienopyridyl group with or without a substituent, a thiazolopyridyl group with or without a substituent, tetra with or without a substituent Hydrothiazolopyridyl groups, thiazolopyridazinyl groups with or without substituents, tetrahydrothiazolopyridazinyl groups with or without substituents, pyranothiazolyl groups with or without substituents, with or without substituents Dihydropyranothiazolyl groups with or without substituents, tetrapyridyl groups with or without substituents, tetrahydrofuropyridyl groups with or without substituents, oxazolopyridyl groups with or without substituents, tetras with or without substituents Hydrooxazolopyridyl groups, pyrrolopyridyl groups with or without substituents, dihydro with or without substituents Rolopyridyl group, tetrahydropyrrolopyridyl group with or without substituent, pyrrolopyrimidinyl group with or without substituent, dihydropyrrolopyrimidinyl group with or without substituent, oxa with or without substituent Zolopyridazinyl groups, tetrahydrooxazolopyridazinyl groups with or without substituents, pyrrolothiazolyl groups with or without substituents, dihydropyrrolothiazolyl groups with or without substituents, with substituents Pyrrolooxazolyl groups with or without substituents, dihydropyrrolooxazolyl groups with or without substituents, benzothiazolyl groups with or without substituents, tetrahydrobenzothiazolyl groups with or without substituents, substituents Thiazolopyrimidinyl groups with or without, dihydrothiazolopyrimidinyl groups with or without substituents, with or without substituents Benzoazinyl group, tetrahydrobenzoazinyl group with or without substituent, thiazoloazinyl group with or without substituent, tetrahydrothiazoloazinyl group with or without substituent, with or without substituent Thienoazinyl group, tetrahydrothienoazinyl group with or without substituent, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group with or without substituent, or a substituent and the group has no or 5,6-trimethylene-4,5,6,7-tetrahydro-thiazolo pyridazinyl that is, it is preferable to group Q ² is a single bond.
[130] In addition, when the group Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent or a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, the group Q ² is It is preferable that it is a divalent saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group with or without a substituent or a divalent saturated or unsaturated 5- to 7-membered heterocyclic group with or without a substituent, and groups Q ¹ -Q ^{As 2,} 4- (4-pyridyl) phenyl group, 4- (2-pyridyl) phenyl group, 5- (4-pyridyl) thiazolyl group, 1- (4-pyridyl) piperidyl group, 4- (4 -Pyridyl) piperidyl group, 4-hydroxy-1- (4-pyridyl) piperidin-4-yl group, biphenylyl group, 4- (2-aminosulfonylphenyl) phenyl group, 4- (2- Amidinophenyl) phenyl group, 4- (2-methylsulfonylphenyl) phenyl group, 4- (2-aminomethylphenyl) phenyl group, 4- (2-carbamoylphenyl) phenyl group, 4- (2-imidazolyl) phenyl group , 4- (1-methyl-2-imidazolyl) phenyl group, 4- (2,3,4,5-te Lahydropyrimidin-2-yl) phenyl group, 4- (1-methyl-2,3,4,5-tetrahydropyrimidin-2-yl) phenyl group, 4- (5-tetrazolyl) phenyl group, 1- ( 4-pyridyl) piperidin-4-yl group, 3- (4-piperidyl) isoxazolin-5-yl group, 3- (4-amidinophenyl) isoxazolin-5-yl group, 3- ( 4-piperidyl) isoxazolidin-5-yl group, 3- (4-amidinophenyl) isoxazolidin-5-yl group, 2- (4-piperidyl) -1,3,4-thia Diazol-5-yl group, 2- (4-aminophenyl) -1,3,4-oxadiazole-5-yl group, 4- (4-piperidyl) piperidin-1-yl group, 4- ( 4-piperidyl) piperazin-1-yl group, 4- (4-piperazinyl) piperazin-1-yl group, 1- (4-pyrimidinyl) piperidin-1-yl group, 1- (2 -Methylpyrimidin-4-yl) piperidin-4-yl group, 1- (4-pyrimidinyl) pyrrolidin-3-yl group, 1- (4-methylpyrimidin-6-yl) piperazin- 4-yl group, 1- (2-methylpyrimidin-4-yl) pyrrolidin-4-yl group, 1- (6-chloropyrimidin-4-yl) piperidin-4-yl group, 5- (4 -Chlorophenyl) thiophen-2-yl group, 2- (4-chlorophenyl) thiazol-4-yl group, 3- (4- clo As there may be mentioned phenyl) -1H- pyrrol-2-yl group, 4- (4-pyrimidinyl) phenyl, 4- (4-imidazolyl) phenyl group or the like as a preferable example.
[131] <Group for Q ^3>
[132] Group Q ³ is a group of the
[133]
[134] Of (groups, - groups of, Q ⁵ is C 1 -C 8 alkylene group, an Al having a carbon number of 2-8 alkenylene group or a group _{- (CH 2) m -CH 2} -A-CH 2 - (CH 2) n m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-, and 1 and 2 represent positions.);
[135] R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, heteroaryl which may have an alkyl group and a substituent Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo A substituent on a 3 to 6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, or an alkyl group N, N-dialkylcarbamoylacyl group which may have, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N- which may have a substituent on the alkyl group Alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group, or R ³ and R ⁴ together represent an alkylene group of 1 to 5 carbon atoms, 2 to 5 carbon atoms Represents an alkenylene group, an alkylenedioxy group having 1 to 5 carbon atoms, or a carbonyldioxy group.].
[136] The following group is demonstrated in detail.
[137]
[138] [In group, Q <^5> , R <^3> and R <^4> show the same thing as the above, and 1 and 2 show a position.]
[139] The part of the cyclic structure containing the above group Q ⁵ is a 3 to 10 membered divalent cyclic hydrocarbon group which may have one double bond or a 5 to 12 membered member having 1 to 2 diatoms. Although it is a bivalent heterocyclic group, a 3-8 membered bivalent cyclic hydrocarbon group or a 5-8 membered bivalent heterocyclic group is preferable, and a 5-7 membered divalent cyclic hydrocarbon group or a 5-7 membered Divalent heterocyclic group is more preferable. Among them, Q ⁵ is an alkylene group having 3 to 6 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (wherein m and n each independently represents 0 or 1). And A is the same as above). It is especially preferable that Q <^5> is a C4 alkylene group.
[140] In addition, although this cyclic hydrocarbon group or heterocyclic group can take a cis and a trans structure in the relationship of a 1st position and a 2nd position, a trans is preferable in the case of 5 member, and a cis in the case of 6-7 member. And trans are both preferred.
[141] Will be described in detail in the substituents R ³ and R ^4. Halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom. Examples of the alkyl group include linear, branched, or cyclic C ₁ -C ₆ alkyl groups (eg, methyl group, cyclopropyl group, isobutyl group, etc.). The atom substituted (for example, a chloromethyl group, a 1-bromoethyl group, a trifluoromethyl group, etc.) is mentioned. Cyano group include may be mentioned that the said C ₁ -C ₆ alkyl group is substituted with one cyano group (for example, cyanomethyl group, 1-cyanoethyl group and the like). Examples of the alkenyl group include straight or branched carbon atoms having one double bond (eg, vinyl group, allyl group, etc.). Examples of the alkynyl group include linear or branched carbon atoms having one triple bond (eg, ethynyl group, propynyl group, etc.). As the acyl group, C ₁ -C ₆ alkanoyl groups (for example, formyl group, acetyl group, etc.), C ₇ -C ₁₅ aroyl groups such as benzoyl group, naphthoyl group, or the C ₁ -C ₆ alkano group It can be given to the group C ₆ -C ₁₄ aryl group, one is the substituted aryl alkanoyl group (for example, the phenacyl group and the like three). As the acyl group may be mentioned that the Oh the first dog group optionally substituted (for example, acetyl group, etc.) on the C ₁ -C ₆ alkyl group. Examples of the alkoxy group include linear, branched, or cyclic C ₁ -C ₆ alkoxy groups (eg, methoxy group, cyclopropoxy group, isopropoxy group, and the like). As the alkoxy group to a C ₁ -C ₆ alkyl group in the dog the C ₁ -C ₆ alkoxy groups substituted with 1, there may be mentioned (for example, methoxymethyl group, ethoxymethyl group the like). Examples of the hydroxyalkyl group include one in which one hydroxyl group is substituted with the C ₁ -C ₆ alkyl group (for example, a hydroxymethyl group, a 1-hydroxyethyl group, and the like). Examples of the carboxyalkyl group include one in which one carboxyl group is substituted with the C ₁ -C ₆ alkyl group (for example, a carboxymethyl group, a 1-carboxyethyl group, and the like). Examples of the alkoxycarbonyl group include groups (eg, methoxycarbonyl group, ethoxycarbonyl group, etc.) composed of the C ₁ -C ₆ alkoxy group and the carbonyl group. Alkoxy may be mentioned a carbonyl group include a C ₁ to said dog alkoxycarbonyl group of 1 -C ₆ alkyl group in the optionally substituted (for example, methoxycarbonyl group, ethoxycarbonyl group the like). Examples of the carbamoylalkyl group include groups in which the carbamoyl group is substituted with the C ₁ -C ₆ alkyl group (for example, carbamoylmethyl group and carbamoylethyl group).
[142] As a heteroaryl group, the same thing as the heteroaryl group in description of Q <^4> of General formula (1) is mentioned. Examples of heteroaryl groups wherein the C ₁ to the dog the heteroaryl group in the 1 -C ₆ alkyl groups may be substituted (e.g., thienyl group, pyridyl group and the like). Examples of the aryl group include those having 6 to 14 carbon atoms such as a phenyl group and a naphthyl group. Examples of the aryl group include the C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkanoyl group, a hydroxyl group, a nitro group, a cyano group, and a halogen atom. , The C ₂ -C ₆ alkenyl group, the C ₂ -C ₆ alkynyl group, the C ₁ -C ₆ halogenoalkyl group, the C ₁ -C ₆ alkoxy group, carboxyl group, carbamoyl group, C ₁ -C ₆ 1-3 groups selected from an alkoxycarbonyl group etc. may be substituted. Examples of the aralkyl group include _{one in} which _one C ₆ -C ₁₄ aryl group is substituted with the C ₁ -C ₆ alkyl group (for example, a benzyl group, a phenethyl group, etc.). It is not specifically limited. As the acylamino group which may have a substituent to the C ₁ -C ₆ alkyl group is substituted with an amino group (e.g., formyl group, acetyl group and the like) in addition to, an acyl group, a halogen atom, a hydroxyl group, a C ₁ -C ₆ An acyl group in which one or more substituted alkoxy groups, amino groups, NC ₁ -C ₆ alkylamino groups, N, N-di-C ₁ -C ₆ alkylamino groups, carboxyl groups, C ₂ -C ₆ alkoxycarbonyl groups and the like (for example, 2-methoxyacetylamino group, 3-aminopropionylamino group, etc. are mentioned. As the acylamino group wherein the C ₁ -C ₆ acylamino group is the one substituted by the above C ₁ -C ₆ alkyl group can be mentioned (for example, formylamino group, acetylamino group, etc.). As the aminoalkyl group can be given to the amino group in the C ₁ -C ₆ alkyl group substituted with one (for example, aminomethyl group, 1-amino group and the like). Examples of the N-alkylaminoalkyl group include one in which one C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of the amino-C ₁ -C ₆ alkyl group (for example, N-methylaminomethyl group or N-methylaminoethyl group). Can be. As the N, N-dialkylaminoalkyl group, two C ₁ -C ₆ alkyl groups are substituted on the nitrogen atom of the amino-C ₁ -C ₆ alkyl group (for example, N, N-dimethylaminomethyl group, N-ethyl- N-methylaminoethyl group etc. are mentioned. Examples of the N-alkenylcarbamoyl group include those in which a linear or branched C ₂ -C ₆ alkenyl group is substituted with a carbamoyl group (for example, an allyl carbamoyl group, and the like). Examples of the N-alkenylcarbamoylalkyl group include those in which the aforementioned NC ₂ -C ₆ alkenylcarbamoyl group is substituted with a C ₁ -C ₆ alkyl group (for example, an allylcarbamoylethyl group and the like). As the N-alkenyl-N-alkylcarbamoyl group, a linear or branched C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of the NC ₂ -C ₆ alkenylcarbamoyl group (for example, N-allyl-N-methylcarbamoyl group etc.) are mentioned. As the N-alkenyl-N-alkylcarbamoylalkyl group, a linear or branched C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of the NC ₂ -C ₆ alkenylcarbamoylalkyl group (for example, N-allyl-N-methylcarbamoylmethyl group etc. are mentioned, for example. Examples of the N-alkoxycarbamoyl group include those in which a linear or branched C ₁ -C ₆ alkoxy group is substituted with a carbamoyl group (for example, a methoxycarbamoyl group or the like). As the N-alkoxycarbamoylalkyl group, the above-mentioned NC ₁ -C ₆ alkoxycarbamoyl group is substituted with a linear or branched C ₁ -C ₆ alkyl group (for example, methoxycarbamoylmethyl group, etc.) Can be mentioned. As the N-alkyl-N-alkoxycarbamoyl group, a linear or branched C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ alkyl group are substituted with a carbamoyl group (for example, N-ethyl-N- Methoxycarbamoyl group, etc.) is mentioned. As the N-alkyl-N-alkoxycarbamoylalkyl group, the above-mentioned NC ₁ -C ₆ alkyl-NC ₁ -C ₆ alkoxycarbamoyl group is substituted with a linear or branched C ₁ -C ₆ alkyl group (for example, For example, N-ethyl-N-methoxycarbamoylmethyl group etc. can be mentioned. As the carbazoyl group which may be substituted with 1 to 3 alkyl groups, a carbazoyl group in which 1 to 3 linear or branched C ₁ -C ₆ alkyl groups in addition to the carbazoyl group is substituted (for example, 1-methylcarbazo Diary, a 1, 2- dimethyl carbazoyl group, etc.) is mentioned. Examples of the alkylsulfonyl group include linear, branched or cyclic C ₁ -C ₆ alkylsulfonyl groups (for example, methanesulfonyl groups). Examples of the alkylsulfonylalkyl group include those in which the aforementioned C ₁ -C ₆ alkylsulfonyl group is substituted with a linear or branched C ₁ -C ₆ alkyl group (for example, a methanesulfonylmethyl group). Examples of the alkoxyimino group include C ₁ -C ₆ alkoxyimino groups (eg, methoxyimino groups, ethoxyimino groups, and the like). Alkoxy-carbonyl may be mentioned as the alkyl group to the dog of the C ₁ -C ₆ alkoxycarbonylalkyl group to an amino group substituted with one (e. G., Methoxycarbonyl methyl group, ethoxycarbonyl propyl group and the like). As the carboxyalkyl group may be mentioned a carboxy C ₁ -C ₆ alkyl group on the amino group to a 1-substituted (for example, carboxymethyl group, carboxyethyl group and the like). As the alkoxycarbonylamino group may be mentioned that the dog of the C ₁ -C ₆ alkoxycarbonyl group on the amino group substituted with one (for example, methoxycarbonyl amino group, tert- butoxycarbonyl group and the like). Alkoxycarbonylamino group include an alkyl group that in the dog C ₁ -C ₆ alkoxycarbonylamino group 1 of the substitution can be mentioned (for example, methoxycarbonyl amino group, tert- butoxycarbonylamino group and the like) have. The N-alkylcarbamoyl group which may have a substituent on the alkyl group is a hydroxy group, an amino group, an NC ₁ -C ₆ alkylamino group, an amidino group, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group, a C ₁ -C ₆ alkoxy group , a C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkanoylamino group, C ₁ -C ₆ alkyl sulfonic linear that may be substituted by sulfonyl group and the like, branched or cyclic C ₁ -C ₆ alkyl group Substituted carbamoyl group, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-isopropylcarbamoyl group, N-cyclopropylcarbamoyl group, N- (2-hydroxyethyl) Carbamoyl group, N- (2-fluoroethyl) carbamoyl group, N- (2-cyanoethyl) carbamoyl group, N- (2-methoxyethyl) carbamoyl group, N-carboxymethylcarbamoyl group , N- (2-aminoethyl) carbamoyl group, N- (2-amidinoethyl) carbamoyl group, and the like. The N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group is a hydroxy group, an amino group, an NC ₁ -C ₆ alkylamino group, an amidino group, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkanoylamino group, C ₁ -C ₆ linear alkylsulfonyl which may be optionally substituted with amino group, such as, branched or cyclic C ₁ -C Carbamoyl group substituted with two ₆ alkyl groups, for example, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl- N-methylcarbamoyl group, N- (2-hydroxyethyl) -N-methylcarbamoyl group, N, N-bis (2-hydroxyethyl) carbamoyl group, N, N-bis (2-fluoro Ethyl) carbamoyl group, N- (2-cyanoethyl) -N-methylcarbamoyl group, N- (2-methoxyethyl) -N-methylcarbamoyl group, N-carboxymethyl-N-methylcarbamo Diary, N, N-Bis (2-Army Noethyl) carbamoyl group, and the like. As the N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, the N-alkylcarbamoyl group which may have a substituent on the C ₁ -C ₆ alkyl group described above is a linear or branched C ₁ -C ₆ alkyl group. The thing substituted by (for example, N-methyl carbamoylmethyl group, N- (2-hydroxyethyl) carbamoylmethyl group, etc.) is mentioned. As the N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, the N, N-dialkylcarbamoyl group which may have a substituent on the C ₁ -C ₆ alkyl group described above is linear or branched. substituted with C ₁ -C ₆ alkyl group can be cited (for example, N, N- dimethylcarbamoyl group, N- (2- hydroxyethyl) -N- methylcarbamoyl group, etc.). The 3-6 membered heterocyclic carbonyl group which may have a substituent is a group which consists of a saturated or unsaturated heterocyclic ring and a carbonyl group, and a heterocyclic ring may contain 1 to 3 binary atoms (nitrogen atom, oxygen atom, sulfur atom, etc.) Or a 6-membered heterocycle, and the heterocycle may have a substituent such as a hydroxy group, a halogen atom, an amino group, a C ₁ -C ₆ alkyl group, and specifically, an aziridinylcarbonyl group, an azetidinylcarbonyl group, and 3-hydride. Hydroxyazetidinylcarbonyl group, 3-methoxyazetidinylcarbonyl group, pyrrolidinylcarbonyl group, 3-hydroxypyrrolidinylcarbonyl group, 3-fluoropyrrolidinylcarbonyl group, piperidylcarbonyl group, piperazinylcarbonyl group, morpholinyl Carbonyl group, tetrahydropyranylcarbonyl group, pyridylcarbonyl group, furoyl group, thiophenecarbonyl group, etc. are mentioned. As to the heterocyclic carbonyl group of 3 to 6 won which may have a substituent dog heterocyclic group of 3 to 6 1 won which may have a substituent group substituted by the above C ₁ -C ₆ alkyl group (e. G., Azetidine Thidinylcarbonylmethyl group, pyrrolidinylcarbonylethyl group, etc.) are mentioned. As a 3-6 membered heterocyclic carbonyloxyalkyl group which may have a substituent, the 3-6 membered heterocyclic carbonyloxy group comprised from the 3-6 membered heterocyclic carbonyl group and oxygen atom which may have said substituent is 1 dog may include a one (e.g., piperidinyl-carbonyl-oxy group, morpholinyl-carbonyl-oxy group, etc.) substituted with the above C ₁ -C ₆ alkyl group. As a carbamoyloxyalkyl group, one carbamoyloxy group composed of a carbamoyl group and an oxygen atom is substituted with the above C ₁ -C ₆ alkyl group (for example, a carbamoyloxymethyl group, a carbamoyloxyethyl group, or the like). ). As the N-alkylcarbamoyloxyalkyl group, _one N-alkylcarbamoyloxy group composed of an N-alkylcarbamoyl group and an oxygen atom which may have a substituent on the C ₁ -C ₆ alkyl group is C _1- substituted with C ₆ alkyl group can be cited (for example, N- methyl-carbamoyl-oxy group, N- methyl-carbamoyl-oxy group and the like). N, N- dialkyl carbamoyl group include N-oxy which may have a substituent on the above-mentioned C ₁ -C ₆ alkyl, N- di-alkyl-carbamoyl group and N, which is comprised of an oxygen atom, N- dialkyl bar And one moyloxy group substituted with the above C ₁ -C ₆ alkyl group (for example, N, N-dimethylcarbamoyloxymethyl group, N-ethyl-N-methylcarbamoyloxyethyl group, etc.). . Examples of the alkylsulfonylamino group include one in which one alkylsulfonyl group having the C ₁ -C ₆ alkyl group is substituted with an amino group (eg, methylsulfonylamino group, isopropylsulfonylamino group, etc.). Examples of the arylsulfonylamino group include one in which one arylsulfonyl group having the aryl group is substituted with an amino group (for example, a phenylsulfonylamino group, naphthylsulfonylamino group, and the like). Alkyl sulfonyl amino group include the one in the C ₁ -C ₆ alkyl of the above C ₁ -C ₆ alkylsulfonyl group one is the substituted (e.g., methyl sulfonyl amino group, methyl sulfonyl amino group and the like) the Can be mentioned. Examples of the arylsulfonyl amonoalkyl group include _{one in which one} of the arylsulfonylamino groups is substituted (for example, a phenylsulfonylaminomethyl group, naphthylsulfonylaminoethyl group, and the like) of the C ₁ -C ₆ alkyl group. Examples of the alkylsulfonylaminocarbonyl group include groups (eg, methylsulfonylaminocarbonyl group, isopropylsulfonylaminocarbonyl group, etc.) composed of the C ₁ -C ₆ alkylsulfonylamino group and carbonyl group. Examples of the arylsulfonylaminocarbonyl group include groups (eg, phenylsulfonylaminocarbonyl group, naphthylsulfonylaminocarbonyl group, etc.) composed of the arylsulfonylamino group and the carbonyl group. Alkylsulfonyl aminocarbonyl group include one of the above C ₁ -C ₆ alkyl-sulfonylamino group is substituted with the above C ₁ -C ₆ alkyl group (e.g., methyl sulfonyl amino carbonyl group, isopropylsulfonyl Aminocarbonylmethyl group etc. are mentioned. Arylsulfonyl aminocarbonyl group include one in which the aryl sulfonyl amino group substituted by the above C ₁ -C ₆ alkyl group (e.g., a phenylsulfonyl-aminocarbonyl group, a naphthyl tilseol -5-carbonyl group, etc.) Can be mentioned. The acyloxy group means the group (for example, formyloxy group, acetyloxy group, etc.) comprised from said acyl group and oxygen atom. As the acyloxy group may be mentioned that in the above-mentioned C ₁ -C ₆ alkyl group of the substituted acyloxy (e.g., formyloxy group, acetyloxy group, and so on). Examples of the aralkyloxy group include groups in which the aryl group is substituted with the C ₁ -C ₆ alkoxy group (for example, benzyloxy group, naphthylmethoxy group, and the like). Examples of the carboxyalkyloxy group include those in which the carboxyl group is substituted (for example, carboxymethoxy group, carboxyethoxy group, etc.).
[143] Examples of the arylsulfonyl group include C ₆ -C ₁₄ arylsulfonyl groups (for example, phenylsulfonyl group, naphthylsulfonyl group, and the like). Examples of the alkoxycarbonylalkylsulfonyl group include groups (for example, methoxycarbonylethylsulfonyl group, ethoxycarbonylethylsulfonyl group, etc.) composed of the C ₁ -C ₆ alkoxycarbonylalkyl group and sulfonyl group described above. have. Examples of the carboxyalkylsulfonyl group include groups (eg, carboxymethylsulfonyl groups, carboxyethylsulfonyl groups, etc.) composed of the above-mentioned carboxyalkyl group and sulfonyl group. Examples of the alkoxycarbonylacyl group include groups (eg, methoxycarbonylmethylcarbonyl group, ethoxycarbonylmethylcarbonyl group, etc.) composed of the alkoxycarbonylalkyl group and carbonyl group described above. Alkoxy alkyloxycarbonyl As is the above C ₁ -C ₆ alkoxy group, one is the number of the one (for example, methoxymethyl-oxycarbonyl group, methoxyethyl-oxy group) substituted with the alkoxycarbonyl group described above. Examples of the hydroxyacyl group include those in which one hydroxyl group is substituted with the above-mentioned acyl group (including C ₁ -C ₆ alkanoyl and aroyl) (for example, a glycoloyl group, a lactoyl group, a benzylyl group, and the like). Can be. Alkoxy acyl group used may of the C ₁ -C ₆ alkoxy group, one is the number of the one (e.g., acetyl group, methoxy, ethoxy, acetyl group) is substituted with the acyl group. Examples of the halogenoacyl group include groups (eg, chloromethylcarbonyl group, trifluoromethylcarbonyl group, etc.) constituted from the halogenoalkyl group and the carbonyl group. Examples of the carboxyacyl group include one in which one carboxyl group is substituted with the above acyl group (for example, a carboxyacetyl group, a 2-carboxypropionyl group, and the like). Amino group is as quinoa dog group 1 would be a (for example, aminomethyl group, 1-aminoethyl group) substituted with (including C ₁ -C ₆ alkanoyl and aroyl) of the acyl group . As an acyloxy acyl group, group (for example, formyloxy methyl carbonyl group, acetyloxy methyl carbonyl group, etc.) comprised from said acyloxy alkyl group and carbonyl group is mentioned. Examples of the acyloxyalkylsulfonyl group include groups (for example, formyloxymethylsulfonyl group, acetyloxymethylsulfonyl group, etc.) composed of the acyloxyalkyl group and sulfonyl group described above. Examples of the hydroxyalkylsulfonyl group include groups (eg, hydroxymethylsulfonyl groups, 1-hydroxyethylsulfonyl groups, etc.) constituted from the above C ₁ -C ₆ hydroxyalkyl groups and sulfonyl groups. Examples of the alkoxyalkylsulfonyl group include groups (for example, methoxymethylsulfonyl group, ethoxyethylsulfonyl group, etc.) composed of the C ₁ -C ₆ alkoxyalkyl group and sulfonyl group. As a 3-6 membered heterocyclic sulfonyl group which may have a substituent, the group comprised from the 3-6 membered heterocycle and sulfonyl group which may have the said substituent (for example, an aziridinyl sulfonyl group, azetidinyl Sulfonyl group, pyrrolidinylsulfonyl group, piperidylsulfonyl group, piperazinylsulfonyl group, morpholinylsulfonyl group, tetrahydropyranylsulfonyl group, and the like). As the N-alkylaminoacyl group, one C ₁ -C ₆ alkyl group is substituted on the nitrogen atom of the aminoacyl group described above (eg, N-methylaminoacetyl group, N-ethylaminoacetyl group, etc.). ). As the N, N-dialkylaminoacyl group, two C ₁ -C ₆ alkyl groups are substituted on the nitrogen atom of the aminoacyl group (for example, N, N-dimethylaminoacetyl group, N- Ethyl-N-methylaminoacetyl group). N, which may have a substituent on the alkyl N- di-alkyl-carbamoyl-substituted acyl group as the N, N- dialkyl-carbamoyl group which may have a substituent on the above-mentioned C ₁ -C ₆ alkyl group is a group of the acyl And the like (eg, N, N-dimethylcarbamoylacetyl group, N, N-diethylcarbamoylacetyl group, N-ethyl-N-methylcarbamoylacetyl group, and the like). Comprised of N, N- dialkyl bar together as alkylsulfonyl group which may have a substituent on the above-mentioned C ₁ -C ₆ alkyl N, N- di-alkyl-carbamoyl group and a sulfonyl group which may have a substituent on the alkyl group Examples thereof include N, N-dimethylcarbamoylmethylsulfonyl group, N- (2-hydroxyethyl) -N-methylcarbamoylmethylsulfonyl group, and the like. Nilah alkylsulfonyl group as a group to the dog one alkylsulfonyl group having the above-mentioned C ₁ -C ₆ alkyl group may be substituted with acyl (e.g., acetyl, methylsulfonyl, isopropylsulfonyl acetyl group, etc.).
[144] The aminocarbothioyl group is a group represented by -C (= S) -NH ₂ , and as the N-alkylaminocarbothioyl group, it represents an aminothiocarbonyl group substituted with one of the alkyl groups described above. A thiothio group, a (ethylamino) carbothioyl group, etc. are mentioned. As N, N-dialkylaminocarbothioyl group, the aminothiocarbonyl group substituted by said 2 alkyl groups is shown, for example, a (dimethylamino) carbothioyl group, (diethylamino) carbothioyl group, (ethyl Methylamino) carbothioyl group etc. are mentioned. As an alkoxyalkyl (thiocarbonyl) group, the group comprised from said alkoxyalkyl group and a thiocarbonyl group is shown, for example, 2-ethoxy ethanethioyl group etc. are mentioned.
[145] As an alkylene group, it is a C1-C5 linear or branched alkylene group, For example, a methylene group, ethylene group, a propylene group, etc. are mentioned. As an alkenylene group, a C2-C5 alkenylene group which has one double bond, a vinylene group, a propenylene group, etc. are mentioned, for example. Examples of the alkylenedioxy group include those having 1 to 5 carbon atoms such as methylenedioxy group, ethylenedioxy group, and propylenedioxy group. The carbonyldioxy group is a group represented by -O-C-(= O) -O-. In addition, in said description, a substitution position is not specifically limited.
[146] Of the substituents represented by these R ³ and R ⁴ , hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group , N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group , N-alkylcarbamoyl group which may have a substituent on an alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, alkyl group, N, N-dialkylcarbamoyl group which may have a substituent on alkyl group, N -Alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N- egg -N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group 3-6 membered heterocyclic carbonyl group which may have a substituent, 3-6 membered heterocyclic carbonyloxyalkyl group which may have a substituent, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxy Alkyl group, N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkyl group, N, N-dialkylcarbamoylalkyl group and alkyl which may have a substituent on an alkyl group Sulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyl group, alkoxyalkyloxy Carbonyl group, halo Noacyl group, N, N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoylacyl group, N, N-dialkyl Carbamoylalkylsulfonyl groups, alkylsulfonylacyl groups, aminocarbothioyl groups, N-alkylaminocarbothioyl groups, N, N-dialkylaminocarbothioyl groups, or alkoxyalkyl (thiocarbonyl) groups are preferred. Moreover, the alkylene group, alkenylene group, alkylenedioxy group, carbonyldioxy group, etc. which R <^3> and R <^4> became one are preferable.
[147] R ³ and R ⁴ are preferably those in which R ³ is a hydrogen atom and R ⁴ is a substituent listed as the above preferred group. The more preferable group as R ⁴ in that case is a hydrogen atom, a hydroxyl group, an alkyl group, a halogen atom, a hydroxyimino group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylamino group which may have a substituent, Acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, carbamoyl group, N-alkylcarbamoyl group, alkyl group which may have a substituent on the alkyl group N, N-dialkylcarbamoyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group and N-alkenyl- which may have a substituent on Carbazo that may be substituted with an N-alkylcarbamoylalkyl group, an N-alkoxycarbamoyl group, an N-alkyl-N-alkoxycarbamoyl group, an N-alkyl-N-alkoxycarbamoylalkyl group, or one to three alkyl groups Diary, alkylsulfonyl group, alkylsulfonyl An alkyl group, a 3-6 membered heterocyclic carbonyl group which may have a substituent, a 3-6 membered heterocyclic carbonyloxyalkyl group, a carbamoylalkyl group, a N, N-dialkylcarbamoyloxyalkyl group which may have a substituent, N-alkylcarbamoylalkyl group which may have a substituent on an alkyl group, N, N-dialkylcarbamoylalkyl group, an alkylsulfonylamino group, an alkylsulfonylaminoalkyl group, an acyloxy group, which may have a substituent on an alkyl group, Arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkylaminoacyl group, acyloxyacyl group , Hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoylacyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group , N-alkylaminocarbothioyl group, N, N-dialkylamino carbothioyl group, an alkoxyalkyl (thiocarbonyl) group, etc. are mentioned.
[148] Moreover, among these groups, particularly preferable groups as R ^{4 are} hydrogen atom, hydroxyl group, alkyl group, N, N-dialkylaminoalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group , N-alkylcarbamoyl group which may have a substituent on an alkoxycarbonyl group, alkoxycarbonylamino group, carbamoyl group, alkyl group, N, N-dialkylcarbamoyl group which may have a substituent on alkyl group, N-alkenyl Carbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkyl-N-alkoxycarbamoyl group, 1 Carbazoyl group, alkylsulfonyl group, alkylsulfonylalkyl group, optionally substituted with 3 to 6 alkyl groups, 3-6 membered heterocyclic carbonyl group, N, N-dialkylcarbamoyloxyalkyl group, alkyl group N-alkylcarba which may have a substituent on N, N-dialkylcarbamoylalkyl group, alkylsulfonylamino group, alkylsulfonylaminoalkyl group, acyloxy group, acyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, which may have a substituent on a monoalkyl group, an alkyl group, N, N-dialkylaminoacyl group, hydroxyacyl group, alkoxyacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thio Carbonyl) group etc. are mentioned.
[149] Examples of preferred specific substituents of R ³ and R ⁴ include hydrogen atom, hydroxyl group, methyl group, ethyl group, isopropyl group, N, N-dimethylaminomethyl group, N, N-dimethylaminoethyl group, N, N-diethylaminomethyl group, acetyl Amino group, methoxyacetylamino group, acetylaminomethyl group, acetylaminoethyl group, methoxy group, ethoxy group, methoxymethyl group, methoxyethyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxy-1-methylethyl group, meth Oxycarbonyl group, ethoxycarbonyl group, methoxycarbonylamino group, ethoxycarbonylamino group, N-allylcarbamoyl group, N-allylcarbamoylmethyl group, N-allyl-N-methylcarbamoyl group, N-allyl-N -Methylcarbamoylmethyl group, N-methoxy-N-methylcarbamoyl group, N, N-dimethylcarbazoyl group, N, N, N'-trimethylcarbazoyl group, methanesulfonyl group, methanesulfonylmethyl group, ethane Sulfonylmethyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, N-tert-butylcarbamoyl group, N-cyclopropylcarbamoyl group, N-cyclopropylmethylcarbamoyl group, N- (1-ethoxycarbonyl Cyclopropyl) carbamoyl group, N- (2-hydroxyethyl) carbamoyl group, N- (2-fluoroethyl) carbamoyl group, N- (2-methoxyethyl) carbamoyl group, N- (carboxy Methyl) carbamoyl group, N- (2-aminoethyl) carbamoyl group, N- (2-amidinoethyl) carbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group, N-methyl-N-propylcarbamoyl group, N- (2-hydroxyethyl) -N-methylcarbamoyl group , N- (2-fluoroethyl) -N-methylcarbamoyl group, N, N-bis (2-hydroxyethyl) carbamoyl group, N, N-bis (2-fluoroethyl) carbamoyl group, N- (2-methoxyethyl) -N-methylcarbamoyl group, N-carboxymethyl-N-methylcarbamo Group, N, N-bis (2-aminoethyl) carbamoyl group, azetidinocarbonyl group, 3-methoxyazetidinocarbonyl group, 3-hydroxyazetidinocarbonyl group, pyrrolidinocarbonyl group, 3-hydroxypyrroli Dinocarbonyl group, 3-fluoropyrrolidinocarbonyl group, 3,4-dimethoxypyrrolidinocarbonyl group, piperidinocarbonyl group, piperazinocarbonyl group, morpholinocarbonyl group, (tetrahydropyran-4-yl) carbonyl group, benzo Diary, pyridylcarbonyl group, N-methylcarbamoylmethyl group, N-methylcarbamoylethyl group, N-ethylcarbamoylmethyl group, N- (2-fluoroethyl) carbamoylmethyl group, N- (2-meth Methoxyethyl) carbamoylmethyl group, N, N-dimethylcarbamoylmethyl group, N, N-dimethylcarbamoylethyl group, N- (2-fluoroethyl) -N-methylcarbamoylmethyl group, N- (2 -Methoxyethyl) -N-methylcarbamoylmethyl group, N, N-dimethylcarbamoyloxymethyl group, 2- (N-ethyl-N-methylcarba Moyloxy) ethyl group, methylsulfonylamino group, ethylsulfonylamino group, methylsulfonylaminomethyl group, methylsulfonylaminoethyl group, acetyl group, propionyl group, isobutyryl group, 2-methoxyethoxycarbonyl group, trifluoroacetyl Group, N, N-dimethylaminoacetyl group, N-ethyl-N-methylaminoacetyl group, hydroxyacetyl group, 1,1-dimethyl-2-hydroxyethylcarbonyl group, methoxyacetyl group, 1,1-dimethyl 2-methoxyethylcarbonyl group, aminocarbothioyl group, (dimethylamino) carbothioyl group, 2-methoxyethanethioyl group, etc. are mentioned.
[150] As described above, R ³ and R ⁴ is R ³ is a hydrogen atom, or the like is preferred when the substituent R ⁴ above concrete. In particular, the N, N-dialkylcarbamoyl group which may have a substituent on an alkyl group is preferable, and the case where it is N, N- dimethyl carbamoyl group is especially preferable. However, R ³ and R ⁴ are not limited to these specific substituents at all.
[151] <About T ⁰ >
[152] The group T ⁰ represents a carbonyl group or a thiocarbonyl group, but a carbonyl group is more preferable.
[153] <About T ¹ >
[154] Group T ¹ is a carbonyl group, a sulfonyl group, a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')- , -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(in the group, R 'is hydrogen Atom, hydroxyl group, alkyl group or alkoxy group.), Group -C (= O) -A ¹ -N (R ")-(wherein, A ¹ is an alkylene group having 1 to 5 carbon atoms with or without a substituent) And R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C = (O) -NH-, a group -C (= S) -NH-, a group -C (= O) -NH- NH-, group ^{-C (= O) -A 2 -C} (= O) - (. of the group, a ² represents a single bond or alkylene of 1 to 5 carbon atoms), group -C (= O) - A ³ -C (= O) -NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms), the group -C (= O) -C (= NOR ^a ) -N (R ^b ) -, group -C (= S) -C (= NOR a) -N (R b) - ( of the group, R ^a represents a hydrogen atom, an alkyl group or an alkanoyl group, R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group Or an alkoxy group.), A group -C (= O) -N = N-, a group -C (= S) -N = N-, a group -C (= NOR ^c ) -C (= O) -N ( R ^d) - (of the group, R ^c is Atom, an alkyl group, an alkanoyl group, an aryl group, or represents an aralkyl group, R ^d represents a hydrogen atom, a hydroxyl group, alkyl group or alkoxy group), group ^{-C (= NN (R e)} (R f)) -. C ( = O) -N (R ^g )-(In the groups, R ^e and R ^f each independently represent a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl (thiocarbonyl) group, and R ^g represents a hydrogen atom, a hydroxyl group, or an alkyl group. Or an alkoxy group.) Or a thiocarbonyl group.
[155] As said C1-C5 alkylene group in A <^1> , A <^2> and A <^3> in the said group, it is a C1-C5 linear, branched, or cyclic alkylene group, For example, a methylene group and ethylene group , Propylene group, cyclopropylene group, 1,3-cyclopentylene group and the like. In R ', R ", R ^<a> , R <^b> , R <^c> , R <^d> , R <^e> , R <^f> and R <^g> , an alkyl group means a C1-C6 linear, branched, or cyclic alkyl group, and it is an example. For example, a methyl group, an ethyl group, etc. As an alkoxy group, it is a C1-C6 linear, branched, or cyclic alkoxy group, For example, a methoxy group, an ethoxy group, etc. are mentioned.
[156] R ^a, R ^c, R ^e and R ^f in an alkanoyl group as the linear, means a group, which is comprised of branched or alkyl group and a carbonyl group of a cyclic group having 1 to 6 carbon atoms and, for example, the acetyl group, propionyl group Etc. can be mentioned.
[157] In ^Rc , a C6-C14 thing is meant as an aryl group, For example, a phenyl group, a naphthyl group, etc. are mentioned. As an aralkyl group, it is meant that the C6-C14 aryl group substituted by the C1-C6 linear, branched, or cyclic alkyl group, For example, a benzyl group, a phenethyl group, etc. are mentioned.
[158] Examples of the group T ¹ include a carbonyl group, a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, a group- C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-and group -C (= O) -CH ₂ -N (R ")-is preferred, especially a carbonyl group, the group -C (= 0) -C (= 0) -N (R ')-, a group -C (= 0) -C (= 0) -N (R ')-, group -C (= O) -C (= S) -N (R')-and group -C (= S) -C (= S) -N (R ')-are preferred. .
[159] <About group R ¹ and group R ² >
[160] R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, preferably a hydrogen atom or an alkyl group, and more preferably a hydrogen atom.
[161] In R <^1> and group R <^2> , an alkyl group means a C1-C6 linear, branched, or cyclic alkyl group, For example, a methyl group, an ethyl group, etc. are mentioned. As an alkoxy group, C1-C6 linear, branched, or cyclic alkoxy group means, For example, a methoxy group, an ethoxy group, etc. are mentioned. In R <^1> and group R <^2> , it is preferable that they are each independently a hydrogen atom or an alkyl group, and it is more preferable that both are hydrogen atoms.
[162] When T ¹ is a carbonyl group or a sulfonyl group, Q ⁵ in the group Q ³ is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q ⁴ represents (b), (f), (g), (h), (i), (j), (k) and (l), where N in group (f) is substituted with two nitrogen atoms of the carbon atom of the ring substituted by R ¹⁹ Is preferable.
[163] In addition, when T ¹ is a carbonyl group or a sulfonyl group, Q ⁵ in the group Q ³ is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, and the substituent on the group Q ⁵ is an N-alkylcarbamoyl group or N, N-dialkylcarbamoyl groups are preferred.
[164] T ¹ is a group -C (= O) -C-(= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, a group -C ( = O) -C (= S) -N (R ')-or the group -C (= S) -C (= S) -N (R')-, Q ⁵ in group Q ³ has 1 to 8 carbon atoms When it is an alkylene group or a C2-C8 alkenylene group, it is preferable that Q <^4> is (i), (j) and (k) among the said 12 types of groups.
[165] Further, T ¹ is a group -C (= O) -C-(= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, a group- C (= O) -C (= S) -N (R ')-or the group -C (= S) -C (= S) -N (R')-, Q ⁵ in group Q ³ has 1 carbon number When the alkylene group is -8 or an alkenylene group having 2 to 8 carbon atoms, the substituent on the group Q ⁵ is preferably an N-alkylcarbamoyl group or an N, N-dialkylcarbamoyl group.
[166] Compounds represented by the general formula (1) of the present invention, salts thereof, solvates thereof or N-oxides thereof are characterized by a combination with groups T ¹ and Q ³ , and are broadly divided into the following two ((I) and (II)) )
[167] (I) T ¹ represents a carbonyl group, a sulfonyl group or a thiocarbonyl group, and Q ³ represents the following group
[168]
[169] (In the group, Q ⁵ represents the group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (In the group, m and n each independently represent an integer of 0, 1 to 3, A is an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-,-NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-.)).
[170] (II) T ¹ is a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, a group- C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(where R 'is a hydrogen atom, hydroxyl group ., represents an alkyl group or an alkoxy group), group ^{-C (= O) -A 1 -N} (R ") - ( in group, a ¹ represents an alkylene group having 1 to 5 carbon atoms which may have a substituent, R Represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C = (O) -NH-, a group -C (= S) -NH-, a group -C (= O) -NH-NH-, Group -C (= O) -A ² -C (= O)-(wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), group -C (= O) -A ^3- C (= O) -NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms), group -C (= O) -C (= NOR ^a ) -N (R ^b )-, group R ^a represents a hydrogen atom, an alkyl group, or an alkanoyl group, and R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group, or an alkoxy group in ^a -C (= S) -C (= NOR ^a ) -N (R ^b )-(group ), Group -C (= O) -N = N-, group -C (= S) -N = N-, group -C (= NOR ^c ) -C (= O) -N (R ^d ) - (in which, R ^c is a hydrogen atom, an alkyl group, an alkanoyl Group, an aryl group or aralkyl, R ^d represents a hydrogen atom, a hydroxyl group, alkyl group or alkoxy group), group ^{-C (= NN (R e)} (R f)) -. C (= O) -N ( R ^g )-(In the groups, R ^e and R ^f each independently represent a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl (thiocarbonyl) group, and R ^g represents a hydrogen atom, a hydroxyl group, an alkyl group, or an alkoxy group.) Or a thiocarbonyl group,
[171] Q ³ is below
[172]
[173] (In the group, Q ⁵ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH Represents -S-NH-, -SO-NH-, or -SO ₂ -NH-.).
[174] In said (I) and (II), the following (i) and (ii) are mentioned as a preferable thing, respectively.
[175] (i) groups R ¹ and R ² are each independently a hydrogen atom or an alkyl group, and the group Q ¹ has a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or with or without a substituent a saturated or unsaturated fused heterocyclic, bicyclic or tricyclic dishes, group Q ² is a single bond, in the group Q ³ group is Q ³ Q ⁵ group in the group _{- (CH 2) m -CH 2} -A-CH _2- (CH ₂ ) _n- ( _wherein m and n each independently represent 0 or 1 and A is the same as above); and Q ⁴ is (a) to (h) among the 12 kinds of groups. ) And (l) nine kinds of groups, group T ⁰ is a carbonyl group or thiocarbonyl group, and group T ¹ is a carbonyl group or sulfonyl group.
[176] (ii) in the formula (1), groups R ¹ and R ² are each independently a hydrogen atom or an alkyl group, and the group Q ¹ has a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a substituent or that is a saturated or condensed heterocyclic unsaturated, bicyclic or tricyclic dishes have, group Q ² is a single bond, group ³ in group Q ³ in the group Q ⁵ is an alkyl group or a group having a carbon number of 3-6 on the Q - ( CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- ( _wherein m and n each independently represent 0 or 1, A is the same as above), and the group Q ⁴ is 12 different groups of (i), will be selected from three types of (j) and (k), group T ⁰ is a carbonyl group or thiocarbonyl group, a group T ¹ is a group -C (= O) -C - ( = O) -N (R ')-, group -C (= S) -C (= O) -N (R')-, group -C (= O) -C (= S) -N (R ') Or the group -C (= S) -C (= S) -N (R ')-.
[177] Although the optical isomer derived from a stereoisomer or subtitle carbon atom may exist in the compound represented by General formula (1) of this invention, all stereoisomers, optical isomers, and mixtures thereof are included in this invention.
[178] The salt of the compound represented by the formula (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate and sulfate, and benzoic acid Organic sulfonates and acetates, such as salts, methanesulfonic acid salts, 2-hydroxyethanesulfonic acid salts and p-toluenesulfonic acid salts, propanoates, oxalate salts, malonates, succinate salts, glutaric acid salts, adipic salt salts, tartarate salts And organic carboxylates such as maleate, malate and mandelate. In addition, when the compound represented by General formula (1) has an acidic group, it may become a salt of alkali metal ion or alkaline earth metal ion. The solvate is not particularly limited as long as it is pharmaceutically acceptable. Specific examples thereof include a hydrate and an ethanolate. In addition, when a nitrogen atom exists in General formula (1), it may be an N-oxide body.
[179] As the compound of the present invention, compounds shown in Examples described later, salts of compounds, the following compounds, salts thereof and the like are particularly preferable.
[180] 1) 3-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) [1,6] naphthyridine-7-carboxamide
[181] 2) 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-fluorocinnoline-3-carboxamide
[182] 3) 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4a, 8a-dihydro-4H-1,2,4-benzoxadiazine-3-carboxamide
[183] 4) N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxamide
[184] 5) 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -5-oxo-4,5-dihydro-1H-1,3,4-benzotriazepine-2-carboxamide
[185] 6) 6-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-oxo-3,4-dihydro-2 (1H) -cinnolinecarboxamide
[186] 7) 6-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -1,2,3,4-tetrahydroquinoline-2-carboxamide
[187] 8) N-{(1R, 2S, 5S) -2-{[3- (3-chlorophenyl) -2-propinoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[188] 9) N-{(1R, 2S, 5S) -2-[(4-chlorobenzoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[189] 10) N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -6-methyl -5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine-2-carboxamide
[190] 11) 5-chloro-N-[(1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-({[5- (3-pyrrolidinyloxy) thiazol-2-yl] Carbonyl} amino) cyclohexyl] indole-2-carboxamide
[191] 12) N ^1- (4-chlorophenyl) -N ² -((1S, 2R) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[192] 13) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[193] 14) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4 -d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[194] 15) N ^1- (4-chlorophenyl) -N ² -((1S, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thia Zol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[195] 16) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4 -d] thiazol-2-yl) carbonyl] amino} cyclopentyl) ethanediamide
[196] 17) N ^1- (4-chlorophenyl) -N ² -((1R, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thia Zol-2-yl) carbonyl] amino} cyclopentyl) ethanediamide
[197] 18) N ^1- (4-chlorophenyl) -N ² -((1R, 2R) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] amino} cycloheptyl) ethanediamide
[198] 19) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] amino} cycloheptyl) ethanediamide
[199] 20) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4 -d] thiazol-2-yl) carbonyl] amino} cycloheptyl) ethanediamide
[200] 21) N ^1- (4-chlorophenyl) -N ² -((1R, 2R) -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thia Zol-2-yl) carbonyl] amino} cycloheptyl) ethanediamide
[201] 22) N ^1- (5-chloro-6-methylpyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[202] 23) N ^1- (5-chloro-3-methylpyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[203] 24) N ^1- (5-chloro-4-methylpyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[204] 25) N ^1- (4-chloro-3-hydroxyphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[205] 26) N ^1- (4-chloro-2-hydroxyphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[206] 27) N ^1- [4-Chloro-2- (fluoromethyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[207] 28) N ^1- [4-chloro-2- (methoxymethyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[208] 29) N-{(1R, 2S, 5S) -2-({[1- (4-chloroanilino) cyclopropyl] carbonyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl}- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[209] 30) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R, 4R) -4- (hydroxymethyl) -2-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclopentyl) ethanediamide
[210] 31) N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R, 4S) -4- (hydroxymethyl) -2-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclopentyl) ethanediamide
[211] 32) N ¹ -((3R, 4S) -1-acetyl-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) -N ² - (5- chloropyridin-2-yl) ethane diamide
[212] 33) N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (methylsulfonyl) -3-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide
[213] 34) N ¹ -{(1S, 2R, 4S) -2-({[(3-chlorobenzothiophen-2-yl) carbonyl] amino} -4-[(dimethylamino) carbonyl] cyclohexyl} -N ^2- (5-chloropyridin-2-yl) ethanediamide
[214] 35) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbothioyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[215] 36) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbothioyl] amino} cyclohexyl) ethanediamide
[216] 37) N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (2-methoxyethanethioyl) -3-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide
[217] 38) N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbothioyl] amino} piperidin-4-yl) ethanediamide
[218] 39) N-[(3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethioyl} amino) -1- (2-methoxyacetyl) Piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[219] 40) N-[(3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-thioxoacetyl} amino) -1- (2-methoxyacetyl) pi Ferridin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[220] 41) N ^1- (4-chlorophenyl) -N ² -((3R, 4S) -1- (2-methoxyethanethioyl) -3-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide
[221] 42) N ^1- (4-chlorophenyl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo [5,4-c] pyridin-2-yl) carbothioyl] amino} piperidin-4-yl) ethanediamide
[222] 43) N-[(3R, 4S) -4-{[2- (4-chloroanilino) -2-oxoethanethioyl] amino} -1- (2-methoxyacetyl) piperidine-3- Yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[223] 44) N-[(3R, 4S) -4-({2-[(4-chlorophenyl) amino] -2-thioxoacetyl} amino) -1- (2-methoxyacetyl) piperidine-3 -Yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[224] 45) N ¹ -((1S, 2R, 4S) -4- (1-azetidinylcarbonyl) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ² - (5- chloropyridin-2-yl) ethane diamide
[225] 46) N ^1- (5-chloropyridin-2-yl) -N ² -[(1S, 2R, 4S) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1-pyrrolidinylcarbonyl) cyclohexyl] ethanediamide
[226] 47) N ^1- (5-chloropyridin-2-yl) -N ² -[(1S, 2R, 4S) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} -4- (1-piperidinylcarbonyl) cyclohexyl] ethanediamide
[227] 48) N ^1- (5-chloropyridin-2-yl) -N ² -[(1S, 2R, 4S) -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} -4- (4-morpholinylcarbonyl) cyclohexyl] ethanediamide
[228] 49) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(methylamino) carbonyl] -2-{[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[229] 50) N-{(1R, 2S, 5S) -2-({2-[(6-chloropyridazin-3-yl) amino] -2-oxoethanethioyl} amino) -5-[(dimethylamino ) Carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[230] 51) N ^1- (4-bromophenyl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide
[231] 52) N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[4- (pyridin-4-yl) benzoyl ] Amino} piperidin-4-yl) ethanediamide
[232] 53) N ^1- (5-chloropyridin-2-yl) -N ² -[(3R, 4S) -1- (2-methoxyacetyl) -3-({[2- (pyridin-4-yl) Pyrimidin-5-yl] carbonyl} amino) piperidin-4-yl] ethanediamide
[233] 54) N ^1- (5-chloropyridin-2-yl) -N ² -[(1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-({[2- (pyridine-4 -Yl) pyrimidin-5-yl] carbonyl} amino) cyclohexyl] ethanediamide
[234] 55) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2-oxoethane (methoxy) imidoyl] amino} -5-((dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[235] 56) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2- (methoxyimino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclo Hexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[236] 57) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(4,4,5- Trimethyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[237] 58) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[4,4-ethylene-5 -Methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[238] 59) N-{(1R, 2S, 5S) -2-({[(E) -2- (4-chlorophenyl) ethenyl] sulfonyl} amino) -5-[(dimethylamino) carbonyl] cyclo Hexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[239] 60) N-{(1R, 2S, 5S) -2-{[(4-chlorobenzyl) sulfonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[240] 61) N-{(1R, 2S, 5S) -2-[(2-{[(4-chlorophenyl) sulfonyl] amino} acetyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[241] 62) N-{(1R, 2S, 5S) -2-({2-[(5-chloropyrimidin-2-yl) amino] -2-oxoethanethioyl} amino) -5-[(dimethylamino ) Carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[242] 63) N-{(1R, 2S, 5S) -2-({2-[(5-chloropyrazin-2-yl) amino] -2-oxoethanethioyl} amino) -5-[(dimethylamino) Carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[243] 64) N-[(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoro-2-thienyl) amino] -2-oxoethanethi Oil} amino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[244] 65) N-{(1R, 2S, 5S) -2-{[2- (3-amino-4-chloroanilino) -2-oxoethanethioyl] amino} -5-((dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[245] 66) N ^1- (4-chlorothiazol-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[246] 67) N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4 -c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (3-fluorophenyl) ethanediamide
[247] 68) N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4 -c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ² -phenylethanediamide
[248] 69) N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4 -c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ² - (pyridin-2-yl) ethane diamide
[249] 70) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5,6,6- Trimethyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[250] 71) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(4,4,5, 6,6-pentamethyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[251] 72) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(2-methyl-2, 3-dihydrothiazolo [5,4-d] isoxazol-5-yl) carbonyl] amino} cyclohexyl) ethanediamide
[252] 73) N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(2-methyl-2, 3-dihydrothiazolo [4,5-d] isoxazol-5-yl) carbonyl] amino} cyclohexyl) ethanediamide
[253] 74) N ^1- (5-chloro- ² -furyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[254] 75) N ^1- (5-chlorooxazol-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[255] 76) N ^1- (5-Chloro-1H-imidazol- ² -yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[256] 77) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -1-ethoxyimino-2-oxoethyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[257] 78) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -1-phenoxyimino-2-oxoethyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[258] 79) N-{(1R, 2S, 5S) -2-{[1-benzyloxyimino-2- (4-chloroanilino) -2-oxoethyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[259] 80) N-{(1R, 2S, 5S) -2-({2- (4-chloroanilino) -1-hydrazono-2-oxoethyl} amino) -5-[(dimethylamino) carbonyl] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[260] 81) N-{(1R, 2S, 5S) -2-({2- (4-chloroanilino) -1- (2-methylhydrazono) -2-oxoethyl} amino) -5-[(dimethyl Amino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[261] 82) N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -1- (2,2-dimethylhydrazono) -2-oxoethyl} Amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[262] 83) N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -1-methylimino-2-oxoethyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[263] 84) N-{(1R, 2S, 5S) -2-{[1- (2-acetylhydrazono) -2- (4-chloroanilino) -2-oxoethyl] amino} -5-[(dimethyl Amino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[264] 85) N-{(1R, 2S, 5S) -2-({2- (4-chloroanilino) -1-[(2-ethanethioylhydrazono) -2-oxoethyl] amino} -5- [(Dimethylamino) carbonyl] cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[265] 86) N-{(1R, 2S, 5S) -2-{[(E) -3- (5-chloropyridin-2-yl) -2-propenoyl] amino} -5-[(dimethylamino) Carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[266] Hereinafter, the manufacturing method of the diamine derivative (1) of this invention is demonstrated.
[267] [Manufacturing method 1]
[268] The compounds represented by the general formula (1), salts thereof, solvates thereof or N-oxides thereof can be produced, for example, by the following method.
[269]
[270] [Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² represent the same as described above, and T ¹ represents a carbonyl group.]
[271] Compound (4) is prepared by inducing carboxylic acid (3) with a mixed acid anhydride, an acid halide or an active ester and reacting with diamine (2) to give carboxylic acid (5) to the obtained compound (4). Compound (1) of this invention can be manufactured by reacting on condition. In the above reactions, reaction reagents and conditions usually used for peptide synthesis may be applied mutatis mutandis. Said mixed acid anhydride can be manufactured, for example by making chloroform acid ester, such as ethyl chloroformate and isobutyl chloroformate, react with carboxylic acid (3) in presence of a base. The acid halide can be produced by treating the carboxylic acid (3) with an acid halide such as thionyl chloride or oxalyl chloride. Although there are many kinds of active esters, for example, phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide and the like, and carboxylic acid (3) are N, N'-dicyclohexyl. It can be manufactured by making it react using condensing agents, such as carbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. In addition, the active ester reacts with carboxylic acid (3) and pentafluorophenyl trifluoroacetate, etc., and with carboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite Reaction, reaction of carboxylic acid (3) with diethyl cyanophosphonic acid dichloride (Shiriiri method), reaction of carboxylic acid (3) with triphenylphosphine and 2,2'-dipyridyl disulfide (Hanoic acid method-Mukaiyama method) etc. can also be manufactured. Compound (4) can be prepared by reacting the mixed acid anhydride, acid halide or active ester of carboxylic acid (3) thus obtained in diamine (2) with an appropriate base at -78 ° C to 150 ° C. have. The compound (1) of this invention can be manufactured by making the obtained compound (4) react with the mixed acid anhydride, acid halide, or active ester of carboxylic acid (5) on the same conditions. The reagents and reaction conditions in the reaction between the compound (4) and the carboxylic acid (5) are the same as the reagents and reaction conditions in the reaction between the diamine (2) and the carboxylic acid (3).
[272] Specific bases used in the above steps include, for example, carbonates and alkalis of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride. Metal alkoxides, alkali metal hydroxides or hydrides, or organometallic bases represented by dialkylaminolithium such as alkyllithium such as n-butyllithium, lithium diisopropylamide, bissilyl such as lithium bis (trimethylsilyl) amide Organometallic bases of amines or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] Organic bases, such as deck-7-ene (DBU), etc. are mentioned.
[273] Examples of the inert solvent used in this reaction include halogenated alkyl solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, Amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, and the like, and in some cases, dimethyl sulfoxide, sulfolane and the like. It is also possible to use ketone solvents, such as a sulfoxide solvent, acetone, and methyl ethyl ketone.
[274] [Manufacturing Method 2]
[275] Compound (1) of the present invention can also be produced by the following method.
[276]
[277] [Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² represent the same as described above, T ¹ represents a carbonyl group, Boc represents a tert-butoxycarbonyl group, and Boc-ON represents 2 -(tert-butoxycarbonyloxyimino) -2-phenylacetonitrile.]
[278] The diamine (2) was treated with Boc-ON (6) as mentioned above, the compound (7) which protected one of the two amino groups by tert-butoxycarbonyl group was manufactured, and the carboxylic acid (5) was obtained to (7) obtained. ) Is reacted to produce compound (8), followed by treatment with acid to form compound (9), followed by reaction with carboxylic acid (3) to produce compound (1) of the present invention. Compound (7) can be produced by reacting in a solvent such as dichloromethane at -10 ° C to 40 ° C in the presence of triethylamine. Compound (8) can be prepared by reacting a mixed acid anhydride, an acid halide or an active ester of compound (7) with carboxylic acid (5) with the reagents or reaction conditions described in Preparation Method 1. The obtained compound (8) can be processed with trifluoroacetic acid etc. at -20 degreeC-70 degreeC, and an amine (9) can be manufactured. In the reaction between the obtained amine (9) and carboxylic acid (3), the same reagents and reaction conditions as those described in Production Method 1 may be used.
[279] By the way, the tert-butoxycarbonyl group of compound (7) can also be changed into the protecting group of another amino group. In that case, it is necessary to replace the reagent 6 with another reagent and to use the reaction conditions and the like accordingly. Examples of the protecting group for other amino groups include alkoxycarbonyl groups such as alkanoyl groups such as acetyl groups, methoxycarbonyl groups and ethoxycarbonyl groups, benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, para (ortho) nitrobenzyloxycarbonyl groups and the like. Aroyl groups, such as an arylmethyl group, such as a carbonyl group, a benzyl group, and a triphenylmethyl group, and a benzoyl group, or an arylsulfonyl group, such as a 2, 4- dinitrobenzenesulfonyl group and an orthonitrobenzenesulfonyl group. What is necessary is just to select these protecting groups according to the property etc. of the compound which protects an amino group, and also to select the reagent and conditions according to the protecting group also at the time of cutting | disconnection of these protecting groups.
[280] [Manufacturing Method 3]
[281] Compound (1) of the present invention can be prepared by reacting diamine (2) with sulfonic acid halide (10) and then condensing with carboxylic acid (5).
[282]
[283] [Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² represent the same as described above, T ¹ represents a carbonyl group, and X represents a halogen atom.]
[284] Compound (4) can be prepared by reacting diamine (2) and sulfonic acid halide (10) at -10 ° C to 30 ° C in the presence of a base such as triethylamine in an inert solvent. What is necessary is just to select an inert solvent and a base suitably from what was described by the manufacturing method 1. Compound (1) of the present invention can be produced by condensation of obtained (4) with carboxylic acid (5) using the reagents and conditions described in Production Method 1. In addition, the sulfonic acid halide (10) can be synthesized by a known method (WO96 / 10022, WO00 / 09480) or a similar method in the presence of a suitable base.
[285] [Manufacturing Method 4]
[286] Compound (1) of the present invention can also be produced by the following method.
[287]
[288] [Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and X represent the same as above and T ¹ represents a sulfonyl group.]
[289] That is, compound (1) can be manufactured by making amine (9) react with sulfonic acid halide (10) in inert solvent in -10 degreeC-30 degreeC in presence of a base. What is necessary is just to select an inert solvent and a base suitably from what was described by the manufacturing method 1.
[290] [Manufacturing Method 5]
[291] In the compound (1) of the present invention, when the part of Q ³ is the following group,
[292]
[293] [Wherein, R ³ , R ⁴ and Q ⁵ represent the same as described above, and the numbers 1 and 2 represent positions.]
[294] The relationship between position 1 and position 2 is the presence of trans and cis-type isomers. Below, the manufacturing method of such a cis type and a trans form compound (1) is demonstrated.
[295] <Production method of trans body>
[296]
[297] [Wherein, Q ⁵ , R ³ and R ⁴ represent the same as described above.]
[298] As examples of the preparation of the trans-diol 12a from the cyclic alkenes 11, for example, conversion of cyclohexene to trans-cyclohexanediol (Organic Synthesis, Vol. 1, III, p. 217) is known. In addition, conversion of trans-cyclopentanediol to trans-cyclopentanediamine (WO98 / 30574) and the like have been reported as preparation examples of the trans-diamine 2a to trans-diol 12a. According to these reports, the trans-diamine 2a can be manufactured from the cyclic alkenes 11.
[299] The trans-diamine (2a) prepared by the above method can be induced into the trans-type compound (1) by the method of the above-described production methods 1-4.
[300] <Production method of the sheath>
[301]
[302] [Wherein, Q ⁵ , R ³ and R ⁴ represent the same as described above.]
[303] Cyclohexene-to-cis-cyclohexanediol conversion (J. Org. Chem., 1998, Vol. 63, p. 6094) and the like are known as examples of the preparation of the cis-diol 12b from the cyclic alkenes 11. In addition, conversion of cis-cyclopentanediol to cis-cyclopentanediamine (WO98 / 30574) and the like have been reported as examples of preparation of cis-diamine (2b) to cis-diol (12b). According to these reports, cis-diamine (2b) can be manufactured.
[304] The cis-diamine (2b) prepared by the above method can be derived from the cis-type compound (1) by the method of Preparation Methods 1 to 4 described above.
[305] [Manufacturing Method 6]
[306] As described above, the compound (1) of the present invention may be a trans form and a cis form in the portion of Q ³ , so that geometric isomers exist, but optical isomers may exist in each of them. Below, the manufacturing method of an optically active body is demonstrated.
[307]
[308] [In formula, Q <^5> , R <^1> , R <^2> , R <^3> and R <^4> show the same thing as the above, and R <^50> shows the protecting group of an amino group.]
[309] For the preparation of the 1,2-trans amino alcohol derivative 15 of the optically active substance, for example, the preparation of 1,2-trans-2-aminocyclopentanol of the optically active substance from cyclopentene oxide or cyclohex The preparation of 1,2-trans-2-aminocyclohexanol of optically actives from senoxides is known (Tetrahedron: Asymmetry, 1996, vol. 7, 843; J. Org. Chem., 1985, vol. 50 , 4154; J. Med. Chem., 1998, Vol. 41, 38). Compound (16) can be prepared by reacting the amino group of the aminoalcohol derivative (15) of the optically active substance prepared by applying such a known method or the method with a suitable protective reagent. As a protecting group corresponding to R <^50> in the compound (16), an alkoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, para (or Aryl sulfonyl groups, such as an aryl methoxycarbonyl group, such as an ortho) nitrobenzyloxycarbonyl group, a 2, 4- dinitrobenzene sulfonyl group, and an orthonitrobenzene sulfonyl group, are preferable. For example, in the case of protecting with a tert-butoxycarbonyl group, the compound (16) can be prepared by reacting the aminoalcohol derivative 15 with di-tert-butyl dicarbonate in an inert solvent at -78 ° C to 50 ° C. . What is necessary is just to select an inert solvent suitably from what was described by the manufacturing method 1.
[310] Compound (17) can be prepared by reacting compound (16) with methanesulfonyl chloride in the inert solvent at -78 ° C to 50 ° C in the presence of a base. What is necessary is just to select an inert solvent suitably from what was described by the manufacturing method 1. Examples of the base include pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene Organic bases such as (DBU) are preferred.
[311] Compound (18) can be prepared by reacting compound (17) with sodium azide at -10 ° C to 150 ° C in a suitable solvent. Examples of the solvent include amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one, alcohol solvents such as methanol and ethanol, tetrahydrofuran and 1,2 Ether solvents such as dimethoxyethane and dioxane, benzene solvents such as toluene, halogenated carbon such as dichloromethane, chloroform and carbon tetrachloride, acetone, dimethyl sulfoxide, mixed solvents of these solvents and water, and the like are suitable.
[312] The method of converting the azide derivative (18) to the compound (7a) is a hydrogenation method using a palladium-based catalyst, a Raney nickel catalyst or a platinum catalyst, lithium aluminum hydride, sodium borohydride, zinc borohydride There are a number of methods such as a reaction using a reducing agent, a reaction using zinc in the presence of nickel chloride or cobalt chloride, and a reaction using triphenylphosphine, and the reaction conditions may be selected according to the properties of the compound. For example, the azide derivative 18 may be hydrogenated at a temperature of −10 ° C. to 70 ° C. as a catalyst with 1 to 20% of palladium carbon in a suitable solvent to prepare compound (7a). Hydrogen pressure can also be raised above atmospheric pressure. Examples of the solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl Amide solvents such as pyrrolidin-2-one, ester solvents such as ethyl acetate, acetic acid, hydrochloric acid, water or a mixed solvent thereof are suitable.
[313] The optically active amine 7a prepared by the above method can be derived from the optically active compound (1) according to the above-mentioned production method 2. In addition, the enantiomer 1 of the optically active substance 1 obtained from the optically active amine 7a can be produced by the same method.
[314] In addition, an optically active compound (1) may be prepared by separating the racemate (1) into a column of an optically active carrier. In addition, intermediates (2), (4), (7), (8) or (9) for producing the racemate (1) were separated by a column made of an optically active carrier, and the optically active (2), ( It is also possible to isolate 4), (7), (8) or (9) and subsequently produce an optically active compound (1) according to the production methods 1 to 4. As a method of isolating (1), (2), (4), (7), (8) or (9) of optical activity, a method of fractionally crystallizing a salt with an optically active carboxylic acid or vice versa A method of fractionally crystallizing salts with bases is also possible.
[315] [Manufacturing Method 7]
[316] Hereinafter, the manufacturing method of the compound (1c) containing a hetero atom in Q <^3> of the compound (1) of this invention is described in detail.
[317] The compounds represented by the general formula (1c), salts thereof, solvates thereof or N-oxides thereof can be produced, for example, by the following method.
[318]
[319] [Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , A, m and n represent the same as described above and T ¹ represents a carbonyl group.]
[320] Compound (4c) is prepared by inducing carboxylic acid (3) with a mixed acid anhydride, an acid halide or an active ester and reacting with compound (2c), to give carboxylic acid (5) to the obtained compound (4c). The compound (1c) of this invention can be manufactured by reacting on condition.
[321] In the above reactions, reaction reagents and conditions usually used for peptide synthesis may be applied mutatis mutandis. Said mixed acid anhydride can be manufactured, for example by making chloroform acid ester, such as ethyl chloroformate and isobutyl chloroformate, react with carboxylic acid (3) in presence of a base. An acid halide can be produced by treating carboxylic acid (3) with an acid halide such as thionyl chloride or oxalyl chloride. There are various kinds of active esters, but for example, phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide, and the like, and carboxylic acid (3) are N, N'-dicyclo It can manufacture by making it react using condensing agents, such as hexyl carbodiimide (DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. In addition, the active ester reacts with carboxylic acid (3) and pentafluorophenyl trifluoroacetate, etc., and with carboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite Reaction, reaction with diethyl cyanophosphonic acid (dyeing method), reaction with carboxylic acid (3), triphenylphosphine, and 2,2'- dipyridyl disulfide (counting-acid method) can also be manufactured. have. Compound (4c) can be prepared by reacting the mixed acid anhydride, acid halide or active ester of carboxylic acid (3) thus obtained with compound (2c) under cooling and heating in an inert solvent in the presence of a suitable base. The compound (1c) of the present invention can be produced by reacting the obtained compound (4c) with a mixed acid anhydride, an acid halide or an active ester of the carboxylic acid (5) under the same conditions. Reagents and reaction conditions in the reaction of compound (4c) with carboxylic acid (5) are the same as the reagents and reaction conditions in reaction of compound (2c) and carboxylic acid (3).
[322] As a specific base used for each said process, For example, Alkali metal alkoxides, such as alkali metals, such as sodium carbonate and potassium carbonate, or alkaline earth metal carbonate, sodium ethoxide, potassium butoxide, alkali, such as sodium hydroxide, potassium hydroxide, etc. Alkali metal hydrides such as metal hydroxides, sodium hydride and potassium hydride, alkyl lithiums such as n-butyllithium, organic metal bases represented by dialkylaminolithiums such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and the like. Organometallic base of bissilylamine or pyridine, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] Organic bases such as deck-7-ene (DBU); and the like.
[323] Examples of inert solvents used in this reaction include halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran and 1,4-dioxane, aromatic solvents such as benzene and toluene, and N, N-dimethylform. Amide solvents, such as an amide, are mentioned, In addition to these, sulfoxide solvents, such as dimethyl sulfoxide, ketone solvents, such as acetone, etc. can also be used.
[324] In addition, the compound (1c) of the present invention can be produced by appropriately adding or removing a protecting group or converting a functional group.
[325] As a protecting group of an amino group, the protecting group normally used as a protecting group of an amino group in synthesis of an organic compound, especially a peptide synthesis, may be used, Specifically, alkoxycarbonyl groups, such as a tert- butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, benzyl Arylmethyl groups such as oxycarbonyl group, paramethoxybenzyloxycarbonyl group, para (or ortho) nitrobenzyloxycarbonyl group, arylmethyl groups such as benzyl group, 4-methoxybenzyl group, triphenylmethyl group, formyl group and acetyl group Aroyl groups, such as an alkanoyl group and a benzoyl group, or an arylsulfonyl group, such as a 2, 4- dinitrobenzene sulfonyl group and an orthonitrobenzene sulfonyl group, etc. are mentioned.
[326] As a protecting group of a hydroxyl group, the protecting group of the hydroxyl group normally used for the synthesis | combination of an organic compound may be used, Specifically, the arylmethyl group, such as the alkoxy methyl group, benzyl group, 4-methoxybenzyl group, and triphenylmethyl group, acetyl, such as a methoxymethyl group, and acetyl Aroyl groups, such as an alkanoyl group, such as a group, and a benzoyl group, tert- butyl diphenyl silyloxy group, etc. are mentioned. The carboxyl group can be protected as an ester with an arylmethyl group such as an alkyl group such as methyl group, ethyl group, tert-butyl group or benzyl group. The desorption of the protecting group may be performed in a general manner.
[327] The compound in the compound (1c) of the present invention can be induced into various derivatives by converting the functional group of the compound. For example, a compound in which A is an unsubstituted nitrogen atom is acylated using a mixed acid anhydride, an acid halide or an active ester, etc. in a conventional organic chemical method to react the amide compound with a sulfonic acid halide or the like to form a sulfonamide compound. The carbamate compound can be produced by, for example, reacting an N-alkyl compound with an alkyl halide and reacting an N-aryl compound with an isocyanate by reacting an aryl halide or the like. In addition, a compound in which A is an unsubstituted nitrogen atom can be produced by, for example, acid treatment of compound (1c) prepared according to Preparation Method 7 from diamine (2c) in which A is protected by tert-butoxycarbonyl group.
[328] The compound of the present invention thus prepared can be isolated and purified by known methods such as extraction, precipitation, fractionation chromatography, fractional crystallization, recrystallization, and the like. In addition, the salt of the compound of the present invention can be derived into a desired salt by treating with a conventional salt forming reaction.
[329] In addition, since the compound of the present invention has a subtitle carbon, optical isomers exist. These optically active bodies are separated from the optically active diamine (2c) in addition to the method of separating racemates by forming an salt with an optically active amine or an acid and fractionating crystallization or by column chromatography using an optically active carrier. It can manufacture by a method.
[330] Furthermore, in the reaction of compound (2c) with carboxylic acid (3), compound (1c) in which T ¹ is a sulfonyl group can be produced by replacing carboxylic acid (3) with sulfonic acid halide (10). .
[331] [Manufacturing Method 8]
[332] Compound (1c) of the present invention can also be produced by the following method.
[333]
[334] [Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , A, m and n represent the same as described above, T ¹ represents a carbonyl group, and R ⁵¹ and R ⁶¹ represent a protecting group of an amino group. ]
[335] Compound 21 can be prepared by removing the protecting group R ⁶¹ of Compound (19) obtained by protecting the amino group of the compound (2c). The protecting group of the amino group exemplified as R ⁵¹ and R ⁶¹ is not particularly limited as long as it is a group usually used for protecting the amino group, and typical examples include protecting groups of the amino group described in Manufacturing Method 7, but in this case R ⁵¹ And R ⁶¹ need to be protecting groups that can be removed by different methods or conditions. For example, the combination etc. which R ⁵¹ is a tert-butoxycarbonyl group and R ⁶¹ is a benzyloxycarbonyl group are mentioned as a typical thing. What is necessary is just to select these protecting groups according to the property etc. of the compound which protects an amino group, and to remove the protecting group, what is necessary is just to select the reagent and conditions according to the protecting group.
[336] The compound (21) can also be produced by converting the hydroxyl group of the aminoalcohol 20 into an amino group. Examples of the preparation of the aminoalcohol 20 include, for example, the conversion of methionine to 3-hydroxy-4-aminothiopyran-1,1-dioxide (Tetrahedron Lett., Vol. 37, p. 7457, 1996) and the like. Known.
[337] As a method of converting the hydroxyl group of the aminoalcohol 20 into an amino group, after reacting the aminoalcohol 20 with methanesulfonyl chloride, p-toluenesulfonyl chloride, anhydrous trifluoromethanesulfonic acid, and the like, ammonia and benzylamine primary arylalkylamines such as p-methoxybenzylamine, 2,4-dimethoxybenzylamine, secondary arylalkylamines such as dibenzylamine, N-benzylhydroxylamine, N, O-dibenzylhydroxyl The method of making diamine 21 by making it react with hydroxylamines, such as an amine, and removing benzyl groups etc. as needed is mentioned. Furthermore, after reacting the aminoalcohol 20 with triphenylphosphine and ethyl azodicarboxylic acid (hindered acid method) and the like with phthalimide or succinimide, the reaction with hydrazine or N-methylhydrazine The treatment can lead to the diamine 21. Furthermore, when A in formula is SO ₂ and n = 0, the aminoalcohol 20 is reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like, followed by appropriate base. Or ammonia, benzylamine, p-methoxybenzylamine, to α, β-unsaturated cyclic sulfones produced by treatment or by directly treating the aminoalcohol 20 with triphenylphosphine and ethyl azodicarboxylic acid. Primary arylalkylamines such as 2,4-dimethoxybenzylamine, secondary arylalkylamines such as dibenzylamine, hydroxylamines such as N-benzylhydroxylamine and N, O-dibenzylhydroxylamine The diamine 21 can be manufactured by adding and removing a benzyl group etc. as needed.
[338] The carboxylic acid (3) is reacted with the obtained diamine compound (21) to produce compound (22). Subsequently, protecting group R ⁵¹ is removed to obtain compound (4c), followed by reaction with carboxylic acid (5). Compound (1c) of the invention can be prepared. In the reaction between the compound (21) and the carboxylic acid (3) and the reaction between the compound (4c) and the carboxylic acid (5), the same reagents or reaction conditions as described in the preparation method 7 may be used.
[339] Similarly, in the reaction of compound (21) with carboxylic acid (3), compound (1c) in which T ¹ is a sulfonyl group can be produced by replacing carboxylic acid (3) with sulfonic acid halide (10). .
[340] [Manufacturing Method 9]
[341] The typical manufacturing method of the manufacturing intermediate (2c) of the manufacturing method 7 is demonstrated.
[342]
[343] (In formula, R <^3> , R <^4> , A, m and n show the same thing as the above.)
[344] As a manufacturing example of the diol body 23, for example, conversion of 1,2,3,6-tetrahydropyridine to 1-benzyloxycarbonyl-3,4-cis-dihydroxypyrrolidine (Japanese Patent Laid-Open) 7-138264), Conversion of L-tartaric acid to (R, R) -tetrahydrofurandiol or (R, R) -N-benzylpyrrolidinediol (Tetrahedron: Asymmetry, Vol. 8, p. 1861). , 1997). The diol body 23 can be manufactured by applying such a known method or the method, and removing a protecting group and converting a functional group as needed.
[345] Compound (24) can be prepared by reacting diol (23) with methanesulfonyl chloride in the presence of a base in an inert solvent under cooling and heating. What is necessary is just to select an inert solvent suitably from what was described in the manufacturing method 7, and especially halogen-type alkyl solvents, such as dichloromethane and chloroform, and ether solvents, such as tetrahydrofuran and 1, 4- dioxane, are preferable. Examples of the base include pyridine, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) Organic bases, such as these, etc. are preferable.
[346] The azide body 25 can be prepared by reacting compound 24 with sodium azide under cooling and heating in a suitable solvent. Examples of the solvent include amide solvents such as N, N-dimethylformamide and N-methylpyrrolidin-2-one, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane. Aromatic solvents such as benzene, toluene, halogenated alkyl solvents such as dichloromethane and chloroform, dimethyl sulfoxide, acetone and the like are suitable. In addition, the said generally used solvent may be made into the mixture with water.
[347] The method of converting the azide substance (25) to the compound (2c) is a hydrogenation method using a palladium-based catalyst, a Raney nickel catalyst or a platinum catalyst, a reaction using a reducing agent such as lithium aluminum hydride, sodium borohydride, chloride There are many methods, such as the reaction using zinc in the presence of nickel or cobalt chloride, and the reaction using triphenylphosphine, and it is good to select and select a reagent and conditions according to the property of a compound. Hydrogen pressure can also be raised above atmospheric pressure. Examples of the solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidin-2-one. And ester solvents such as ethyl acetate, acetic acid, hydrochloric acid, water or a mixed solvent thereof are suitable. The diamine (2c) prepared by the above method can be led to the compound (1c) of the present invention according to the above-mentioned production method 7.
[348] When the diol body 23 is trans-3,4-dihydroxytetrahydrofuran or trans-1-substituted-3,4-dihydroxypyrrolidine or the like, a light activator is present. These optically active diols 23 can be derived from the optically active diamines 2c, and can also be derived from the optically active compound (1c) according to Production Method 7.
[349] [Manufacturing Method 10]
[350] Representative production methods will be described for the optically active compounds (30), (31) and (32) contained in the compound (19) described in Production Method 8. In addition, the arrangement of the subsidiary carbon shown in the following production route is shown as an example.
[351]
[352] [In formula, m, n, R <^3> , R <^51> and R <^61> represent the same thing as the above, and R <^71> represents a protecting group of a carboxy group.]
[353] Optically active α, β-unsaturated esters 26 are described in J. Org. Chem., 61, 581 pages, 1996; J. Org. Chem., 57, 6279 pages, 1992, etc. It can manufacture by applying the method as described, or the method. Diastereomers 27a and 27b can be prepared by acting optically active α, β-unsaturated ester bodies 26 and amines under cooling and heating in a suitable solvent. What is necessary is just to select an amine suitably from the thing described by the manufacturing method 8 mentioned above. Preferred solvents include organic solvents that do not react with substrates, products, or reagents, in particular alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane. Do. In addition, organic metals such as α, β-unsaturated ester body 26 and lithium N-benzyl (trimethylsilyl) amide may be applied by applying the method described in J. Org.Chem., Vol.63, p. 7263, 1998. The diastereomer 27a and 27b can be manufactured also by making a base etc. react. By separating this diastereomer, for example, (27a) can be used for the following reaction.
[354] Compound (28a) can be prepared by acid treatment of compound (27a) under cooling and heating in a suitable solvent. Examples of the acid to be used include Lewis acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, trifluoroacetic acid, and p-toluenesulfonic acid. Examples of the solvent used in the application include alcohol solvents such as water, methanol, and ethanol. This is used. The solvent may be a mixture with water. In addition, the protecting group R ⁶¹ of an amino group may be cleaved during this reaction. In that case, it is necessary to react with the appropriate protective reagent of the amino group as needed.
[355] The optically active compound (30) can be prepared by acid treatment of compound (28) under cooling and heating in a solvent. What is necessary is just to select suitably from the said acid as an acid to be used, and Lewis acids, such as boron trifluoride, p-toluenesulfonic acid, etc. are especially preferable. As a solvent used for reaction, aromatic solvents, such as ether solvents, such as 1, 4- dioxane and tetrahydrofuran, benzene, and toluene, are used. In addition, the compound (30) can also be produced from the azide body (29). As an example of manufacture of the optically active azide body 29, the conversion from L-aspartic acid to (R, R)-(3S, 4S) -3-amino-4-azide-5-oxotetrahydrofuran ( Can. J. Chem., Vol. 71, p. 1407, 1993). The optically active azide body 29 can be manufactured by applying such a known method or the method and removing the protecting group or converting the functional group as necessary. The azide of the azide compound 29 may be reduced to an amino group, and then reacted with a protective reagent of an appropriate amino group to prepare compound 30. In the reduction of azide, the same reagents and reaction conditions as those described in the method for converting the azide body 25 of the production method 9 to the compound (2c) may be used.
[356] Compound (31) can be treated by converting the hydroxyl group portion of Compound (28) to an amino group and then treating with a base. As a method of converting the hydroxyl group of compound (28) to an amino group, it can carry out according to the said manufacturing method 8, for example. Alternatively, the compound 31 can be produced by treating the alcohol 28 with an oxidizing agent and then reductively aminating the obtained aldehyde. Specific examples of the oxidizing agent used in the reaction include pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), pyridine trioxide complex salt, and the like. Examples of the amine include primary alkylamines such as ammonia, methylamine and ethylamine, primary arylalkylamines such as benzylamine, p-methoxybenzylamine and 2,4-dimethoxybenzylamine. Reduction methods include hydrogenation using a palladium-based catalyst, a Raney nickel catalyst or a platinum catalyst, a reaction using a reducing agent such as sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, and the like. What is necessary is just to select and select a reagent and conditions according to a property. In addition, what is necessary is just to select the base used for the said process suitably from the base described in the manufacturing method 7. Compound (31) can also be prepared using the method (30) and amines described in (Tetrahedron Lett., 41, 1141, 2000; Heterocycles, 53, 173, 2000) or a method thereof. It can manufacture by application. Examples of the amines to be used include primary alkylamines such as ammonia, methylamine and ethylamine, primary arylalkylamines such as benzylamine and p-methoxybenzylamine, and aniline.
[357] Compound (32) can be prepared by treating compound (31) with a reducing agent under cooling and heating in a solvent. Examples of the reducing agent include reducing agents such as borane tetrahydrofuran complex, borane methyl sulfide complex, lithium aluminum hydride, and the like. As the solvent, an organic solvent which does not react with a substrate, a product, a reagent, or the like, particularly an ether solvent such as tetrahydrofuran or 1,4-dioxane is preferable.
[358] Compounds (30), (31) and (32) prepared by the above method can be induced into the optically active material (1c) of the compound of the present invention according to the above-mentioned preparation method 8.
[359] Although the above manufacturing process has been exemplified for one of the optically active materials, the same process can be prepared by using starting materials having different stereoconfigurations for optically active materials having different stereoconfigurations.
[360] [Manufacturing Method 11]
[361] Compound (1) in which T ¹ is a group -CO-CO-N (R ')-(wherein R' represents the same as above) can be produced by the following route.
[362]
[363] [In formula, Q <^1> , Q <^2> , Q <^3> , Q <^4> , R <^1> , R <^2> and R 'represent the same thing as the above, and T <^1> is group -CO-CO-N (R')-(in group, R 'represents the same as the above.).
[364] That is, compound (4) is prepared by inducing carboxylic acid (33) to an acid halide or an active ester and reacting with diamine (2), and carboxylic acid (5) to compound (4) obtained under the same conditions. The compound (1) of this invention can be manufactured by making it react. In the above reactions, reaction reagents and conditions usually used for peptide synthesis may be applied mutatis mutandis. The acid halide can be produced by treating the carboxylic acid 33 with an acid halide such as thionyl chloride or oxalyl chloride. There are various kinds of active esters, but for example, phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide and the like, and carboxylic acid (33) are N, N'-dicyclohexyl. It can be manufactured by making it react using condensing agents, such as carbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. In addition, the active ester reacts with carboxylic acid (33) and pentafluorophenyl trifluoroacetate, etc., and with carboxylic acid (33) with 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphite Reaction, reaction of carboxylic acid (33) with diethyl cyanophosphonic acid (dyeing method), reaction of carboxylic acid (33) with triphenylphosphine and 2,2'-dipyridyl disulfide (counting-acid method) It can also manufacture. Compound (4) was prepared by reacting the mixed acid anhydride, acid halide or active ester of carboxylic acid (33) thus obtained in diamine (2) with an appropriate base at -78 ° C to 150 ° C in an inert solvent. can do. The compound (1) of this invention can be manufactured by making the obtained compound (4) react with the mixed acid anhydride, acid halide, or active ester of carboxylic acid (5) on the same conditions. Reagents and reaction conditions in the reaction between the compound (4) and the carboxylic acid (5) are the same as the reagents and reaction conditions in the reaction between the diamine (2) and the carboxylic acid (33). What is necessary is just to select suitably as a base and a solvent used for each said process from what was described in the manufacturing method 1.
[365] In addition, Q ³ is
[366]
[367] [Wherein, R ³ , R ⁴ and Q ⁵ represent the same as described above, and the numbers 1 and 2 represent positions.]
[368] When the relationship between the 1st position and the 2nd position produces the cis type or trans type compound (1), the diamine (2a) or (2b) described in the manufacturing method 5 may be used.
[369] Furthermore, in the case of producing compound (1) containing hetero atoms such as nitrogen atom, oxygen atom or sulfur atom in Q ^5, in the reaction of compound (2c) and carboxylic acid (3) described in Production Process 7 The carboxylic acid 3 may be replaced with the carboxylic acid 33. That is, the compound (1), ie, the compound (1c) containing a hetero atom in Q ⁵ can be prepared by the following route.
[370]
[371] [Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , R ', A, m and n represent the same as above, and T ¹ represents a group -CO-CO-N (R')-( In the group, R 'represents the same as the above.).
[372] [Manufacturing Method 12]
[373] Compound (1) in which T ¹ is a group -CO-CO-N (R ')-(wherein R' represents the same as above) can also be produced by the following route.
[374]
[375] [In formula, Q <^1> , Q <^2> , Q <^3> , Q <^4> , R <^1> , R <^2> and R 'represent the same thing as the above, and T <^1> is group -CO-CO-N (R')-(in group, R 'represents the same as the above.).
[376] In the reaction between the amine (9) and the carboxylic acid (33), the same reagents and conditions as those described in Production Method 1 may be used.
[377] The amine 9 used here can be manufactured also by the route shown as a manufacturing route of the following amine 41 besides the route described by the manufacturing method 2, for example.
[378]
[379] [In formula, R <^3> , R <^4> , Q <^1> , Q <^2> and Q <^5> show the same thing as the above, and R <^52> shows the protecting group of an amino group.]
[380] The compound (34) in the said manufacturing process can be manufactured by treating cycloalkene with benzoic acid, its derivatives, etc. in a solvent, such as methylene chloride, and epoxidizing. These reaction conditions should just apply the normal conditions which epoxidize an alkene. In addition, compound (34) is described in J. Org. It is also possible to manufacture by the method described in Chem., Vol. 61, 8687-8691 (1996) or a method similar thereto.
[381] Compound (34) can be reduced to azide (35) obtained by treatment with sodium azide or the like according to a general method, and then protected to amino group to lead to compound (36). Examples of the protecting group for the amino group in this case include those described in Production Method 2. Compound (36) was prepared in the same manner as described in Production Method 5 to form azide (38), followed by removal of the protecting group for the amino group. To (39). The compound (39) can be made into the compound (40) by reacting with the carboxylic acid (5), and then contact reduction can be made into the compound (41).
[382] [Manufacturing Method 13]
[383] Compound (1) in which T ¹ is a group -CO-CO-N (R ')-(wherein R' represents the same as above) is a compound (9) and a carbon in the route described in Preparation Method 2. The reaction with the acid (3) can also be produced by changing the reaction with the compound (9) and the carboxylic acid (33).
[384]
[385] [In formula, Q <^1> , Q <^2> , Q <^3> , Q <^4> , R <^1> , R <^2> and R 'represent the same thing as the above, and T <^1> is group -CO-CO-N (R')-(in group, R 'represents the same as the above.).
[386] What is necessary is just to apply reaction conditions to what was described in the manufacturing method 2.
[387] In addition, Q ³ is
[388]
[389] (In the group, R ³ , R ⁴ and Q ⁵ represent the same as above, and the numbers 1 and 2 represent positions.)
[390] In the case of preparing compound (1) containing hetero atoms such as nitrogen atom, oxygen atom or sulfur atom in Q ⁵ , the reaction between compound (21) and carboxylic acid (3) described in preparation method 8 is carried out. The acid (3) may be replaced with the carboxylic acid (33). Compound (1), ie, compound (1c) containing a hetero atom in Q ⁵ can be prepared by the following route.
[391]
[392] [Wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , R ', A, m and n represent the same as above, and T ¹ represents a group -CO-CO-N (R')-( R 'represents the same as the above.), And R ⁵¹ represents a protecting group of an amino group.]
[393] [Manufacturing Method 14]
[394] T ¹ represents a group -CO-A ¹ -N (R ″)-(where R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, and A ¹ represents an alkylene having 1 to 5 carbon atoms with or without a substituent; Compound (1) is -50 using compound (9) and Q ⁴ -N (R ")-A ¹ -CO ₂ H (42) described in the preparation method 2 using a condensing agent in an inert solvent. It can manufacture by making it react at C ~ 50 degree C. As a condensing agent, N, N'- dicyclohexyl carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, etc. are mentioned, for example. Examples of the inert solvent include halogenated alkyl solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, and N. Amide solvents such as N-dimethylformamide and the like.
[395]
[396] Of (group ^{[wherein, Q 1, Q 2, Q} 3, Q 4, R 1, R 2 and R "have the same meanings as defined above, T ¹ is a group ^{-CO-A 1 -N (R"} ) Represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, and A ¹ represents an alkylene group having 1 to 5 carbon atoms with or without a substituent.
[397] Compound (42) described in the above production method is, for example, an ester of arylamine such as 4-chloroaniline and bromoalkanoic acid in the presence of a base such as potassium carbonate in acetonitrile or a solvent such as N, N-dimethylformamide. After reacting at 40 degreeC-120 degreeC, ester can be manufactured by hydrolyzing using alkali, such as lithium hydroxide, potassium hydroxide, and sodium hydroxide. The compound (42) may use potassium salt etc. for reaction as it is.
[398] [Manufacturing Method 15]
[399] Compound (1) wherein T ¹ is a group -C (= O) -NH- or a group -C (= S) -NH- is a compound (9) described in Preparation Method 2 and an isocyanate (Q ⁴ -N = C = O ) Or isothiocyanate (Q ⁴ -N = C = S) can be produced by reacting at -20 ° C to 50 ° C in an inert solvent. As an inert solvent, the thing described in the manufacturing method 14 is mentioned as a representative example. What is necessary is just to manufacture the isocyanate and isothiocyanate used here by the method generally used as a manufacturing method of an isocyanate or isothiocyanate, when a commercially available thing is not available.
[400]
[401] [Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² represent the same as above, and T ¹ represents a group —C (═O) —NH— or a group —C (= S) — NH-.]
[402] [Manufacturing Method 16]
[403] Compound (1), wherein T ¹ is a group -CO-NH-NH-, is prepared from compound (9) and Q ⁴ -NH-NH-CO ₂ Ph (43) described in Preparation Method 2 in an inert solvent, if necessary, in the presence of a base. It can manufacture by making it react at room temperature-150 degreeC. As an inert solvent, what was described in the manufacturing method 14 other than acetonitrile and N, N- dimethylformamide is mentioned as a representative example. Examples of the base include pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) is mentioned.
[404]
[405] [In formula, Q <^1> , Q <^2> , Q <^3> , Q <^4> , R <^1> and R <^2> show the same thing as the above, T <^1> represents group -CO-NH-NH-, and Ph represents a phenyl group.]
[406] Compound (43) described in the above production method is, for example, arylhydrazine and diphenyl carbonate such as 4-chlorophenyl hydrazine, acetonitrile, N, N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, 1,2 It can manufacture by making it react at room temperature-120 degreeC in solvent, such as dimethoxyethane, dioxane, benzene, and toluene.
[407] [Manufacturing Method 17]
[408] Compound (1) wherein T ¹ is a group -CO-A ² -CO- (wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), Compound (9) and Q described in Preparation Method 2; ⁴ -CO-A ² -CO ₂ H (44) can be prepared by reacting at -50 ° C to 50 ° C using a condensing agent in an inert solvent. Examples of the condensing agent include N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the like. The solvent etc. which were described in the manufacturing method 16 are mentioned as a solvent.
[409]
[410] [Wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² represent the same as described above, and T ¹ represents a group —CO—A ² —CO— (wherein A ² represents a single bond or And an alkylene group having 1 to 5 carbon atoms.).
[411] When A ² is a single bond, the compound (44) described in the above production method is, for example, an aromatic heterocycle such as chlorobenzene or an aromatic heterocycle such as thiophene and chlorooxoacetic acid ester (e.g., ClCO-CO ₂ Et). Compounds prepared by the Friedel-Crafts reaction (eg, Q ⁴ -CO-CO ₂ Et) can be prepared by hydrolysis using alkalis such as lithium hydroxide, potassium hydroxide, sodium hydroxide and the like.
[412] In addition, when A ² is a methylene group, the compound (44) contains, for example, arylcarbonyl chlorides such as 4-chlorobenzoic acid chloride or heteroarylcarbonyl chlorides such as thiophencarbonyl chloride in the presence of magnesium chloride and triethylamine. Ketoester derivatives (e.g., Q ⁴ -CO-CH ₂ -CO ₂ Et) obtained by reacting with malonic acid monoester monocarboxylic acid potassium salts under hydrolysis using alkalis such as lithium hydroxide, potassium hydroxide, sodium hydroxide and the like It can manufacture by doing. The said keto ester derivative may use the carboxylic acid obtained by hydrolyzing the carbonyl group after ethylene ketalization, for reaction with compound (9). In addition, when compound (44) is a C2 or more alkylene group with A <^2> , For example, Friedel of aromatic heterocycles, such as benzene or aromatic heterocycle, such as thiophene, and alkylene dicarboxylic acid monoester monochloride The keto ester derivative (e.g., Q ⁴ -CO-A ² -CO ₂ Et) obtained by the kraft reaction can be prepared by hydrolysis using an alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxide and the like.
[413] [Manufacturing Method 18]
[414] Compound (1) in which T ¹ is a group -CO-A ³ -CO-NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms) is used for compound (9) and Q ⁴ described in Production Process 2. -NH-CO-A ³ -CO ₂ H (45) can be prepared by reacting at -50 ° C to 50 ° C using a condensing agent in an inert solvent. Examples of the condensing agent include N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the like. Examples of inert solvents include halogenated alkyl solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, and N, N-dimethyl. Amide system solvents, such as formamide, etc. are mentioned.
[415]
[416] ^{[Wherein, Q 1, Q 2, Q} 3, Q 4, R 1 and R ² have the same meanings as defined above, T ¹ is a group -CO-A ³ -CO- (of the group, A ³ is C 1 -C An alkylene group of 5).
[417] Compound (45) is a condensing agent of an arylamine such as 4-chloroaniline such as Q ⁴ -NH ₂ or a heteroarylamine such as aminopyridine and an alkylenedicarboxylic acid monoester monocarboxylic acid potassium salt in an inert solvent. Hydrolyzed the compound (eg Q ⁴ -NH-CO-A ³ -CO ₂ Et) prepared by reaction at -50 ° C to 50 ° C using an alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxide, and the like. It can manufacture.
[418] [Manufacturing Method 19]
[419] Compound (1) in which T ¹ is a group -CS-CO-N (R ')-(wherein R' represents the same as above) can be produced by the following route.
[420]
[421] [In formula, Q <^1> , Q <^2> , Q <^3> , Q <^4> , R <^1> , R <^2> and R 'represent the same thing as the above, and T <^1> is group -CS-CO-N (R')-(in the group, R 'represents the same as the above.).
[422] That is, the compound (1) of the present invention can be produced by dissolving or suspending the sodium thiosulfate salt (46) and the compound (9) in a solvent. 80 degreeC-200 degreeC is preferable and 150 degreeC around reaction temperature is especially preferable. As a solvent used for this reaction, alcohols, such as water, methanol, and ethanol, basic solvents, such as pyridine and N-methylmorpholine, halogenated alkyl solvents, such as dichloromethane and chloroform, tetrahydrofuran, 1,2-dimethoxy Ether solvents such as ethane and dioxane, amide solvents such as N, N-dimethylformamide, and the like, and these solvents may be appropriately mixed. Examples of the mixed solvents include a mixed solvent of methanol and dichloromethane. Can be mentioned. In addition, in this reaction, it is not necessary to reflux the solvent. For example, when a mixed solvent of methanol and dichloromethane is used, the reaction solution (or reaction mixture) is heated to an external temperature of 150 ° C, and the solvent is distilled off. The residue is subsequently heated at the same temperature.
[423] [Manufacturing Method 20]
[424] Compound (1) in which T ¹ is a group -CO-CS-N (R ')-(wherein R' represents the same as above) can be produced by the following route.
[425]
[426] [In formula, Q <^1> , Q <^2> , Q <^3> , Q <^4> , R <^1> , R <^2> and R 'represent the same thing as the above, and T <^1> is group -CO-CS-N (R')-(in group, R 'represents the same as the above.).
[427] That is, sodium thiosulfate derivative 48 can be prepared by reacting compound (9) with chloroacetic acid chloride in the presence of a base to lead to compound (47), and then heating compound (47) in sodium thiosulfate and a solvent. Thus obtained compound (1) of the present invention can be prepared by heating the obtained compound (48) with an amine, that is, HN (R ')-Q ⁴ .
[428] What is necessary is just to apply the conditions which produce compound (47) from compound (9), a solvent, etc. are common in reaction of an amine and an acid chloride. In order to manufacture compound (48) from compound (47), what is necessary is just to reflux with sodium thiosulfate about 1 hour in solvent, such as ethanol. When compound (47) is salt, such as hydrochloric acid, what is necessary is just to react in presence of base, such as sodium hydrogencarbonate. The production conditions of the compound (48) are not limited to those described herein, and the temperature, the kind of the solvent, and the kind of the base can be appropriately changed. The reaction conditions of the compound (48) and HN (R ')-Q ⁴ are the same as those described in Preparation 19.
[429] [Manufacturing Method 21]
[430] Compound (1) in which T ⁰ is a thiocarbonyl group (group -CS-) can be prepared by the following route.
[431]
[432] ^{[Wherein, Q 1, Q 2, Q} 3, Q 4 and R ² have the same meanings as defined above, T ¹ is a group -SO ₂ -, -CO- group, group -CO-NH-, group -CS- NH-, group -CO-NH-NH-, group -CO-CO-N (R ')-(wherein R' represents the same as above), group -CO-CS-N (R ') -(Wherein R 'represents the same as above), group -CS-CO-N (R')-(wherein R 'represents the same as above), group -CS-CS-N (R ') - (in group, R' has the same meaning as defined above), a group ^{-CO-a 1 -N (R "} ) - ( in group, a ¹ and R" has the same meaning as defined above.) , Group -CO-A ² -CO- (wherein A ² represents the same as above), group -CO-A ³ -CO-NH- (wherein, A ³ represents the same as above). , Group -CO-A ³ -CO- (wherein A ³ represents the same as above).]
[433] That is, the compound (49) is dehydrated with the amine (50) in the presence of an acid catalyst such as p-toluenesulfonic acid to guide the compound (51), and then heated in a solvent such as sulfur powder and a methanol / methylene chloride mixture solution. Compound (1) of can be prepared. The conditions for producing the compound (51) from the compound (49) and the amine 50 may be generally applied mutatis mutandis during the production of the Schiff base. Specifically, heating and refluxing in benzene or toluene in the presence of an acid catalyst may be performed under conditions of removing water from the reaction system by using a Dean-Stark apparatus. In addition, when removing water from the reaction system, a molecular sieve may be used.
[434] Below, the important intermediate described in the manufacturing methods 1-21 of compound (1) in this invention is described.
[435] 1) The compound represented by the following general formula (4) described in the above-mentioned production methods 1, 3 and 11 is important as a production intermediate of the compound (1) in the present invention.
[436]
[437] [In formula, R <^1> , R <^2> , Q <^3> and Q <^4> show the same thing as the above, T <^1> is a carbonyl group, a sulfonyl group, or group -CO-CO-N (R ')-(In group, R' is The same thing as.
[438] Among the above intermediates, a compound wherein T ¹ is a group -C (= O) -C (= O) -N (R ')-(wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group) and the above formula T ¹ is a carbonyl group, and Q ³ is a group of
[439]
[440] (In the group, R ³ and R ⁴ represent the same as above, Q ⁵ represents the group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (wherein m and n are respectively Independently, an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, -NH-NH-, -S- NH-, -SO-NH- or -SO ₂ -NH-.) Are preferred.
[441] 2) The compounds represented by the following formula (9) described in Production Methods 2, 4 and 12 are important as intermediates for the preparation of Compound (1) in the present invention.
[442]
[443] [Wherein, R ¹ , R ² , Q ¹ , Q ² and Q ³ represent the same as described above.]
[444] Among the intermediates, Q ³ is a group represented by
[445]
[446] (In the group, R ³ and R ⁴ represent the same as above, Q ⁵ represents the group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (wherein m and n are respectively Independently, an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, -NH-NH-, -S- NH-, -SO-NH- or -SO ₂ -NH-.) Are preferred.
[447] 3) The following compound (4c) described in Production Methods 7, 11 and 13 is important as a production intermediate of Compound (1) in the present invention.
[448]
[449] [Wherein, Q ⁴ , R ³ , R ⁴ , A, m and n represent the same as described above, and T ¹ represents a carbonyl group, sulfonyl group or group —CO—CO—N (R ′) — (wherein R is 'Represents the same as above).].
[450] Among these intermediates, a compound wherein T ¹ in the formula is -CO-CO-N (R ')-(wherein R' represents the same as above) and T ¹ is a carbonyl group, A is an oxygen atom, nitrogen A compound that is an atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH-, or -SO ₂ -NH- desirable.
[451] 4) The following compound (22) described in Production Methods 8 and 13 is important as a production intermediate of Compound (1) in the present invention.
[452]
[453] [Wherein, Q ⁴ , R ³ , R ⁴ , A, m and n represent the same as described above, and T ¹ represents a carbonyl group, sulfonyl group or group —CO—CO—N (R ′) — (wherein R is 'Represents the same as above.), And R ⁵¹ represents a protecting group of an amino group.]
[454] Among these intermediates, a compound wherein T ¹ in the formula is -CO-CO-N (R ')-(wherein R' represents the same as above) and T ¹ is a carbonyl group, A is an oxygen atom, nitrogen A compound that is an atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH-, or -SO ₂ -NH- desirable.
[455] 5) The optically active compound (7a) described in Production Method 6 is important as a production intermediate of Compound (1) in the present invention.
[456]
[457] [In formula, Q <^5> , R <^1> , R <^2> , R <^3> and R <^4> show the same thing as the above, and R <^50> shows the protecting group of an amino group.]
[458] Among the intermediates, Q ⁵ in the above formula represents a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (wherein m and n each independently represent an integer of 0, 1 to 3). A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH- or- SO ₂ -NH-.
[459] 6) The following compound (21) described in Production Method 8 is important as a manufacturing intermediate of Compound (1) in the present invention.
[460]
[461] [Wherein, R ³ , R ⁴ , A, m and n represent the same as described above, and R ⁵¹ represents a protecting group of an amino group.]
[462] Among the intermediates, A in the formula is an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO- Preference is given to compounds which are NH- or -SO ₂ -NH-.
[463] 7) The following compounds described in Production Method 10 are important as intermediates for the preparation of Compound (1) in the present invention.
[464] That is, the following trans-type compounds (30), (31) and (32) of optical activity,
[465]
[466] [In formula, R <^3> , m and n represent the same thing as the above, and R <^51> and R <^61> represent the protecting group of an amino group.]
[467] Enantiomers (30a), (31a) and (32a) of the compounds prepared in the same manner,
[468]
[469] [In formula, R <^3> , m and n represent the same thing as the above, and R <^51> and R <^61> represent the protecting group of an amino group.]
[470] Cis-type compounds (30b), (31b) and (32b),
[471]
[472] [In formula, R <^3> , m and n represent the same thing as the above, and R <^51> and R <^61> represent the protecting group of an amino group.]
[473] And their enantiomers 30c, 31c and 32c
[474]
[475] [In formula, R <^3> , m and n represent the same thing as the above, and R <^51> and R <^61> represent the protecting group of an amino group.]
[476] Is important as an intermediate for producing Compound (1) in the present invention.
[477] Since the diamine derivative of the present invention exhibits a potent activating coagulation factor X inhibitor, the drug for mammals, including humans, activating coagulation factor X inhibitors, coagulation inhibitors, thrombus or embolism prevention and / or Therapeutic agents, prophylactic and / or therapeutic agents for thrombotic disease, further cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, after artificial valve / joint replacement It is useful as a prophylactic and / or therapeutic agent for thrombus formation, thrombus formation and reclosure after blood circulation reconstruction, systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), thrombus formation in extracorporeal circulation or blood clotting in blood collection.
[478] When the compound of the present invention is used as a human medicine, the dosage is in the range of 1 mg to 1 g, preferably 10 mg to 300 mg per adult. In addition, the dosage for the animal depends on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infected pathogen, but the daily dosage is generally 0.1 mg to 200 per kg body weight of the animal. mg, preferably in the range of 0.5 mg to 100 mg. This daily dose is administered once a day or divided into two to four times. In addition, the daily amount may exceed the said amount as needed.
[479] The pharmaceutical composition containing the compound of this invention can be prepared by the preparation method of the various formulations currently used by selecting a suitable manufacturing method according to the administration method. As a formulation of the pharmaceutical composition based on the compound of the present invention, for example, tablets, powders, granules, capsules, liquids, syrups, elixirs, oily to aqueous suspensions, and the like can be exemplified as oral preparations.
[480] As injections, stabilizers, preservatives, and dissolution aids may be used in the preparations, and solutions that may contain these auxiliaries may be prepared as preparations when used as solid preparations by storage in a container and lyophilization. In addition, one dose may be accommodated in one container, and many doses may be accommodated in one container.
[481] Examples of the external preparations include liquids, suspensions, emulsions, ointments, gels, creams, lotions, sprays, and plasters.
[482] As the solid preparation, a pharmaceutically acceptable additive with the compound of the present invention, for example, fillers, extenders, binders, disintegrating agents, dissolution accelerators, wetting agents, lubricants and the like are selected and mixed as necessary. It may be formulated.
[483] Examples of the liquid preparation include solutions, suspensions, emulsions, and the like, but may include suspending agents, emulsifiers, and the like as additives.
[484] Examples of the compound of the present invention include the following compounds (A) to (E).
[485] (A) Formula 1
[486]
[487] [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
[488] Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without substituent, a saturated or unsaturated 5-6 membered heterocyclic group with or without substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
[489] Q ² is
[490]
[491] (In the group, Q ⁴ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-, and 1 and 2 represent positions.);
[492] R ³ and R ⁴ are substituted on a carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁴ , and each independently hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group , Cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acylamino Alkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on an alkyl group, N, N-dialkylcarbamoyl which may have a substituent on an alkyl group , N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkyl N, N which may have a substituent on a sulfonylalkyl group, a 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, and an N-N which may have a substituent on an alkyl group -Dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, a 3-6 membered heterocyclic carbonylalkyl group which may have a substituent , 3-6 membered heterocyclic carbonyloxyalkyl group, aryl group, aralkyl group, heteroaryl which may have a substituent Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo A substituent on a 3 to 6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, or an alkyl group N, N-dialkylcarbamoylacyl group which may have, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, etc. which may have a substituent on an alkyl group, or R <^3> and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group having 1 to 5 carbon atoms or a carbonyldioxy group.);
[493] Q ³ is an aryl group with or without a substituent, an aryl alkenyl group with or without a substituent, a heteroaryl group with or without a substituent, a heteroaryl alkenyl group with or without a substituent, saturation with or without a substituent Or an unsaturated dicyclic or tricyclic condensed hydrocarbon group, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
[494] T ¹ represents a carbonyl group or a sulfonyl group.], A salt thereof, a solvate thereof, or an N-oxide thereof.
[495] (B) Formula 1
[496]
[497] [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
[498] Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without substituent, a saturated or unsaturated 5-6 membered heterocyclic group with or without substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
[499] Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-6 membered heterocyclic group with or without a substituent, and a substituent. A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a divalent saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, and
[500] Q ³ is
[501]
[502] (In the group, Q ⁵ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-.
[503] R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group which may have an alkyl group and a substituent, an aryl group, an aralkyl group, heteroa Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo Substituted on a 3-6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an alkyl group which may have a nil group, a substituent An N, N- di-alkyl which may have carbamoyl acyl group, N, which may have a substituent on the alkyl N- di-alkyl-carbamoyl-alkyl sulfonyl, alkylsulfonyl nilah or indicate the group and the like, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group having 1 to 5 carbon atoms or a carbonyldioxy group.);
[504] Q ⁴ is an aryl group with or without a substituent, an aryl alkenyl group with or without a substituent, a heteroaryl group with or without a substituent, a heteroaryl alkenyl group with or without a substituent, saturation with or without a substituent Or an unsaturated dicyclic or tricyclic condensed hydrocarbon group, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
[505] T ¹ represents a carbonyl group, a sulfonyl group or a group -C (= 0) -C (= 0) -N (R ')-(wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group). ], Their salts, their solvates or their N-oxides.
[506] (C) Formula 1
[507]
[508] [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
[509] Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
[510] Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, and a substituent A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a divalent saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, and
[511] Q ³ is
[512]
[513] (In the group, Q ⁵ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-.
[514] R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group which may have an alkyl group and a substituent, an aryl group, an aralkyl group, heteroa Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo Substituted on a 3-6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an alkyl group which may have a nil group, a substituent That may have an N, N- di-alkyl-carbamoyl-acyl, N, which may have a substituent on the alkyl N- di-alkyl-carbamoyl-alkyl sulfonyl group or an alkyl-sulfonyl or represents an acyl group, or R ³ and R ⁴ together represents an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group having 1 to 5 carbon atoms or a carbonyldioxy group.);
[515] Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, heteroaryl with or without a substituent An alkenyl group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
[516] T ¹ represents a carbonyl group, sulfonyl group, group -C (= 0) -C (= 0) -N (R ')-(wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group- C (= O) -A ¹ -N (R ")-(wherein A ¹ represents an alkylene group having 1 to 5 carbon atoms with or without a substituent, and R '' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group ), Group -C (= O) -NH-, group -C (= S) -NH-, group -C (= O) -NH-NH-, group -C (= O) -A ^2- C (= 0)-(wherein, A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), and the group -C (= 0) -A ³ -C (= 0) -NH- (in the group And A ³ represents an alkylene group having 1 to 5 carbon atoms.) Or a thiocarbonyl group.], A salt thereof, a solvate thereof or an N-oxide thereof.
[517] (D) Formula 1
[518]
[519] [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
[520] Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
[521] Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, and a substituent A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a divalent saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, and
[522] Q ³ is
[523]
[524] (In the group, Q ⁵ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-.
[525] R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group which may have an alkyl group and a substituent, an aryl group, an aralkyl group, heteroa Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo Substituted on a 3-6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an alkyl group which may have a nil group, a substituent That may have an N, N- di-alkyl-carbamoyl-acyl, N, which may have a substituent on the alkyl N- di-alkyl-carbamoyl-alkyl sulfonyl group or an alkyl-sulfonyl or represents an acyl group, or R ³ and R ⁴ together represents an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group having 1 to 5 carbon atoms or a carbonyldioxy group.);
[526] Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, heteroaryl with or without a substituent An alkenyl group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
[527] T ⁰ represents a carbonyl group or a thiocarbonyl group;
[528] T ¹ represents a carbonyl group, a sulfonyl group, a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(where R 'is a hydrogen atom , represents a hydroxyl group, alkyl group or alkoxy group), group ^{-C (= O) -A 1 -N} (R ") -. ( group of, a ¹ represents an alkylene group having 1 to 5 carbon atoms which may have a substituent , R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C (= O) -NH-, a group -C (= S) -NH-, a group -C (= O) -NH-NH -, Group -C (= O) -A ² -C (= O)-(wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), and the group -C (= O) -A ³ -C (= O) -NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms), the group -C (= O) -C (= NOR ^a ) -N (R ^b )- R ^a represents a hydrogen atom, an alkyl group, or an alkanoyl group in the group -C (= S) -C (= NOR ^a ) -N (R ^b )-(group, R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or An alkoxy group.), A group -C (= O) -N = N-, a group -C (= S) -N = N- or a thiocarbonyl group.]. A compound, salt thereof, a solvate thereof, or N- oxide thereof.
[529] (E) Formula 1
[530]
[531] [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
[532] Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
[533] Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, and a substituent A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a divalent saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, and
[534] Q ³ is
[535]
[536] (In the group, Q ⁵ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-.)));
[537] R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group which may have an alkyl group and a substituent, an aryl group, an aralkyl group, heteroa Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo Substituted on a 3-6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an alkyl group which may have a nil group, a substituent That may have an N, N- di-alkyl-carbamoyl-acyl, N, which may have a substituent on the alkyl N- di-alkyl-carbamoyl-alkyl sulfonyl group or an alkyl-sulfonyl or represents an acyl group, or R ³ and R ⁴ together represents an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group having 1 to 5 carbon atoms or a carbonyldioxy group.);
[538] Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, heteroaryl with or without a substituent An alkenyl group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
[539] T ⁰ represents a carbonyl group or a thiocarbonyl group;
[540] T ¹ represents a carbonyl group, a sulfonyl group, a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(where R 'is a hydrogen atom , represents a hydroxyl group, alkyl group or alkoxy group), group ^{-C (= O) -A 1 -N} (R ") -. ( group of, a ¹ represents an alkylene group having 1 to 5 carbon atoms which may have a substituent , R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C (= O) -NH-, a group -C (= S) -NH-, a group -C (= O) -NH-NH -, Group -C (= O) -A ² -C (= O)-(wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), and the group -C (= O) -A ³ -C (= O) -NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms), the group -C (= O) -C (= NOR ^a ) -N (R ^b )- R ^a represents a hydrogen atom, an alkyl group, or an alkanoyl group in the group -C (= S) -C (= NOR ^a ) -N (R ^b )-(group, R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or An alkoxy group.), A group -C (= O) -N = N-, a group -C (= S) -N = N- or a thiocarbonyl group.]. A compound, salt thereof, a solvate thereof, or N- oxide thereof.
[541] Although this invention is demonstrated to the following by a reference example, an Example, and a test example, this invention is not limited to this at all.
[542] Reference Example 1 Pyridin-4-ylcarbamic acid tert-butyl ester
[543]
[544] 4-aminopyridine (10 g) was dissolved in tetrahydrofuran (500 ml), di-tert-butyl dicarbonate (25.5 g) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the precipitated solid was washed with hexane to obtain the title compound (16.9 g).
[545]
[546] Reference Example 2 3-Sulfanylpyridin-4-ylcarbamic acid tert-butyl ester
[547]
[548] The compound (61.6 g) obtained in Reference Example 1 was dissolved in tetrahydrofuran (2000 ml) and stirred at -78 ° C for 10 minutes. After n-butyllithium (1.59 prescribed hexane solution, 500 ml) was added dropwise to the reaction solution, the mixture was stirred for 10 minutes, and then stirred under ice cooling for 2 hours. After cooling the reaction solution to -78 ° C, sulfur powder (12.2 g) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. Water (1000 ml) was added to the reaction solution and the mixture was separated. 3N hydrochloric acid was added to the aqueous layer to adjust the pH to 3-4, and methylene chloride was added thereto for separation. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1) to give the title compound (33.2 g).
[549]
[550] Reference Example 3 Thiazolo [5,4-c] pyridine
[551]
[552] The compound (33.2 g) obtained in Reference Example 2 was dissolved in formic acid (250 ml) and heated to reflux for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was separated by adding 5 ml aqueous potassium hydroxide solution (100 ml) and diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain the title compound (9.03 g).
[553]
[554] Reference Example 4 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine
[555]
[556] The compound (1.61 g) obtained in the reference example 3 was dissolved in N, N-dimethylformamide (50 ml), methyl iodide (1.50 ml) was added, and it stirred at 80 degreeC for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (100 ml), sodium borohydride (1.53 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and an aqueous saturated potassium carbonate solution and diethyl ether were added to the residue. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain the title compound (1.28 g).
[557]
[558] Reference Example 5 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt
[559]
[560] The compound (6.43 g) obtained in the reference example 4 was dissolved in anhydrous tetrahydrofuran (200 ml), n-butyllithium (1.47 regulatory hexane solution, 34.0 ml) was dripped at -78 degreeC, and it stirred for 40 minutes. Carbon dioxide gas was introduced to the reaction solution at -78 ° C for 1 hour, and then the temperature was raised to room temperature, and the reaction solution was concentrated under reduced pressure to obtain the title compound (9.42 g).
[561]
[562] Reference Example 6 2-Amino-6,7-dihydrothiazolo [5,4-c] pyridine-5 [4H] -carboxylic acid tert-butyl ester
[563]
[564] Dissolve 1-tert-butoxycarbonyl-4-piperidone (40.0 g) in cyclohexane (80 ml), add p-toluenesulfonic acid monohydrate (191 mg) and pyrrolidine (17.6 ml) It was heated to reflux for 2 hours while dehydrating with a stark apparatus. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (60 ml) and sulfur powder (6.42 g) was added. Under ice-cooling, a methanol solution (10 ml) of cyanamide (8.44 g) was slowly added dropwise and stirred at room temperature for 5 hours. The precipitated solid was collected by filtration to give the title compound (31.0 g).
[565]
[566] Reference Example 7 2-Bromo-6,7-dihydrothiazolo [5,4-c] pyridine-5- [4H] -carboxylic acid tert-butyl ester
[567]
[568] Copper (II) bromide (1.05 g) was suspended in N, N-dimethylformamide (20 ml), tert-butyl nitrite (0.696 ml) and the compound obtained in Reference Example 6 (1.00 g) were added under ice-cooling, The reaction solution was heated and stirred at 40 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 5) to obtain the title compound (568 mg).
[569]
[570] Reference Example 8 2-Bromo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine trifluoroacetate
[571]
[572] The compound (890 mg) obtained in Reference Example 7 was dissolved in methylene chloride (2 ml), trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 30 seconds. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (867 mg).
[573]
[574] Reference Example 9 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine
[575]
[576] The compound (422 mg) obtained in Reference Example 8 was suspended in methylene chloride (10 ml), and dissolved by addition of triethylamine (0.356 ml), followed by acetic acid (0.216 ml) and aqueous formaldehyde solution (35% solution, 0.202 ml). Sodium triacetoxy borohydride (428 mg) was added sequentially, and it stirred at room temperature for 1 hour. Saturated sodium hydrogencarbonate aqueous solution (100 ml), methylene chloride (100 ml), and 3 prescribed sodium hydroxide aqueous solutions (3 ml) were added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain the title compound (286 mg).
[577]
[578] Reference Example 10 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt
[579]
[580] The compound (531 mg) obtained in Reference Example 9 was dissolved in anhydrous diethyl ether (20 ml), n-butyllithium (1.54 hexane solution, 1.63 ml) was added dropwise at -78 ° C, and stirred for 30 minutes under ice-cooling. Carbon dioxide gas was introduced to the reaction solution at -78 ° C for 10 minutes, and the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure to give the title compound (523 mg).
[581]
[582] Reference Example 11 2-[(E) -2-phenylethenyl] oxazole-4-carboxylic acid ethyl ester
[583]
[584] It was synthesized according to the report of Panek et al. (J. Org. Chem., 1996, vol. 61, page 6496). To a solution of tetrahydrofuran (250 ml) of cinnamic acid amide (10.0 g) was added sodium bicarbonate (22.8 g) and ethyl bromopyruvate (10.5 ml) at room temperature to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to obtain a residue. To this tetrahydrofuran (30 ml) solution was added trifluoroacetic anhydride (30 ml) at 0 ° C, and the temperature was gradually raised to room temperature. After stirring for 63 hours, saturated aqueous sodium hydrogen carbonate solution (500 ml) and acetic acid ethyl ester (150 ml) were added to the reaction mixture, and the aqueous layer was extracted with acetic acid ethyl ester (150 ml). The combined organic layers were washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ethyl acetate = 5: 1 → 3: 1) to give the title compound ( 10.9 g) was obtained.
[585]
[586] Reference Example 12 2-[(E) -2-phenylethenyl] oxazole-4-carbaldehyde
[587]
[588] To a methylene chloride (80 ml) solution of the compound (8.57 g) obtained in Reference Example 11, diisobutylaluminum hydride (1.0 hexane solution, 66 ml) was added dropwise at -78 ° C. After stirring for 15 minutes, methanol (11 ml) was added dropwise and the temperature was raised to room temperature over 1 hour. The reaction mixture was filtered through Celite, the resulting paste was dissolved in ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml) and separated, and the aqueous layer was extracted with methylene chloride (2 x 100 ml). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml), combined with the filtrate during Celite filtration, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate ethyl ester = 5: 1-methylene chloride: methanol = 10: 1) to obtain the title compound (5.86 g).
[589]
[590] Reference Example 13 2-[(E) -2-phenylethenyl] -4-vinyloxazole
[591]
[592] To a tetrahydrofuran (80 ml) solution of brominated (methyl) triphenylphosphonium (8.16 g) was added dropwise n-butyllithium (1.54 hexane solution, 14.2 ml) at 0 ° C and stirred for 30 minutes at room temperature. The reaction mixture was cooled to 0 ° C., a tetrahydrofuran (20 ml) solution of the compound (3.64 g) obtained in Reference Example 12 was added thereto, and the temperature was raised to room temperature. After stirring for 2 hours, water (200 ml) and acetic acid ethyl ester (100 ml) were added and separated, and the aqueous layer was extracted with acetic acid ethyl ester (50 ml). The combined organic layers were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 1) to obtain the title compound (2.84 g).
[593]
[594] Reference Example 14 2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} -1-ethanol
[595]
[596] To tetrahydrofuran (500 ml) solution of the compound (13.0 g) obtained in Reference Example 13, 9-borabicyclo [3.3.1] nonane (0.5 prescribed tetrahydrofuran solution, 158 ml) was added at 0 ° C. The mixture was stirred at room temperature for 15 hours. Water (10 ml), 3 prescribed sodium hydroxide solutions (80 ml) and hydrogen peroxide solution (80 ml) were added dropwise to the reaction mixture at 0 ° C, and the mixture was stirred at room temperature for 6 hours. Water (600 ml) and acetic acid ethyl ester (200 ml) were added to the reaction mixture, and the aqueous layer was extracted with acetic acid ethyl ester (200 ml). The combined organic layers were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-ethyl acetate only) to give the title compound (14.1 g).
[597]
[598] Reference Example 15 2- (2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} ethyl) -1H-isoindole-1,3 (2H) -dione
[599]
[600] To a tetrahydrofuran (15 ml) solution of the compound (292 mg) obtained in Reference Example 14, phthalimide (200 mg), triphenylphosphine (357 mg) and diethyl azodicarboxylic acid (0.214 ml) were added at room temperature. It was added and stirred for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (447 mg).
[601]
[602] Reference Example 16 2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} ethylcarbamic acid tert-butyl ester
[603]
[604] To the ethanol (150 ml) solution of the compound (6.40 g) obtained in Reference Example 15, hydrazine monohydrate (1.50 ml) was added at room temperature and stirred for 1 hour, followed by addition of hydrazine monohydrate (0.500 ml) at room temperature, followed by stirring for 2 hours. . Methylene chloride (150 ml), saturated aqueous sodium hydrogencarbonate solution (150 ml) and di-tert-butyldicarbonate (13.4 g) were added to the reaction mixture at room temperature. After stirring for 30 minutes, the mixture was separated and the aqueous layer was extracted with methylene chloride (50 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 2: 1 → 1: 1) to give the title compound (5.06 g).
[605]
[606] Reference Example 17 2-[(E) -2-phenylethenyl] -6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester
[607]
[608] Paraformaldehyde (54.5 mg) and p-toluenesulfonic acid (7.2 mg) were added to a toluene (15 ml) solution of the compound (190 mg) obtained in Reference Example 16 at room temperature. After heating to reflux for 1 hour, the mixture was allowed to cool, and the reaction mixture was separated by adding ethyl acetate (15 ml) and saturated aqueous sodium hydrogen carbonate (15 ml). The aqueous layer was extracted with ethyl acetate (10 ml), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-2: 1) to obtain the title compound (153 mg).
[609]
[610] Reference Example 18 2-formyl-6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester
[611]
[612] To a tetrahydrofuran (16 ml) solution of compound (803 mg) obtained in Reference Example 17, acetone (8.0 ml), water (4.0 ml), N-methylmorpholine, N-oxide (577 mg) and 0.039 mole yarn An aqueous osmium oxide solution (3.20 ml) was added at room temperature and stirred overnight. Ethyl acetate (50 ml) and 10% aqueous sodium thiosulfate solution (50 ml) were added to the reaction mixture, and the aqueous layer was extracted with acetic acid ethyl ester (30 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the tetrahydrofuran (16 ml) solution of the residue was added methanol (8.0 ml), water (8.0 ml) and sodium metaiodate (790 mg) at room temperature. After stirring for 3 hours, acetic acid ethyl ester (30 ml) and water (50 ml) were added to the reaction mixture, and the aqueous layer was extracted with acetic acid ethyl ester (20 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-2: 1) to obtain the title compound (234 mg). This aldehyde was unstable and was used for the next reaction.
[613]
[614] Reference Example 19 6,7-Dihydrooxazolo [5,4-c] pyridine-2,5 (4H) -dicarboxylic acid 5- (tert-butyl) 2-methyl ester
[615]
[616] Sodium cyanide (220 mg) and manganese dioxide (780 mg) were added to a methanol (9.0 ml) solution of the compound (225 mg) obtained in Reference Example 18 at room temperature, followed by stirring for 30 minutes, followed by celite filtration using ethyl acetate. The filtrate was washed with water (50 ml) and saturated brine (50 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 2 → 1: 1) to give the title compound (120 mg).
[617]
[618] Reference Example 20 5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid methyl ester
[619]
[620] Trifluoroacetic acid (15 ml) was added to a solution of methylene chloride (15 ml) of the compound (500 mg) obtained in Reference Example 19, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with methylene chloride (20 ml), triethylamine (0.495 ml), acetic acid (205 ml), formalin (0.230 ml) and sodium triacetoxyborohydride (570 mg). Was added in. After stirring for 15 minutes, methylene chloride (20 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) were added to the reaction mixture, and the aqueous layer was extracted with methylene chloride (3 x 20 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1-&gt; 10: 1) to obtain the title compound (257 mg).
[621]
[622] Reference Example 21 5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid lithium salt
[623]
[624] To a tetrahydrofuran (24 ml) solution of the compound (800 mg) obtained in Reference Example 20, water (6.0 ml) and lithium hydroxide (99.7 mg) were added at room temperature, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (825 mg).
[625]
[626] Reference Example 22 5-Chloro-6-fluoroindole-2-carboxylic acid methyl ester
[627]
[628] After a mixture of 3-chloro-4-fluoro-α-azide cinnamic acid methyl ester (JP-A-7-149723) (1.85 g) and xylene (140 ml) was heated under reflux for 1 hour. The solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride) to give the title compound (491 mg).
[629]
[630] Reference Example 23 5-Chloro-6-fluoroindole-2-carboxylic acid
[631]
[632] The compound (461 mg) obtained in Reference Example 22 was dissolved in a mixed solvent of tetrahydrofuran (15 ml), methanol (10 ml) and water (10 ml), and lithium hydroxide (283 mg) was added at room temperature, followed by stirring for 4 hours. It was. The solvent was distilled off under reduced pressure, 1N hydrochloric acid was added to the residue, the powder obtained by being slightly acidic was collected by filtration and dried to obtain the title compound (422 mg).
[633]
[634] Reference Example 24 5- (Pyridin-4-yl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine
[635]
[636] 1) Phosphorous pentasulphide (500 g) was suspended in formamide (3000 ml) under ice-cooling and stirred overnight. Water and diethyl ether were added to the reaction solution, and liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oily substance. 3-chloro-4-oxo-1-piperidinecarboxylic acid ethyl ester (150 g) dissolved in n-butanol (350 ml) and synthesized by the method described in the literature (Tetrahedron, 1983, Vol. 39, p. 3767). ) Was added, followed by stirring at 100 ° C for 2.5 hours. The reaction solution was filtered through Celite and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (methylene chloride to ethyl acetate ethyl hexane: hexane = 1: 2) to give 6,7-dihydrothiazolo [5,4-c] pyridine-5 (4H) -carr Acid ethyl ester (79.0 g) was obtained.
[637]
[638] 2) To the product (33.5 g) was added 3.5 ml sodium hydroxide aqueous solution (250 ml) and heated to reflux overnight. After cooling the reaction solution to room temperature, di-tert-butyldicarbonate (103 g) was added under ice-cooling, and it stirred at room temperature overnight. After the addition of 3N hydrochloric acid to the reaction solution to adjust the pH to 1 to 2, methylene chloride was added to carry out a liquid separation operation. The organic layer was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine in that order, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 2) to give 6,7-dihydrothiazolo [5,4-c] pyridine-5 (4H) -carr Acid tert-butyl ester (21.1 g) was obtained.
[639]
[640] 3) Trifluoroacetic acid (25 ml) was added to a methylene chloride (25 ml) solution of the compound (5.00 g) obtained in 2) above at room temperature. After stirring for 10 minutes, the reaction solution was concentrated under reduced pressure. 4-Bromopyridine (5.20 g), N, N-dimethylformamide (30 ml) and triethylamine (15.5 ml) were added to the residue at room temperature, stirred at 150 ° C for 2 days, and allowed to cool to room temperature. The resulting colorless precipitate was separated by filtration and the filtrate was concentrated under reduced pressure, then methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml) were added and the aqueous layer was saturated with salt. After separating, the aqueous layer was extracted with methylene chloride (5 x 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 8: 1) to give the title compound (2.97 g).
[641]
[642] Reference Example 25 2-Chloro-6,7-dihydro-4H-pyrano [4,3-d] thiazole
[643]
[644] 1) Tetrahydro-4H-pyran-4-one (5.0 g) was dissolved in cyclohexane (20 ml), pyrrolidine (4.35 ml) and p-toluenesulfonic acid monohydrate (48 mg) were added to Dean Stark. Heated to reflux for 70 minutes while removing water with the apparatus. The reaction solution was cooled to room temperature, the supernatant was aliquoted and concentrated under reduced pressure. The residue was dissolved in methanol (15 ml), sulfur powder (1.60 g) was added under water cooling, and after 15 minutes, methanol solution (10 ml) of cyanoamide (2.10 g) was added dropwise over 20 minutes and stirred for 3 days. It was. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 10: 1 → 4: 1) to give 6,7-dihydro-4H-pyrano [4,3-d ] Thiazol-2-ylamine (3.97 g) was obtained.
[645]
[646] 2) Copper (II) chloride (4.10 g) was dissolved in acetonitrile (50 ml) and tert-butyl nitrite (3.93 g) was added at once under water cooling. After 10 minutes, the compound (3.97 g) obtained in the above reaction was added over about 1 hour and stirred at room temperature for 1 hour. Subsequently, the reaction solution was heated to 65 ° C and stirring was continued for 2 hours. Silica gel (20 g) was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was treated with silica gel column chromatography (hexane: ethyl acetate ethyl ester = 3: 1) to obtain the title compound (1.78 g).
[647]
[648] Reference Example 26 6,7-Dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid lithium salt
[649]
[650] 1) The compound (1.78 g) obtained in Reference Example 25 was dissolved in methanol (30 ml), 10% palladium carbon (300 mg) and sodium acetate (830 mg) were added, and the mixture was stirred for 5 days under 5 atmospheres of hydrogen. The catalyst was separated by filtration, the solvent was concentrated, and the residue was treated with silica gel column chromatography (hexane: acetic acid ethyl ester = 2: 1) to give 6,7-dihydro-4H-pyrano [4,3-d]. Thiazole (1.14 g) was obtained.
[651]
[652] 2) The product (1.14 g) was dissolved in diethyl ether (30 ml), cooled to -78 ° C, and 1.6 butyl lithium (6.6 ml) was added and stirred. After 20 minutes, carbon dioxide gas was introduced for 15 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure to obtain the title compound (1.65 g).
[653]
[654] Reference Example 27 Thiazolo [4,5-c] pyridine
[655]
[656] 3- (tert-butoxycarbonylamino) -4-mercaptopyridine (JP-A 4-321691) (9.20 g) was dissolved in formic acid (60 ml) and heated to reflux for 4 hours. . The reaction solution was concentrated under reduced pressure, and the residue was separated by adding 5 ml aqueous potassium hydroxide solution (100 ml) and diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (3.97 g).
[657]
[658] Reference Example 28 5-Methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine
[659]
[660] The title compound was obtained from the compound obtained in Reference Example 27 in the same manner as in Reference Example 4.
[661]
[662] Reference Example 29 5-Methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine-2-carboxylic acid lithium salt
[663]
[664] The title compound was obtained from the compound obtained in Reference Example 28 in the same manner as in Reference Example 5.
[665]
[666] Reference Example 30 2-Chloro-N, N-dimethyl-4,5,6,7-tetrahydro-benzothiazole-6-amine
[667]
[668] 2-chloro-4,7-dihydro-1,3-benzothiazol-6 (5H) -one (Helv. Cim. Acta., 1994, Vol. 77, p. 1256) (2.0 g) was added to methanol (100 g). ml), ammonium acetate (8.2 g) and sodium cyanoborohydride (4.0 g) were added, and the mixture was heated to reflux for 20 hours. Hydrochloric acid was added to the reaction solution to decompose excess sodium cyanoborohydride, and the solvent was distilled off under reduced pressure, made alkaline with 1N sodium hydroxide solution, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil. This oily substance was dissolved in methanol (50 ml), an aqueous formaldehyde solution (4.29 g) and sodium cyanoborohydride (3.49 g) were added, followed by stirring at room temperature for 12 hours. The solvent was distilled off under reduced pressure, methylene chloride was added, the mixture was washed with saturated sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to obtain the title compound (740 mg).
[669]
[670] Reference Example 31 6- (dimethylamino) -4,5,6,7-tetrahydrobenzothiazole-2-carboxylic acid lithium salt
[671]
[672] The compound (750 mg) obtained in Reference Example 30 was dissolved in diethyl ether (15 ml), cooled to −78 ° C., and stirred for 20 minutes by addition of 1.5 N-tert-butyllithium (3.5 ml), followed by stirring of carbon dioxide gas. Introduced for 15 minutes. The title compound was obtained by returning the reaction solution to room temperature and concentrating under reduced pressure.
[673]
[674] Reference Example 32 2-Amino-4,6-dihydro-5H-pyrrolo [3,4-d] thiazole-5-carboxylic acid tert-butyl ester
[675]
[676] 1-tert-butoxycarbonyl-3-pyrrolidone (1.58 g) was dissolved in cyclohexane (10 ml), p-toluenesulfonic acid monohydrate (8.12 mg) and pyrrolidine (607 mg) were added It was heated to reflux for 1.5 hours while dehydrating with a Dean Stark apparatus. The supernatant was aliquoted and concentrated under reduced pressure, and then the residue was dissolved in methanol (5 ml), sulfur powder (274 mg) was added, and the mixture was stirred for 15 minutes under ice cooling. Cyanamide (377 mg) methanol solution (2 ml) was slowly added dropwise to the reaction mixture, which was stirred overnight at room temperature. The mixture was heated to reflux for 2 hours, and the reaction solution was concentrated. Then, methylene chloride and saturated aqueous sodium hydrogen carbonate were added, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 39) to obtain the title compound (248 mg).
[677]
[678] Reference Example 33 2-Bromo-4,6-dihydro-5H-pyrrolo [3,4-d] thiazole-5-carboxylic acid tert-butyl ester
[679]
[680] Copper (II) bromide (445 mg) was suspended in N, N-dimethylformamide, and tert-butyl nitrite (256 mg) was added dropwise at room temperature. Under ice-cooling, an N, N-dimethylformamide solution (1 ml) of the compound (400 mg) obtained in Reference Example 32 was added, and the reaction solution was stirred at 60 ° C for 1.5 hours. Diethyl ether and saturated brine were added to the reaction mixture, and the organic layer was dried over anhydrous magnesium sulfate. Concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to give the title compound (174 mg).
[681]
[682] Reference Example 34 5- (tert-Butoxycarbonyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt
[683]
[684] In the same manner as in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 7.
[685]
[686] Reference Example 35 2-Bromo-4- (2-methoxy-2-oxoethyl) thiazole-5-carboxylic acid methyl ester
[687]
[688] To acetonitrile (500 ml) solution of tert-butyl nitrite (15.5 g) was added copper (II) bromide (26.8 g) at once under ice cooling. To this reaction solution, acetonitrile solution (500 ml) of 2-amino-5-methoxycarbonyl-4-thiazole acetate methyl ester (Pharmaceutical magazine, 1966, 86 volumes, 300 pages) (23.0 g) was 45 minutes. It was dripped over, and it stirred for 1 hour and room temperature for 30 minutes under ice-cooling. The reaction solution was concentrated, 10% hydrochloric acid and diethyl ether were added to the residue, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to obtain the title compound (25.9 g).
[689]
[690] Reference Example 36 2- [5- (hydroxymethyl) thiazol-4-yl] -1-ethanol
[691]
[692] A tetrahydrofuran (500 ml) solution of the compound (23.4 g) obtained in Reference Example 35 was added dropwise over 1 hour to a tetrahydrofuran (500 ml) suspension of lithium aluminum hydride (9.03 g) under ice cooling. After stirring for 1 hour under ice cooling, water (9 ml), 35% aqueous sodium hydroxide solution (9 ml) and water (27 ml) were added in this order and stirred at room temperature for 1 hour. Anhydrous magnesium sulfate was added to the reaction mixture, after stirring, the insolubles were removed by Celite filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 7: 93) to give the title compound (8.64 g).
[693]
[694] Reference Example 37 Methanesulfonic Acid 2- (5-{[(methylsulfonyl) oxy] methyl} thiazol-4-yl) ethyl ester
[695]
[696] In a solution obtained by dissolving the compound (8.64 g) and triethylamine (45.4 ml) obtained in Reference Example 36 in methylene chloride (500 ml), methanesulfonyl chloride (12.6 ml) methylene chloride solution at -78 ° C was added for 20 minutes. It was dripped over. After 15 minutes at -78 ° C and 1 hour at 0 ° C, water was added to separate the organic layer and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (13.4 g).
[697]
[698] Reference Example 38 5- (1-Methylcyclopropyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine
[699]
[700] To methylene chloride (20 ml) containing the compound obtained in Reference Example 37 (4.46 g), 1-methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, Vol. 54, p. 1815) under ice cooling (1.89 g) ) Was added and stirred overnight at room temperature. Furthermore, 1-methylcyclopropylamine hydrochloride (1.89 g) was added, and it heated and refluxed further at room temperature for 20 hours, and stirred for 5 hours. Methylene chloride and water were added to the reaction mixture, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 49) to obtain the title compound (944 mg).
[701]
[702] Reference Example 39 5- (1-Methylcyclopropyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt
[703]
[704] The title compound was obtained from the compound obtained in Reference Example 38 in the same manner as in Reference Example 5.
[705]
[706] Reference Example 40 2- [6,7-Dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] -2-methyl-1-propanol
[707]
[708] In the same manner as in Reference Example 38, the title compound was obtained from the compound obtained in Reference Example 37 and 2-amino-2-methyl-1-propanol.
[709]
[710] Reference Example 41 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridine
[711]
[712] To the N, N-dimethylformamide (5 ml) solution of the compound (1.24 g) obtained in Reference Example 40, tert-butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg) were added and stirred overnight at room temperature. . Water and diethyl ether were added to the reaction mixture, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 1: 2) to obtain the title compound (2.46 g).
[713]
[714] Reference Example 42 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridine-2-carboxylic acid lithium salt
[715]
[716] The title compound was obtained from the compound obtained in Reference Example 41 in the same manner as in Reference Example 5.
[717]
[718] Reference Example 43 4,7,8,10-Tetrahydro-6H-pyrazolo [1,2-a] thiazolo [4,5-d] pyridazine
[719]
[720] 1) 4,5-dimethylthiazole (5.00 g), N-bromosuccinimide (15.7 g) and α, α'-azobisisobutyronitrile (362 mg) were diluted with ethylene dichloride (500 ml) at room temperature. ) Was heated to reflux for 1 hour. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: diethyl ether = 1: 4) to give 4,5-bis (bromomethyl) thiazole (5.24 g).
[721]
[722] 2) 4,5-bis (bromomethyl) thiazole (1.37 g) and 1,2-trimethylenehydrazine hydrochloride (WO9532965) (732 mg) were suspended in ethanol (15 ml) under ice-cooling to give triethylamine (2.82). ml) was added dropwise over 5 minutes. After stirring for 2 hours at room temperature, the solvent was distilled off, and an organic layer was separated by adding methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution to the residue, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 47) to obtain the title compound (358 mg).
[723]
[724] Reference Example 44 4,7,8,10-Tetrahydro-6H-pyrazolo [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt
[725]
[726] The title compound was obtained from the compound obtained in Reference Example 43 in the same manner as in Reference Example 5.
[727]
[728] Reference Example 45 4,6,7,8,9,11-hexahydropyridazino [1,2-a] thiazolo [4,5-d] pyridazine
[729]
[730] In the same manner as in Reference Example 43, the title compound was obtained from 4,5-bis (bromomethyl) thiazole (2.20 g) and 1,2-tetramethylenehydrazine hydrochloride (US5726126) obtained in 1) of Reference Example 43.
[731]
[732] Reference Example 46 4,6,7,8,9,11-hexahydropyridazino [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt
[733]
[734] The title compound was obtained from the compound obtained in Reference Example 45 in the same manner as in Reference Example 5.
[735] Reference Example 47 2- (Methylsulfanyl) -5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester
[736]
[737] 1- (tert-butoxycarbonyl) -3-pyrrolidone (4.57 g) was added N, N-dimethylformamide dimethylacetal (30 ml) at room temperature and heated at 140 ° C for 1 hour. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. Hexane was added to the residue, and the precipitated yellow powder was collected by filtration, dissolved in ethanol (100 ml) and heated to the solution by adding methylisothiourea sulfate (9.24 g) and sodium ethoxide (4.52 g) at room temperature for 24 hours. It was refluxed. Saturated brine and diethyl ether were added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. Concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 99) to give the title compound (1.10 g).
[738]
[739] Reference Example 48 2- (methylsulfonyl) -5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester
[740]
[741] To methylene chloride solution (20 ml) of the compound (1.08 g) obtained in Reference Example 47, m-chloro perbenzoic acid (1.99 g) was added under ice cooling, and the mixture was stirred for 5 hours. After saturated aqueous sodium sulfite solution, saturated aqueous sodium hydrogencarbonate solution and methylene chloride were added to the reaction solution, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, and the precipitated powder was collected by filtration to obtain the title compound (1.09 g).
[742]
[743] Reference Example 49 2-Cyano-5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester
[744]
[745] Tetrabutylammonium cyanide (1.04 g) was added to a methylene chloride (30 ml) solution of the compound (1.05 g) obtained in Reference Example 48, and the mixture was stirred at room temperature for 1 hour. 1 N sodium hydroxide was added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: acetone = 20: 1) to obtain the title compound (776 mg).
[746]
[747] Reference Example 50 5,7-Dihydro-6H-pyrrolo [3,4-d] pyrimidine-2,6-dicarboxylic acid 6- (tert-butyl) 2-methyl ester
[748]
[749] To the methanol (10 ml) solution of the compound (776 mg) obtained in Reference Example 49, concentrated hydrochloric acid (5 ml) was added at room temperature, followed by stirring at 100 ° C for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml), and triethylamine (2.20 ml) and di-tert-butyldicarbonate (1.37 g) were added and stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, followed by separation by adding methylene chloride and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 97) to give the title compound (317 mg).
[750]
[751] Reference Example 51 5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt
[752]
[753] 1) 4,5-bis (bromomethyl) thiazole (600 mg) obtained in 1) of Reference Example 43 was dissolved in ethanol (20 ml), and 1,2-dimethylhydrazine hydrochloride (294 mg) was dissolved under ice cooling. After addition, triethylamine (1.23 ml) was added in one portion, and stirred at room temperature for 30 minutes and at 50 ° C for 30 minutes. The solvent was distilled off and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to give 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine (90 mg) was obtained.
[754]
[755] 2) The title compound was obtained from [4,5-d] pyridazine with 5,6-dimethyl-4,5,6,7-tetrahydrothiazole in the same manner as in Reference Example 5.
[756]
[757] Reference Example 52 5-Chloroindole-2-carboxylic Acid 4-Nitrophenyl Ester
[758]
[759] 5-chloroindole-2-carboxylic acid (20 g) is suspended in methylene chloride (1500 ml), N, N-dimethylformamide (2 ml) is added, and thionyl chloride (11 ml) is added dropwise at room temperature. It was. The reaction solution was heated to reflux overnight, and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (1000 ml), triethylamine (84.7 ml) was added under ice cooling, and then p-nitrophenol (14.2 g) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate and 0.2N hydrochloric acid were added to the residue to carry out a liquid separation operation. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (29.9 g).
[760]
[761] Reference Example 53 6-Chloro-2-quinolinecarbonitrile
[762]
[763] 6-chloroquinoline (2.50 g) was dissolved in methylene chloride (25 ml), m-chloro perbenzoic acid (3.71 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After dilution with methylene chloride, the mixture was washed with aqueous sodium thiosulfate solution and aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride (40 ml), trimethylsilyl cyanide (2.0 ml) and N, N-dimethylcarbamoyl chloride (1.50 ml) were added, and the mixture was heated to reflux for 9 hours. Further trimethylsilyl cyanide (1.0 ml) and N, N-dimethylcarbamoyl chloride (0.80 ml) were added and refluxed for 16 hours, followed by dilution with methylene chloride and 10% aqueous potassium carbonate solution (40 ml), followed by stirring for 30 minutes. It was. The organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Methylene chloride was added to the residue, and the precipitated crystals were collected by filtration to obtain the title compound (1.77 g). The mother liquor was further concentrated and purified by silica gel column chromatography (methylene chloride) to give the title compound (0.80 g).
[764]
[765] Reference Example 54 6-Chloro-2-quinolinecarboxylic acid
[766]
[767] The compound (1.73 g) obtained in Reference Example 53 was dissolved in concentrated hydrochloric acid (40 ml), and heated to reflux for 19 hours. The precipitate was collected at room temperature, collected by filtration, and washed with water to obtain the title compound (1.81 g).
[768]
[769] Reference Example 55 3- (4-Chlorophenyl) -2- (formylamino) propionic acid methyl ester
[770]
[771] (±)-(4-chlorophenyl) alanine methyl ester hydrochloride (2.00 g) is suspended in methylene chloride (20 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.60 g) , 1-hydroxybenzotriazole monohydrate (1.23 g), N-methylmorpholine (1.90 ml) and formic acid (0.30 ml) were added, followed by stirring for 15 minutes. After adding formic acid (0.30 ml) and stirring for 15 minutes three times, the reaction solution was diluted with methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to give the title compound (1.21 g).
[772]
[773] Reference Example 56 7-Chloro-3-isoquinolinecarboxylic Acid Methyl Ester
[774]
[775] The compound (1.45 g) obtained in the reference example 55 was dissolved in methylene chloride (40 ml), and oxalyl chloride (0.57 ml) was added dropwise. After stirring at room temperature for 30 minutes, ferric chloride (1.17 g) was added at an external temperature of about -10 ° C, and stirred for 4 days at room temperature. 1N hydrochloric acid was added, diluted with methylene chloride and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (38 ml), concentrated sulfuric acid (2 ml) was added, and the mixture was heated to reflux for 20 hours. An aqueous sodium hydrogen carbonate solution was added, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 2: 1 → acetic acid ethyl ester) to obtain the title compound (0.25 g).
[776]
[777] Reference Example 57 7-Chloro-3-isoquinolinecarboxylic Acid Hydrochloride
[778]
[779] The compound (0.23 g) obtained in Reference Example 56 was dissolved in concentrated hydrochloric acid (10 ml) and heated to reflux for 18 hours. The temperature of the reaction solution was lowered to room temperature, and the precipitates were collected by filtration and washed with water to obtain the title compound (0.21 g).
[780]
[781] Reference Example 58 (3R) -1-Benzyl-3-{[tert-butyl (diphenyl) silyl] oxy} pyrrolidine
[782]
[783] (3R) -1-benzyl-3-hydroxypyrrolidine (500 μl) and imidazole (466 mg) were dissolved in N, N-dimethylformamide (15 ml) and tert-butyldiphenylsilyl under ice-cooling Chloride (1.57 ml) was added and stirred for 9 days at room temperature. The solvent was distilled off under reduced pressure, liquid separation was performed by adding methylene chloride and water to the residue, and then the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was treated by silica gel flash column chromatography (hexane: acetic acid ethyl ester = 3: 1) to give the title compound (1.27 g).
[784]
[785] Reference Example 59 N-[(1R ^* , 2S ^* )-2-Aminocyclopropyl] -5-chloroindole-2-carboxamide
[786]
[787] cis-1,2-cyclopropanediamine hydrochloride (J. Med. Chem., 1998, Vol. 41, pages 4723-4732) (405 mg) and N of 5-chloroindole-2-carboxylic acid (546 mg) 1-hydroxybenzotriazole monohydrate (377 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (642 mg) and diiso in, N-dimethylformamide (10 ml) solution Propylethylamine (1.95 ml) was added at room temperature and stirred for 50 hours. After the reaction mixture was concentrated under reduced pressure, methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (200 ml) were added thereto, and the precipitated colorless solid was separated by filtration. The filtrate was separated and the aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel flash column chromatography (methylene chloride; methanol = 100: 7 → 10: 1) to obtain the title compound (110 mg).
[788]
[789] Reference Example 60 N-[(1R ^* , 2S ^* )-2-Aminocyclobutyl] -5-chloroindole-2-carboxamide
[790]
[791] In the same manner as in Reference Example 59, the title compound was obtained from cis-1,2-cyclobutanediamine hydrochloride (J. Am. Chem. Soc., 1942, Vol. 64, pages 2696-2700).
[792]
[793] Reference Example 61 (1R ^* , 2R ^* )-2-Aminocyclopentylcarbamic acid tert-butyl ester
[794]
[795] (±) -trans-1,2-cyclopentanediamine (WO98 / 30574) (692 mg) is dissolved in methylene chloride (10 ml), triethylamine (1.1 ml), 2- (tert-part) at 0 ° C. Toxycarbonyloxyimino) -2-phenylacetonitrile (493 mg) was added, and it stirred at 0 degreeC for 1 hour. Thereafter, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (493 mg) was added and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 9: 1) to obtain the title compound (395 mg).
[796]
[797] Reference Example 62 N-[(1R ^* , 2R ^* )-2-Aminocyclopentyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Carboxamide Hydrochloride
[798]
[799] The compound obtained in Reference Example 61 (175 mg) was dissolved in N, N-dimethylformamide (3 ml), and 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-carboxylic acid lithium salt (purity 90%, 258 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (252 mg), 1-hydroxybenzotriazole monohydrate (60 mg) was added and stirred for 2 days at room temperature. The solvent was distilled off under reduced pressure with a pump, and the residue was separated by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 47: 3). The obtained pale yellow oily substance was dissolved in ethanol hydrochloride (5 ml), stirred at room temperature for 1 hour, and ethyl acetate was added thereto, and the solvent was concentrated under reduced pressure. Acetic acid ethyl ester was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (120 mg).
[800]
[801] Reference Example 63 N-[(1R ^* , 2R ^* )-2-Aminocyclopentyl] -5-chloro-1H-indole-2-carboxamide hydrochloride
[802]
[803] Compound (1.40 g) obtained in Reference Example 61 was dissolved in N, N-dimethylformamide (15 ml), and 5-chloroindole-2-carboxylic acid (1.64 g) and 1- (3-dimethylaminopropyl) 3-Ethylcarbodiimide hydrochloride (2.68 g) and 1-hydroxybenzotriazole monohydrate (473 mg) were added, followed by stirring at room temperature for 23 hours. The solvent was distilled off under reduced pressure, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the precipitate was collected by filtration. The precipitate was washed with acetic acid ethyl ester, methylene chloride, methanol. On the other hand, the filtrate was separated, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 19: 1) to obtain a pale yellow solid. The pale yellow solid and the precipitate obtained by filtration were combined, dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and methylene chloride and 1 N sodium hydroxide aqueous solution were added to the residue, and the precipitate was collected by filtration. The organic layer of the filtrate was aliquoted and dried over anhydrous sodium sulfate. A precipitate collected by filtration was added to this solution, and further 4 dioxane hydrochloric acid solution (20 ml) was added, and the solvent was distilled off under reduced pressure. Methylene chloride (10 ml) and tetrademic dioxane solution (10 ml) were added to the residue, and the solvent was distilled off again under reduced pressure. Ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (1.83 g).
[804]
[805] Reference Example 64 (1R ^* , 2R ^* )-2-Aminocyclohexylcarbamic acid tert-butyl ester
[806]
[807] The title compound was obtained from (±) -trans-1,2-cyclohexanediamine in the same manner as in Reference Example 61.
[808] m. p. 79-81 ° C.
[809]
[810] Reference Example 65 N-[(1R ^* , 2R ^* )-2-Aminocyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Carboxamide Trifluoroacetic Acid (and Hydrochloride)
[811]
[812] In the same manner as in Reference Example 62, the title compound was obtained from the compound obtained in Reference Example 64.
[813]
[814] In the same manner, hydrochloride was obtained.
[815] Reference Example 66 (1R ^* , 2S ^* )-2-Aminocyclohexylcarbamic acid tert-butyl ester
[816]
[817] The title compound was obtained from cis-1,2-cyclohexanediamine in the same manner as in Reference Example 61.
[818]
[819] Reference Example 67 N-[(1R ^* , 2S ^* )-2-Aminocyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Carboxamide Hydrochloride (and Trifluoroacetate)
[820]
[821] The title compound was obtained from the compound obtained in Reference Example 66 in the same manner as in Reference Example 62.
[822]
[823] In the same manner, trifluoroacetate was obtained.
[824] Reference Example 68 (1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester
[825]
[826] To a N, N-dimethylformamide (10 ml) solution of the compound (3.00 g) obtained in Reference Example 64, 5-chloroindole-2-carboxylic acid (2.88 g) and 1-hydroxybenzotriazole monohydrate (2.08) g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.95 g) were added at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and methylene chloride (30 ml), saturated aqueous sodium hydrogen carbonate solution (150 ml) and water (150 ml) were added to the obtained residue, and the resulting colorless precipitate was collected by filtration. And dried to obtain the title compound (5.21 g).
[827]
[828] Reference Example 69 N-[(1R ^* , 2R ^* )-2-Aminocyclohexyl] -5-chloroindole-2-carboxamide hydrochloride
[829]
[830] To a methylene chloride (100 ml) solution of the compound (5.18 g) obtained in Reference Example 68, an ethanol hydrochloride solution (100 ml) was added at room temperature. After stirring for 2 days, the reaction mixture was concentrated under reduced pressure, diethyl ether (300 ml) was added to the obtained residue, and the resulting colorless precipitate was collected by filtration and dried to obtain the title compound (4.30 g).
[831]
[832] Reference Example 70 (1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester
[833]
[834] The title compound was obtained from the compound obtained in Reference Example 66 in the same manner as in Reference Example 68.
[835]
[836] Reference Example 71 N-[(1R ^* , 2S ^* )-2-Aminocyclohexyl] -5-chloroindole-2-carboxamide hydrochloride
[837]
[838] In the same manner as in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 70.
[839]
[840] Reference Example 72 (1R ^* , 2R ^* )-1,2-cycloheptanediol
[841]
[842] Cycloheptene (3.85 g) was added to 30% hydrogen peroxide (45 ml) and 88% formic acid (180 ml) in small portions, and stirred at 40-50 ° C. for 1 hour, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure and 35% sodium hydroxide solution was added to the residue to make it alkaline. After stirring this for 10 minutes at 40-50 degreeC, acetic acid ethyl ester was added and liquid-separated, and extraction operation was performed 4 times with acetic acid ethyl ester from the water layer. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound (4.56 g).
[843]
[844] Reference Example 73 (1R ^* , 2R ^* )-1,2-cycloheptandiamine hydrochloride
[845]
[846] The compound (4.56 g) obtained in Reference Example 72 was dissolved in methylene chloride (35 ml), and triethylamine (29 ml) was added and cooled to -78 ° C. Methanesulfonyl chloride (8.13 ml) was added dropwise thereto. Methylene chloride (10 ml) was added and the mixture was stirred at the same temperature for 20 minutes, followed by stirring at 0 ° C for 1.5 hours. Water was added to the reaction solution, the mixture was separated, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance. This was dissolved in N, N-dimethylformamide (90 ml), sodium azide (13.65 g) was added, and the mixture was stirred at 65 ° C for 18 hours. Diethyl ether and water were added to the reaction mixture, and the diethyl ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance.
[847] This was dissolved in ethanol (70 ml), 10% palladium carbon (50% water content, 4 g) was added, and stirred for 4 days under hydrogen (3.5 atmosphere) atmosphere. 10% palladium carbon was filtered and 1N ethanol hydrochloric acid solution (70 ml) was added to the filtrate, and the solvent was distilled off under reduced pressure. This was dissolved in methanol, ethyl acetate ether was added, and the solvent was distilled off again under reduced pressure. The resulting precipitate was collected by filtration to give the title compound (3.57 g).
[848]
[849] Reference Example 74 N-[(1R ^* , 2R ^* )-2-Aminocycloheptyl] -5-chloroindole-2-carboxamide
[850]
[851] In the same manner as in Reference Example 59, the title compound was obtained from the compound obtained in Reference Example 73.
[852]
[853] Reference Example 75 (1R ^* , 2S ^* )-1,2-cyclooctanediol
[854]
[855] Cyclooctene (4.41 g) was dissolved in acetonitrile (45 ml) and water (15 ml), N-methylmorpholine N-oxide (5.15 g), microencapsulated osmium tetraoxide (1 g, 10% tetraoxide) Osmium-containing) was added and stirred at 40-50 ° C for 21 hours. Insoluble microencapsulated osmium was filtered off and washed with acetonitrile. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography (hexane: acetic acid ethyl ester = 1: 1) to give the title compound (4.97 g).
[856]
[857] Reference Example 76 (1R ^* , 2S ^* )-1,2-diazidecyclooctane
[858]
[859] cis-1,2-cyclooctanediol (4.82 g) was dissolved in methylene chloride (60 ml), triethylamine (27.7 ml) was added, argon was substituted in the vessel, and the mixture was cooled to -78 DEG C. Ponyyl (7.7 ml, 100 mmol) was added dropwise. After stirring at the same temperature for 1 hour, the mixture was stirred at 0 ° C for 1 hour, water was added to the reaction solution, and the organic layer was washed with water, 0.5 normal hydrochloric acid solution, water, and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (80 ml), sodium azide (13.0 g) was added, and the mixture was stirred at 65 ° C for 19 hours. Diethyl ether and water were added to the reaction mixture, and the diethyl ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel flash column chromatography (hexane: acetic acid ethyl ester = 6: 1) to give the title compound (4.85 g).
[860]
[861] Reference Example 77 (1R ^* , 2S ^* )-1,2-cyclooctanediamine hydrochloride
[862]
[863] The compound (4.85 g) obtained in Reference Example 76 was dissolved in ethanol (55 ml), 10% palladium carbon (50% water content, 3.0 g) was added, and stirred for 21 hours under a hydrogen (4.5 atmosphere) atmosphere. The catalyst was separated by filtration, 1N ethanol hydrochloric acid solution (50 ml) was added to the filtrate, and the solvent was distilled off under reduced pressure. Acetic acid ethyl ester was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (4.14 g).
[864]
[865] Reference Example 78 N-[(1R ^* , 2S ^* )-2-Aminocyclooctyl] -5-chloroindole-2-carboxamide
[866]
[867] In the same manner as in Reference Example 59, the title compound was obtained from the compound obtained in Reference Example 77.
[868]
[869] Reference Example 79 (1R ^* , 2R ^* )-4-methoxy-1,2-cyclopentanediol (mixture of stereoisomers at position 4)
[870]
[871] To a solution of 3-cyclopenten-l-ol (1.68 g) and methyl iodide (1.25 ml) in tetrahydrofuran (20 ml) was added 60% sodium hydride (800 mg) little by little under ice-cooling and stirred overnight at room temperature. Water and diethyl ether were added to this reaction solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude 4-methoxy-1-cyclopentene.
[872] 88% formic acid (90 ml) and 30% hydrogen peroxide (3.17 ml) were added to the obtained 4-methoxy-1-cyclopentene at room temperature, and it stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, 35% aqueous sodium hydroxide solution was added to the residue, and the reaction solution was made alkaline and stirred at 50 ° C for 10 minutes. The mixture was cooled to room temperature, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to give the title compound (1.21 g).
[873]
[874] Reference Example 80 (1R ^* , 2R ^* )-1,2-diazide-4-methoxycyclopentane (mixture of stereoisomers at position 4)
[875]
[876] The compound (1.21 g) and triethylamine (7.66 ml) obtained in Reference Example 79 were dissolved in methylene chloride (20 ml), and methanesulfonyl chloride (2.13 ml) was added dropwise at -78 ° C over 20 minutes. After completion of dropping, the mixture was heated up to 0 ° C and stirred for 80 minutes to obtain a crude (1R ^* , 2R ^* )-1,2-bis (methanesulfonyloxy) -4-methoxycyclopentane. This was dissolved in N, N-dimethylformamide (20 ml), sodium azide (3.57 g) was added and the mixture was heated and stirred at 65 ° C for 22 hours. Further sodium azide (3.57 g) was added and the mixture was stirred at 70 ° C for 2 days. The reaction mixture was allowed to cool and separated with water and diethyl ether, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 2: 1) to give the title compound (584 mg).
[877]
[878] Reference Example 81 (1R ^* , 2R ^* )-4-methoxy-1,2-cyclopentanediamine hydrochloride (mixture of stereoisomers in position 4)
[879]
[880] The compound (584 mg) obtained in Reference Example 80 was dissolved in ethanol, 10% palladium carbon (321 mg) was added, and hydrogenated at room temperature and normal pressure for 2 days. The catalyst was removed by filtration, concentrated and 1N ethanol hydrochloric acid solution and acetic acid ethyl ester were added to the residue and concentrated to give the title compound (488 mg).
[881]
[882] Reference Example 82 N-[(1R ^* , 2R ^* )-2-amino-4-methoxycyclopentyl] -5-chloroindole-2-carboxamide (mixture of stereoisomers in position 4)
[883]
[884] The compound (470 mg) obtained in Reference Example 81 was suspended in N, N-dimethylformamide (5 ml), and triethylamine (0.966 ml) and 5-chloroindole-2-carboxylic acid p-nitrophenyl ester ( 805 mg) was added and stirred for 4 days at room temperature. The solvent was distilled off under reduced pressure, and the mixture was separated by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 9) to obtain the title compound (268 mg).
[885] Reference Example 83 (1R ^* , 2R ^* )-4-[(benzyloxy) methyl] -1,2-cyclopentanediol (mixture of stereoisomers in position 4)
[886]
[887] 4-hydroxymethyl-1-cyclopentene (J. Heterocycl. Chem., 1989, Vol. 26, p. 451) was benzylated using benzyl bromide in the same manner as in Reference Example 79, and then titled with formic acid-hydrogen peroxide. The compound was obtained.
[888]
[889] Reference Example 84 (1R ^* , 2R ^* )-4-[(benzyloxy) methyl] -1,2-cyclopentanediamine (mixture of stereoisomers in position 4)
[890]
[891] (1R ^* , 2R ^* )-4-benzyloxymethyl-1,2-diazidecyclopentane was obtained from the compound obtained in Reference Example 83 in the same manner as in Reference Example 80. The title compound was obtained in the same manner as the Reference Example 81 without purification.
[892] Reference Example 85 N-{(1R ^* , 2R ^* )-2-amino-4-[(benzyloxy) methyl] cyclopentyl} -5-chloroindole-2-carboxamide (stereoisomer at position 4) Mixture of
[893]
[894] The title compound was obtained from the compound obtained in Reference Example 84 in the same manner as in Reference Example 59.
[895]
[896] Reference Example 86 (1R ^* , 3R ^* , 6S ^* )-7-oxabicyclo [4.1.0] heptane-3-carboxylic acid ethyl ester
[897]
[898] (1R ^* , 4R ^* , 5R ^* )-4-iodine-6-oxabicyclo [3.2.1] octane-7-one (J. Org. Chem., 1996, vol. 61, p. 8687) (14.3 g ) Was dissolved in ethanol (130 ml), and 2N aqueous sodium hydroxide solution (34.5 ml) was added under ice-cooling, followed by stirring at room temperature for 7 hours. The solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with methylene chloride, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 83: 17) to obtain the title compound (6.54 g).
[899]
[900] Reference Example 87 (1R ^* , 3S ^* , 4S ^* )-3-azide-4-hydroxycyclohexanecarboxylic acid ethyl ester
[901]
[902] The compound (13.6 g) obtained in Reference Example 86 was dissolved in N, N-dimethylformamide (100 ml), and ammonium chloride (6.45 g) and sodium azide (7.8 g) were sequentially added at room temperature, followed by 75 ° C. Stir at 12 h. The solvent was concentrated to about one third, diluted with water and acetic acid ethyl ester and stirred for 3 minutes. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to obtain the title compound (15.8 g).
[903]
[904] Reference Example 88 (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-hydroxycyclohexanecarboxylic acid ethyl ester
[905]
[906] Compound (100 mg) and di-tert-butyldicarbonate (133 mg) obtained in Reference Example 87 were dissolved in acetic acid ethyl ester (12 ml), and a catalytic amount of 10% palladium carbon was added thereto, followed by stirring at room temperature under hydrogen stream for 12 hours. It was. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 3: 1) to obtain the title compound (145 mg).
[907]
[908] Reference Example 89 (1R ^* , 3S ^* , 4R ^* )-4-azide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester and (1R ^* , 3S ^* , 4S ^* ) -4-azide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[909]
[910] Compound (16 g) and triethylamine (38 ml) obtained in Reference Example 88 were dissolved in methylene chloride (150 ml), cooled to −78 ° C., and methanesulfonyl chloride (13 ml) was added dropwise at the same temperature. . After stirring at the same temperature for 15 minutes, the temperature was raised to 0 ° C, followed by stirring for 30 minutes at room temperature for 2 hours. After adding 0.1 N hydrochloric acid and diluting with methylene chloride, the organic layer was separated, washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to prepare (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-[(methylsulfonyl) oxy] cyclohexanecarboxylic acid ethyl ester Got.
[911] The product was dissolved in N, N-dimethylformamide (100 ml), sodium azide (18 g) was added at room temperature, and the temperature was raised to 75 ° C and stirred for 12 hours. The solvent was concentrated to about one third, diluted with water and acetic acid ethyl ester and stirred for 3 minutes. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to give the title compound [(1R ^* , 3S ^* , 4R ^* )-form, 6.74 g] and [(1R ^*). , 3S ^* , 4S ^* ) -form, 1.32 g].
[912] (1R ^* , 3S ^* , 4R ^* ) -sieve:
[913]
[914] (1R ^* , 3S ^* , 4S ^* ) -sieve:
[915]
[916] Reference Example 90 (1R ^* , 3S ^* , 4R ^* )-4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[917]
[918] (1R ^* , 3S ^* , 4R ^* )-4-azide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester (5.4 g) obtained in Reference Example 89 was ethanol (10 ml). ) And acetic acid ethyl ester (10 ml) were dissolved, and a catalytic amount of 10% palladium carbon was added, followed by stirring at room temperature for 20 hours under a hydrogen stream. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure to obtain the title compound (4.7 g).
[919] Reference Example 91 (1R ^* , 3S ^* , 4R ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclo Hexanecarboxylic Acid Ethyl Ester
[920]
[921] The compound (4.62 g) obtained in Reference Example 90 was dissolved in methylene chloride (50 ml), and 5-chloroindole-2-carboxylic acid (3.63 g) and 1-hydroxybenzotriazole monohydrate (2.43 g) at room temperature were obtained. ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.45 g) was added, and it stirred for 12 hours. An aqueous solution of 0.1 N hydrochloric acid was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 2: 3) to obtain the title compound (5.3 g).
[922]
[923] Reference Example 92 (1S, 3S, 6R) -7-Oxabicyclo [4.1.0] heptane-3-carboxylic acid ethyl ester
[924] (1S, 4S, 5S) -4-iodine-6-oxabicyclo [3.2.1] octan-7-one (J. Org. Chem., 1996, vol. 61, p. 8687) (89.3 g) It was suspended in (810 ml) and added 2 nd sodium hydroxide aqueous solution (213 ml), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with methylene chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 17: 3) to give the title compound (41.3 g).
[925] α _D ²⁵ = − 58 ° (c = 1.0, chloroform).
[926] Reference Example 93 (1S, 3R, 4R) -3-Azide-4-hydroxycyclohexanecarboxylic acid ethyl ester
[927] The compound (41 g) obtained in Reference Example 92 was dissolved in N, N-dimethylformamide (300 ml), and ammonium chloride (19.3 g) and sodium azide (23.5 g) were sequentially added at room temperature, followed by 76 ° C. Stirred for 13 hours. The reaction solution was filtrated to concentrate the filtrate. The filtrate was collected and the residue was dissolved by adding water. Extracted with ethyl acetate and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (51.5 g).
[928] [α] _D ²⁵ = + 8 ° (c = 1.0, chloroform).
[929] Reference Example 94 (1S, 3R, 4R) -3-[(tert-butoxycarbonyl) amino] -4-hydroxycyclohexanecarboxylic acid ethyl ester
[930] Compound (51.2 g) and di-tert-butyldicarbonate (68.1 g) obtained in Reference Example 93 were dissolved in ethyl acetate (1000 ml), 5% palladium carbon (5.0 g) was added, and the hydrogen pressure at room temperature was 7 kg. Stir overnight at / cm 2. After filtering off the insoluble matter, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 4: 1 → 3: 1), and hexane was added to solidify the title compound (46.9 g). Got it.
[931] [α] _D ²⁵ = + 25 ° (c = 1.0, chloroform).
[932] Reference Example 95 (1S, 3R, 4S) -4-Azide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester and (1S, 3R, 4R) -4-a Zide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[933] The compound (53.5 g) and triethylamine (130 ml) obtained in Reference Example 94 were dissolved in methylene chloride (500 ml), and cooled to −10 ° C. to −15 ° C. to methanesulfonyl chloride (42 ml) for 20 minutes. It was dripped over. After stirring at the same temperature for 20 minutes, it took 2 hours and heated up to room temperature. The reaction solution was cooled to 0 deg. C, 0.5N hydrochloric acid (800 ml) was added dropwise and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1S, 3R, 4R) -3-[(tert-butoxycarbonyl) amino] -4-[(methylsulfonyl) oxy] cyclohexanecarboxylic acid ethyl ester.
[934] The crude compound was dissolved in N, N-dimethylformamide (335 ml), sodium azide (60.5 g) was added, and the mixture was stirred at 67 to 75 ° C for 16 hours. The reaction solution was filtered and the filtrate was concentrated to distill 250 ml of solvent. The residue and the collected material were combined, dissolved in water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 4) to give the title compound (1S, 3R, 4S) -form (18.4 g) and the title compound (1S, 3R, 4R) -form (3.3 g )
[935] (1S, 3R, 4S) -form: [α] _D ²⁵ = + 62 ° (c = 1.0, chloroform).
[936] (1S, 3R, 4R) -form: [α] _D ²⁵ = -19 ° (c = 1.0, chloroform).
[937] Reference Example 96 (1S, 3R, 4S) -4-Amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[938] Compound (4.0 g) obtained in Reference Example 95 was dissolved in a mixed solvent of ethanol (150 ml) and acetic acid ethyl ester (150 ml), and 5% palladium carbon (0.5 g) was added thereto under a hydrogen atmosphere (5 kg / cm 2). Stir at room temperature for 17 hours. After the insolubles were removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.2 g).
[939] Reference Example 97 (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxyl Acid ethyl ester
[940]
[941] The compound (4.2 g) obtained in Reference Example 96 was dissolved in methylene chloride (50 ml), and 5-chloroindole-2-carboxylic acid (3.33 g) and 1-hydroxybenzotriazole monohydrate (2.52 g) at room temperature were obtained. ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.15 g) was added, and it stirred for 12 hours. An aqueous solution of 0.1 N hydrochloric acid was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 1) to obtain the title compound (4.36 g).
[942] [α] _D ²⁵ = -27 ° (c = 1.0, chloroform).
[943] Reference Example 98 (1R ^* , 3S ^* , 4R ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[(5-methyl-4,5,6,7-tetrahydrothia Solo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester
[944]
[945] In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 90 and the compound obtained in Reference Example 10.
[946] Reference Example 99 3-cyclohexene-1-carboxylic acid benzyl ester
[947]
[948] (±) -3-cyclohexene-1-carboxylic acid (50 g) is dissolved in N, N-dimethylformamide (550 ml), triethylamine (170 ml) and benzyl bromide (61 ml) under ice-cooling. Was added and stirred at room temperature for 12 hours. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 1) to give the title compound (70.8 g).
[949]
[950] Reference Example 100 (1R ^* , 3S ^* , 6S ^* )-7-oxabicyclo [4.1.0] heptane-3-carboxylic acid benzyl ester
[951]
[952] The compound (40 g) obtained in the reference example 99 was dissolved in methylene chloride (500 ml), and m-chloro perbenzoic acid (86 g) was added under ice cooling, followed by stirring for 2 hours. An aqueous 10% sodium thiosulfate solution was added thereto, stirred for 20 minutes, the organic layer was separated, washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 9) to give the title compound (23.4 g) and (1R ^* , 3R ^* , 6S ^* )-7-oxabicyclo [ 4.1.0] heptan-3-carboxylic acid benzyl ester (12.1 g) was obtained.
[953]
[954] Reference Example 101 (1R ^* , 3S ^* , 4S ^* )-4-azide-3-hydroxycyclohexanecarboxylic acid benzyl ester
[955]
[956] The compound (52.3 g) obtained in Reference Example 100 was dissolved in N, N-dimethylformamide (1000 ml), and ammonium chloride (21.9 g) and sodium azide (18.1 g) were added thereto, heated to 70 ° C, and stirred for 24 hours. It was. The solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (61.8 g).
[957]
[958] Reference Example 102 (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-hydroxycyclohexanecarboxylic acid benzyl ester
[959]
[960] The compound (5.27 g) obtained in the reference example 101 was dissolved in tetrahydrofuran (25 ml), triphenylphosphine (5.53 g) and water (0.55 ml) were added, and it stirred at room temperature for 20 hours. Di-tert-butyldicarbonate (4.82 g) was added to the reaction liquid, and stirring was further continued for 2 hours. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 2: 1) to give the title compound (6.22 g).
[961]
[962] Reference Example 103 (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-hydroxycyclohexanecarboxylic acid methyl ester
[963]
[964] The compound (2.54 g) obtained in Reference Example 102 was dissolved in acetic acid ethyl ester (15 ml), and a catalytic amount of 10% palladium carbon was added, followed by stirring at room temperature under hydrogen stream for 20 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to afford (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-hydroxycyclohexanecarboxylic acid as a colorless oil. This was dissolved in a mixed solution of methanol (8 ml) and toluene (15 ml), 2 ml trimethylsilyldiazomethane hexane solution (10 ml) was added under ice cooling, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 1: 1) to give the title compound (1.82 g).
[965]
[966] Reference Example 104 (1R ^* , 3R ^* , 4S ^* )-3-azide-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester and (1R ^* , 3S ^* , 4S ^* ) -3-azide-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester
[967]
[968] The compound (1.81 g) obtained in Reference Example 103 was dissolved in methylene chloride (36 ml), and triethylamine (4.6 ml) and methanesulfonyl chloride (1.63 ml) were added at -78 ° C, and the temperature was raised to 0 ° C after 30 minutes. And it stirred for 30 minutes further. 1N hydrochloric acid was added, extraction was performed with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to prepare (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-[(methylsulfonyl) oxy] cyclohexanecarboxylic acid methyl ester Got.
[969] The crude compound was dissolved in N, N-dimethylformamide (23 ml), sodium azide (1.29 g) was added, heated to 70 ° C and stirred for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 17) to give (1R ^* , 3S ^* , 4S ^* )-3-azide-4-[(tert-butoxy Carbonyl) amino] cyclohexanecarboxylic acid methyl ester (85 mg) and (1R ^* , 3R ^* , 4S ^* )-3-azide-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxyl Acid methyl ester (590 mg) was obtained.
[970]
[971]
[972] Reference Example 105 (1R ^* , 3R ^* , 4S ^* )-3-amino-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester
[973]
[974] The (1R ^* , 3R ^* , 4S ^* ) compound (230 mg) obtained in Reference Example 104 was dissolved in acetic acid ethyl ester (8 ml), and a catalytic amount of 10% palladium carbon was added and stirred for 20 hours under hydrogen stream. The insolubles were filtered off and the filtrate was concentrated under reduced pressure to give the title compound (220 mg).
[975] Reference Example 106 (1R ^* , 3R ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-{[(5-methyl-4,5,6,7-tetrahydrothia Solo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester
[976]
[977] In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 105 and the compound obtained in Reference Example 10.
[978]
[979] Reference Example 107 (1R ^* , 3R ^* , 4S ^* )-4-[(tert-butoxycarbonyl) amino] -3-{[(5-chloroindol-2-yl) carbonyl] amino} cyclo Hexanecarboxylic Acid Methyl Ester
[980]
[981] The title compound was obtained from the compound obtained in Reference Example 105 in the same manner as in Reference Example 91.
[982]
[983] Reference Example 108 (1S, 3R, 6R) -7-oxabicyclo [4.1.0] heptan-3-carboxylic acid benzyl ester
[984] 1) (1R) -3-cyclohexene from (1R) -3-cyclohexene-1-carboxylic acid (J. Am. Chem. Soc, 1978, 100, 5199) in the same manner as in Reference Example 99 -1-carboxylic acid benzyl ester was obtained.
[985] 2) The title compound was obtained from the above product in the same manner as in Reference Example 100.
[986]
[987] Reference Example 109 (1R, 3S, 4S) -4-[(tert-butoxycarbonyl) amino] -3-hydroxycyclohexanecarboxylic acid benzyl ester
[988] 1) (1R, 3S, 4S) -4-azide-3-hydroxycyclohexanecarboxylic acid benzyl ester was obtained from the compound obtained in Reference Example 108 in the same manner as Reference Example 101.
[989] 2) The title compound was obtained from the above product in the same manner as in Reference Example 102.
[990]
[991] Reference Example 110 (1R, 3R, 4S) -3-azide-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid benzyl ester
[992]
[993] The title compound was obtained from the compound obtained in Reference Example 109 in the same manner as in Reference Example 104.
[994]
[995] Reference Example 111 (1R, 3R, 4S) -3-Azide-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester
[996]
[997] The compound (3.5 g) obtained in the reference example 110 was dissolved in tetrahydrofuran (130 ml) and water (16 ml), lithium hydroxide (291 mg) was added under ice cooling, and after 10 minutes, it returned to room temperature and stirred for 20 hours. After distilling off the solvent under reduced pressure, the obtained residue was treated with silica gel column chromatography (methanol: methylene chloride = 1: 20) to give (1R, 3R, 4S) -3-azide-4-[(tert-butoxycarbonyl ) Amino] cyclohexanecarboxylic acid (3.34 g) was obtained as a pale yellow oil. This was dissolved in methanol (18 ml) and toluene (64 ml), 2 mol trimethylsilyldiazomethanehexane solution (6.1 ml) was added under ice cooling, and after 10 minutes, the mixture was returned to room temperature and stirred for 2 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to obtain the title compound (3.35 g).
[998]
[999] Reference Example 112 (1R, 3R, 4S) -4-[(tert-butoxycarbonyl) amino] -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester
[1000]
[1001] 1) (1R, 3R, 4S) -3-amino-4-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid methyl ester was obtained from the compound obtained in Reference Example 111 in the same manner as in Reference Example 105. .
[1002] 2) In the same manner as in Reference Example 106, the title compound was obtained from the product and the compound obtained in Reference Example 10.
[1003]
[1004] Reference Example 113 (1R ^* , 2S ^* , 5S ^* )-5-Aminocarbonyl-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester
[1005]
[1006] The compound (590 mg) obtained in Reference Example 91 was dissolved in a mixed solvent of ethanol (3 ml) and tetrahydrofuran (6 ml), and 1 N sodium hydroxide solution (2.5 ml) was added at room temperature, followed by stirring for 12 hours. The solvent was distilled off to give (1R ^* , 3S ^* , 4R ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexane The carboxylic acid sodium salt was obtained. This was suspended in N, N-dimethylformamide (4 ml), di-tert-butyldicarbonate (654 mg) and ammonium bicarbonate (1 g) were added and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, water was added, extraction was performed with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to obtain the title compound (82 mg).
[1007]
[1008] Reference Example 114 (1R, 6S) -6-{[(benzyloxy) carbonyl] amino} -3-cyclohexen-1-ylcarbamic acid benzyl ester
[1009]
[1010] 4-cyclohexene-1,2-diamine hydrochloride (4.0 g) is dissolved in a mixed solvent of water (20 ml) and acetonitrile (20 ml), and benzyl chloroformate (7.66 ml) and potassium carbonate (14.9 g) It was added and stirred at room temperature for 3 days. The reaction solution was poured into water, extracted with methylene chloride, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride) to obtain the title compound (8.22 g).
[1011]
[1012] Reference Example 115 (1R ^* , 2S ^* )-2-{[(benzyloxy) carbonyl] amino} -5-hydroxycyclohexylcarbamic acid benzyl ester
[1013]
[1014] The compound (10 g) obtained in the reference example 114 was dissolved in anhydrous tetrahydrofuran (70 ml), borane dimethyl sulfide complex (7.4 ml) was added at 0 degreeC, it heated up gradually to room temperature and stirred for 14 hours. Ice was added to the reaction solution to decompose excess borane, and 1 N aqueous sodium hydroxide solution (80 ml) and 30% hydrogen peroxide solution (80 ml) were added and stirred for 1 hour as it was. Extracted with ethyl acetate and washed the organic layer with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 2: 1) to obtain the title compound (9.2 g).
[1015]
[1016] Reference Example 116 (1R ^* , 2S ^* )-2-{[(benzyloxy) carbonyl] amino} -5-oxocyclohexylcarbamic acid benzyl ester
[1017]
[1018] Dimethyl sulfoxide (8.2 ml) was added to a solution of oxalyl chloride (9.9 ml) dissolved in methylene chloride (90 ml) under cooling and stirring at −60 ° C., and tetrahydro of the compound (9.2 g) obtained in Reference Example 115 was further added. Furan (90 ml) solution was added in one portion. After 1 h, triethylamine (26 ml) was added at a temperature up to -40 ° C. It heated up to room temperature as it was, and stirred for 3 hours. The reaction solution was poured into water, extracted with methylene chloride, the organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 1) to obtain the title compound (8.0 g).
[1019]
[1020] Reference Example 117 (1R ^* , 2S ^* )-2-{[(benzyloxy) carbonyl] amino} -5,5-dimethoxycyclohexylcarbamic acid benzyl ester
[1021]
[1022] The compound (3.89 g) obtained in Reference Example 116 was dissolved in a mixed solvent of methanol (15 ml) and tetrahydrofuran (15 ml), and 2,2-dimethoxypropane (10.7 ml) and p-toluenesulfonic acid (187 mg) was added and stirred at room temperature for 3 hours. The solution was concentrated and added with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 1: 2) to give the title compound (3.54 g).
[1023]
[1024] Reference Example 118 N-[(1R ^* , 2S ^* )-2-amino-4,4-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide and N-[(1R ^* , 2S ^* ) -2-amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide
[1025]
[1026] The compound (1.45 g) obtained in Reference Example 117 was dissolved in methanol (12 ml), 10% palladium carbon (290 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 20 hours. In addition, 10% palladium carbon (290 mg) and methanol (10 ml) were added and stirred for 8 hours. After the reaction solution was filtered through Celite and the mother liquor was concentrated, the residue was dissolved in N, N-dimethylformamide (10 ml), and 5-chloroindole-2-carboxylic acid (320 mg) and 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (377 mg), 1-hydroxybenzotriazole monohydrate (301 mg) and N-methylmorpholine (360 ml) were added and stirred at room temperature for 14 hours. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 93: 7) and purified by N-[(1R ^* , 2S ^* )-2-amino-4,4-dimethoxycyclohexyl]. -5-chloroindole-2-carboxamide (or N-[(1R ^* , 2S ^* )-2-amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide) ( 98 mg) and N-[(1R ^* , 2S ^* )-2-amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide (or N-[(1R ^* , 2S ^* ) -2-amino-4,4-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide) (105 mg) was obtained.
[1027] N-[(1R ^* , 2S ^* )-2-amino-4,4-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide:
[1028]
[1029] N-[(1R ^* , 2S ^* )-2-amino-5,5-dimethoxycyclohexyl] -5-chloroindole-2-carboxamide:
[1030]
[1031] Reference Example 119 (7R ^* , 8S ^* )-7-{[(benzyloxy) carbonyl] amino} -1,4-dioxaspiro [4.5] dec-8-ylcarbamic acid benzyl ester
[1032]
[1033] The compound (4.0 g) obtained in the reference example 116 was dissolved in tetrahydrofuran anhydride (30 ml), ethylene glycol (5.6 ml) and p-toluenesulfonic acid (192 mg) were added, and it stirred at room temperature for 17 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 1) to obtain the title compound (4.23 g).
[1034]
[1035] Reference Example 120 N-[(7R ^* , 8S ^* )-7-Amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindole-2-carboxamide and N- [(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindole-2-carboxamide
[1036]
[1037] N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindole from the compound obtained in Reference Example 119 in the same manner as in Reference Example 118. 2-carboxamide (or N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindol-2-carboxamide ) And N-[(7R ^* , 8S ^* )-8-amino-1, 4-dioxaspiro [4.5] dec-7-yl] -5-chloroindol-2-carboxamide (or N-[( 7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindole-2-carboxamide) was obtained.
[1038] N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindol-2-carboxamide (or N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindol-2-carboxamide):
[1039]
[1040] N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro [4.5] dec-7-yl] -5-chloroindol-2-carboxamide (or N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro [4.5] dec-8-yl] -5-chloroindol-2-carboxamide):
[1041]
[1042] Reference Example 121 (1R, 6S) -6-[(tert-Butoxycarbonyl) amino] -3-cyclohexene-1-ylcarbamic acid tert-butyl ester
[1043]
[1044] Cis-4-cyclohexene-1,2-diamine hydrochloride (4.0 g) is dissolved in water (40 ml) and acetonitrile (40 ml), di-tert-butoxycarbonate (11.8 g), triethylamine ( 12 ml) was added and stirred at room temperature for 4.5 hours. The reaction solution was poured into water, extracted with methylene chloride, the methylene chloride layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to obtain the title compound (6.12 g).
[1045]
[1046] Reference Example 122 (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5-hydroxycyclohexylcarbamic acid tert-butyl ester (mixture of stereoisomers)
[1047]
[1048] The compound (6.1 g) obtained in Reference Example 121 was dissolved in anhydrous tetrahydrofuran (40 ml), borane-dimethylsulfide complex (2.22 ml) was added under ice-cooling, and the mixture was stirred for 16 hours while gradually warming to room temperature. Ice was added to the reaction solution, 1N aqueous sodium hydroxide solution and 30% hydrogen peroxide solution (50 ml) were added thereto, and the mixture was stirred at room temperature as it was for 2 hours. Extracted with acetic acid ethyl ester and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 2 → 2: 1) to obtain the title compound (6.1 g).
[1049]
[1050] Reference Example 123 (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5-oxocyclohexylcarbamic acid tert-butyl ester
[1051]
[1052] Oxalyl chloride (8.2 ml) and dimethylsulfoxide (6.8 ml) were dissolved in methylene chloride (100 ml) and cooled to -60 ° C, and tetra (tetra of the compound (stereoisomer) (6.32 g) obtained in Reference Example 122 was obtained. Hydrofuran solution (80 ml) was added at once and stirred for 1 hour. It heated up to -40 degreeC, triethylamine (21 ml) was added, it heated up to room temperature, and poured in water after 3 hours. The mixture was extracted with methylene chloride and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 1) to obtain the title compound (3.8 g).
[1053]
[1054] Reference Example 124 (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5- (methoxyimino) cyclohexylcarbamic acid tert-butyl ester
[1055]
[1056] The compound (1.5 g) obtained in the reference example 123 was dissolved in methanol (30 ml), O-methylhydroxylamine hydrochloride (572 mg) and pyridine (737 ml) were added, and it stirred at room temperature for 17 hours. The reaction solution was concentrated, water was added, extraction was performed with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (1.52 g).
[1057]
[1058] Reference Example 125 (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5-{[tert-butyl (diphenyl) silyl] oxy} cyclohexylcarbamate tert-butyl Ester (stereoisomer A)
[1059]
[1060] In the same manner as in Reference Example 58, the title compound was obtained from the compound (mixture of stereoisomers) obtained in Reference Example 122. In addition, (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl) amino] -5-hydroxycyclohexylcarbamic acid tert-butyl ester (stereoisomer B) was recovered.
[1061]
[1062] Reference Example 126 (1R ^* , 2S ^* )-2-{[(benzyloxy) carbonyl] amino} -5-hydroxy-5-methylcyclohexylcarbamic acid benzyl ester
[1063]
[1064] Anhydrous cerium chloride (6.4 g) was suspended in tetrahydrofuran (50 ml) and cooled to -78 ° C under argon. A methyllithium solution (1.14 prescribed diethyl ether solution, 22.5 ml) was added to the suspension, followed by stirring at -78 ° C for 30 minutes. Tetrahydrofuran solution (50 ml) of the compound (3.0 g) obtained in Reference Example 116 was added dropwise at -78 ° C, and stirred for 30 minutes. The reaction solution was poured into 3% aqueous acetic acid solution (100 ml), diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified twice by silica gel column chromatography (methanol: chloroform = 1: 100-1: 19) to give the title compound (stereoisomer A) (780 mg) and the title compound (stereoisomer B) (1.1 g) was obtained.
[1065] Stereoisomer A:
[1066]
[1067] Stereoisomer B:
[1068]
[1069] Reference Example 127 (3R ^* , 4S ^* )-3,4-diamino-1-methylcyclohexanol (stereoisomer A)
[1070]
[1071] 10% palladium carbon (350 mg) was suspended in a methanol solution (100 ml) of the compound (stereoisomer A) (780 mg) obtained in Reference Example 126, and stirred for 5 hours under hydrogen stream. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain the title compound (stereoisomer A) (190 mg).
[1072]
[1073] Reference Example 128 N-[(1R ^* , 2S ^* )-2-Amino-4-hydroxy-4-methylcyclohexyl] -5-chloroindole-2-carboxamide (stereoisomer A) and N- A mixture of [(1R ^* , 2S ^* )-2-amino-5-hydroxy-5-methylcyclohexyl] -5-chloroindole-2-carboxamide (stereoisomer A)
[1074]
[1075] The title compound was obtained from the compound (stereoisomer A) and 5-chloroindole-2-carboxylic acid obtained in Reference Example 127 in the same manner as in Reference Example 59.
[1076]
[1077] Reference Example 129 (1R ^* , 2R ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexylcarbamic acid tert- Butyl ester
[1078]
[1079] 1) (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxy) from (1R ^* , 3S ^* , 4S ^* ) body obtained in Reference Example 89 in the same manner as described in Reference Examples 90-91 Carbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester was obtained.
[1080]
[1081] 2) The product (735 mg) was dissolved in methylene chloride (10 ml), diisobutylaluminum hydride monobasic hexane solution (5 ml) was added at -78 ° C, stirred for 3 hours, and stirred at 0 ° C for 30 minutes. . Saturated ammonium chloride solution was added at -78 ° C, extracted with methylene chloride, and the organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 19: 1) to obtain the title compound (480 mg).
[1082]
[1083] Reference Example 130 (1R ^* , 3R ^* , 6S ^* )-3- (methoxymethyl) oxabicyclo [4.1.0] heptane
[1084]
[1085] 1) (1R ^* , 4R ^* , 5R ^* )-4-iodine-6-oxabicyclo [3.2.1] octane-7-one (2.8 g) in tetrahydrofuran (27 ml) and water (3 ml) Dissolved in a mixed solvent, concentrated hydrochloric acid (0.1 ml) was added, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain (1R ^* , 3R ^* , 4R ^* )-3-hydroxy-4-iodinecyclohexanecarboxylic acid (3.23 g) as a colorless solid.
[1086] 2) The product (3.22 g) obtained in the above reaction was dissolved in tetrahydrofuran (50 ml), and borane-dimethylsulfide complex (2 mol tetrahydrofuran solution, 47 ml) was added under ice cooling, followed by stirring at room temperature for 12 hours. . The solvent was distilled off under reduced pressure, and the residue was dissolved in isopropanol (10 ml), and 1 N sodium hydroxide aqueous solution (12 ml) was added at room temperature, followed by stirring for 12 hours. The solvent was concentrated to about one fifth, diluted with water and methylene chloride, and stirred for 10 minutes. The organic layer was separated, washed sequentially with saturated ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 2) to give (1R ^* , 3R ^* , 6S ^* )-7-oxabicyclo [4.1.0] hepto-3. -Methanol (1.25 g) was obtained as a colorless oil.
[1087] 3) The product (4.63 g) obtained in the reaction of 2) above was dissolved in tetrahydrofuran (50 ml), and potassium bis (trimethylsilyl) amide (0.5 prescribed toluene solution, 80 ml) was added at -78 ° C to obtain the same temperature. After stirring for 10 min, methyl iodide (2.93 ml) was added. It heated up to 0 degreeC, stirred for 1 hour, and added saturated aqueous ammonium chloride, and diluted with diethyl ether. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to obtain the title compound (3.7 g).
[1088]
[1089] Reference Example 131 (1R ^* , 2R ^* , 4S ^* )-2-azide-4- (methoxymethyl) cyclohexanol
[1090]
[1091] The title compound was obtained from the compound obtained in Reference Example 130 in the same manner as in Reference Example 87.
[1092]
[1093] Reference Example 132 (1R ^* , 2R ^* , 5S ^* )-2-hydroxy-5- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester
[1094]
[1095] The title compound was obtained from the compound obtained in Reference Example 131 in the same manner as in Reference Example 88.
[1096]
[1097] Reference Example 133 (1R ^* , 2S ^* , 5S ^* )-2-azide-5- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester
[1098]
[1099] In the same manner as in Reference Example 89, the title compound was obtained from the compound obtained in Reference Example 132 through its methanesulfonic acid ester.
[1100]
[1101] Reference Example 134 (1R ^* , 2S ^* , 5S ^* )-2-Amino-5- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester
[1102]
[1103] The title compound was obtained from the compound obtained in Reference Example 133 in the same manner as in Reference Example 90.
[1104] Reference Example 135 (1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (methoxymethyl) cyclohexylcarbamic acid tert- Butyl ester
[1105]
[1106] In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 134 and 5-chloroindole-2-carboxylic acid.
[1107]
[1108] Reference Example 136 (1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexylcarbamic acid tert- Butyl ester
[1109]
[1110] The title compound was obtained from the compound obtained in Reference Example 91 in the same manner as in Reference Example 129.
[1111]
[1112] Reference Example 137 (1R ^* , 2S ^* , 5S ^* )-5- (azidemethyl) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert- Butyl ester
[1113]
[1114] The title compound was obtained from the compound obtained in Reference Example 136 in the same manner as in Reference Example 80.
[1115] Reference Example 138 3-cyclohexene-1-ylcarbamic acid tert-butyl ester
[1116]
[1117] 3-cyclohexene-1-carboxylic acid (25.3 g) was dissolved in tert-butanol (250 ml), triethylamine (28 ml) and diphenylphosphoryl azide (43.0 ml) were added, followed by 1 hour at room temperature. Furthermore, it stirred at 90 degreeC for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride), and then purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the title compound (24.9 g).
[1118]
[1119] Reference Example 139 (3R ^* , 4S ^* )-3,4-dihydroxycyclohexylcarbamic acid tert-butyl ester
[1120]
[1121] The compound (1.24 g) obtained in Reference Example 138 was dissolved in a mixed solvent of acetonitrile (15 ml) and water (5 ml), and N-methylmorpholine N-oxide (0.90 g) and microencapsulated 10% tetraoxide Osmium (1 g) was added and stirred at about 80 ° C for 1 day. After the insolubles were removed by filtration, the filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to obtain the title compound (1.28 g).
[1122]
[1123] Reference Example 140 (3R ^* , 4S ^* )-3,4-diazidecyclohexylcarbamic acid tert-butyl ester (stereoisomer A and stereoisomer B)
[1124]
[1125] In the same manner as in Reference Example 80, the title compound (stereoisomer A and stereoisomer B) was obtained from the compound obtained in Reference Example 139.
[1126] Stereoisomer A:
[1127]
[1128] Stereoisomer B:
[1129]
[1130] Reference Example 141 (1S, 3R, 4S) -4-{[(benzyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[1131]
[1132] The compound (3.10 g) obtained in Reference Example 96 was dissolved in tetrahydrofuran (50 ml), and saturated aqueous sodium hydrogen carbonate solution (50 ml) was added. Benzyloxycarbonyl chloride (1.71 ml) was added dropwise to the reaction solution under ice-cooling, followed by stirring at room temperature for 4 days. Ethyl acetate (200 ml) and water (200 ml) were added to the reaction solution, and a liquid separation operation was performed. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration to obtain the title compound (3.24 g).
[1133]
[1134] Reference Example 142 (1S, 3R, 4S) -4-{[(benzyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid
[1135]
[1136] The compound (620 mg) obtained in Reference Example 141 was dissolved in tetrahydrofuran (20 ml), an aqueous solution of lithium hydroxide monohydrate (93 mg) was added and stirred at room temperature for 16 hours. Lithium hydroxide monohydrate (217 mg) was added to the reaction solution, the mixture was stirred at room temperature for 2 hours, and then neutralized by adding 1 N hydrochloric acid aqueous solution, and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (600 mg).
[1137]
[1138] Reference Example 143 (1S, 2R, 4S) -2-[(tert-butoxycarbonyl) amino] -4-[(dimethylamino) carbonyl] cyclohexylcarbamic acid benzyl ester
[1139]
[1140] The compound (600 mg) and dimethylamine hydrochloride (240 mg) obtained in Reference Example 142 were suspended in methylene chloride (50 ml), and then an appropriate amount of tetrahydrofuran was added to make a solution. Triethylamine (0.41 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (422 mg) and 1-hydroxybenzotriazole monohydrate (338 mg) were added to this solution at room temperature. Stirred for 1 hour. Dimethylamine hydrochloride (480 mg) and triethylamine (0.82 ml) were added to the reaction mixture, which was further stirred at room temperature for 18 hours. The reaction solution was poured into water, the organic layer was separated, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 47 → 2: 23) to give the title compound (620 mg).
[1141]
[1142] Reference Example 144 (1R, 2S, 5S) -2-Amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester
[1143]
[1144] 10% palladium carbon (57 g) was added to a methanol (8000 ml) solution of the compound (190 g) obtained in Reference Example 143, and the mixture was stirred under 7 atmospheres of hydrogen for 3 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. Toluene was added to the residue, concentrated under reduced pressure, and hexane (2500 ml) was added to solidify. The residue was filtered, collected and dried to obtain the title compound (121 g).
[1145]
[1146] Reference Example 145 (1R, 2S, 5S) -2-{[(6-chloroquinolin-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert- Butyl ester
[1147]
[1148] In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 54.
[1149]
[1150] Reference Example 146 (1R, 2S, 5S) -2-{[(7-chloroquinolin-3-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert- Butyl ester
[1151]
[1152] In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 57.
[1153]
[1154] Reference Example 147 2-Bromo-5-isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine
[1155]
[1156] In the same manner as in Reference Example 9, the title compound was obtained from the compound obtained in Reference Example 8.
[1157]
[1158] Reference Example 148 5-Isopropyl-4,5,6,7-tetrahydrothiazolo [5.4-c] pyridine-2-carboxylic acid lithium salt
[1159]
[1160] In the same manner as in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 147.
[1161]
[1162] Reference Example 149 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid 4-nitrophenyl ester
[1163]
[1164] In the same manner as in Reference Example 52, the title compound was obtained from the compound obtained in Reference Example 10 and p-nitrophenol.
[1165]
[1166] Reference Example 150 3-Oxocyclobutanecarboxylic Acid Benzyl Ester
[1167]
[1168] To a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., Vol. 53, pages 3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml), triethylamine (2.0 ml) and Benzyl bromide (1.2 ml) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate ethyl hexane: 1: 6) to obtain the title compound (886 mg).
[1169]
[1170] Reference Example 151 3-hydroxycyclobutanecarboxylic acid benzyl ester
[1171]
[1172] To a mixture of tetrahydrofuran (10 ml) and methanol (0.5 ml) of the compound (781 mg) obtained in Reference Example 150 was added sodium borohydride (76 mg) at 0 ° C and stirred for 30 minutes at the same temperature. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (770 mg).
[1173]
[1174] Reference Example 152 3-hydroxycyclobutanecarboxylic acid
[1175]
[1176] To the ethanol (10 ml) solution of the compound (706 mg) obtained in Reference Example 151, 10% palladium carbon (108 mg) was added and stirred at room temperature under hydrogen atmosphere for 2 hours. The catalyst was filtered using celite and the filtrate was concentrated under reduced pressure to give the title compound (399 mg).
[1177]
[1178] Reference Example 153 3-methoxycyclobutanecarboxylic acid benzyl ester
[1179]
[1180] Methyl iodide (194 µl) and silver oxide (237 mg) were added to an N, N-dimethylformamide (3.0 ml) solution of the compound (317 mg) obtained in Reference Example 151, and the mixture was stirred at 45 ° C for 1 hour. Methyl iodide (194 µl) and silver oxide (226 mg) were added to the reaction mixture, and the mixture was stirred at 45 ° C for 16 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain the title compound (152 mg).
[1181]
[1182] Reference Example 154 3-methoxycyclobutanecarboxylic acid
[1183]
[1184] In the same manner as in Reference Example 152, the title compound was obtained from the compound obtained in Reference Example 153.
[1185]
[1186] Reference Example 155 3-methoxy-2- (methoxymethyl) propionic acid methyl ester
[1187]
[1188] To a methanol (10 ml) solution of 2- (bromomethyl) acrylic acid methyl ester (1.0 ml) was added sodium methoxide (1.21 g) and refluxed for 26 hours. The reaction solution was cooled, diluted with diethyl ether, and the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 4) to give the title compound (726 mg).
[1189]
[1190] Reference Example 156 Tetrahydro-2H-pyran-4-carboxylic acid
[1191]
[1192] 20% hydrochloric acid (20 ml) was added to tetrahydro-4H-pyran-4,4-dicarboxylic acid dimethyl ester (4.04 g), followed by heating to reflux for 19 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After the obtained residue was solidified with hexane, the obtained solid was collected by filtration and washed to give the title compound (2.63 g).
[1193]
[1194] Reference Example 157 3-{[tert-butyl (diphenyl) silyl] oxy} -2,2-dimethylpropionic acid methyl ester
[1195]
[1196] In the same manner as in Reference Example 41, the title compound was obtained from 2,2-dimethyl-3-hydroxypropionic acid methyl ester.
[1197]
[1198] Reference Example 158 3-{[tert-butyl (diphenyl) silyl] oxy} -2,2-dimethylpropionic acid
[1199]
[1200] To a suspension of potassium tert-butoxide (5.32 g) and diethyl ether (100 ml) was added water (0.24 ml) under ice cooling, followed by stirring for 5 minutes. The compound (2.22 g) obtained in the reference example 157 was added here, and it stirred at room temperature overnight. Water was added to the reaction solution, which was made acidic with 1N aqueous hydrochloric acid solution and extracted three times with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 6) to obtain the title compound (735 mg).
[1201]
[1202] Reference Example 159 3-methoxy-2,2-dimethylpropionic acid methyl ester
[1203]
[1204] Tetrahydrofuran (300 ml) of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (25.0 g) under ice cooling in a suspension of 60% sodium hydride (8.32 g), tetrahydrofuran (100 ml) in an oil suspension. The solution was added dropwise and stirred at 60 ° C for 1 hour. Methyl iodide (53.7 g) was added to this reaction liquid, and it stirred at room temperature for further 2 hours. Water was carefully added, extracted twice with methylene chloride, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oily substance was distilled off and the title compound (12.8g) was obtained.
[1205] Boiling Point: 140-142 ° C. (atmospheric pressure).
[1206]
[1207] Reference Example 160 3-methoxy-2,2-dimethylpropionic acid
[1208]
[1209] The compound obtained in Reference Example 159 was treated in the same manner as Reference Example 158 to obtain the title compound.
[1210]
[1211] Reference Example 161 1- (methoxycarbonyl) cyclopropanecarboxylic acid
[1212]
[1213] 1,1-cyclopropanedicarboxylic acid dimethyl ester (25 g) was dissolved in methanol (250 ml) and ice-cooled. Subsequently, 1 N sodium hydroxide aqueous solution (158 ml) was added dropwise, and the mixture was returned to room temperature and stirred overnight. The methanol was distilled off, washed with chloroform, the water layer was cooled with ice, concentrated to pH 2 with concentrated hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (16.8 g).
[1214]
[1215] Reference Example 162 1- (hydroxymethyl) cyclopropanecarboxylic acid methyl ester
[1216]
[1217] Compound (9.0 g) and triethylamine (9.7 ml) obtained in Reference Example 161 were dissolved in tetrahydrofuran (180 ml), cooled to -10 ° C, isobutyl chloroformate (9.1 ml) was added dropwise, and stirred for 1 hour. It was. Meanwhile, sodium borohydride (7.1 g) was dissolved in tetrahydrofuran (100 ml) -water (25 ml) and ice-cooled. The solution was added dropwise while filtering out the insolubles and stirred for 1 hour at the same temperature. The reaction solution was poured into cold 10% citric acid solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-2: 1) to obtain the title compound (4.25 g).
[1218]
[1219] Reference Example 163 1- (Bromomethyl) cyclopropanecarboxylic acid methyl ester
[1220]
[1221] Triphenylphosphine (10 g) and carbon tetrabromide (16 g) were added to a methylene chloride solution (168 ml) of the compound (4.20 g) obtained in Reference Example 162 at room temperature under a nitrogen atmosphere. After 2 minutes, saturated sodium bicarbonate was added. An aqueous solution was added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate ethyl hexane: hexane = 1:19) to obtain the title compound (2.15 g).
[1222]
[1223] Reference Example 164 (4S) -4-[(E) -3-ethoxy-3-oxo-1-propenyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester
[1224]
[1225] (4R) -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (11.7 g), (carboethoxymethylene) triphenylphosphorane (20.7 g) and a mixed solution of toluene (100 ml) were stirred by heating at 100 ° C. for 18 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound (17 g).
[1226]
[1227] Reference Example 165 (4S) -4- [1- (benzylamino) -3-ethoxy-3-oxopropyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert -Butyl ester
[1228]
[1229] The mixed solution of the compound (22.2 g), benzylamine (16 g) and ethanol (100 ml) obtained in Reference Example 164 was heated to reflux for 2 days. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound (26 g).
[1230]
[1231] Reference Example 166 (4S) -4- (1-Amino-3-ethoxy-3-oxopropyl) -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester
[1232]
[1233] To the ethanol (200 ml) solution of the compound (13.6 g) obtained in Reference Example 165, 10% palladium carbon (10 g) was added and stirred under a hydrogen atmosphere for 2 days. The insolubles were filtered off through a celite pad and the filtrate was concentrated under reduced pressure to afford the title compound (10.5 g).
[1234]
[1235] Reference Example 167 (4S) -4- (1-{[(benzyloxy) carbonyl] amino} -3-ethoxy-3-oxopropyl) -2,2-dimethyl-1,3-oxazolidine 3-carboxylic acid tert-butyl ester
[1236]
[1237] The compound (3.0 g) obtained in Reference Example 166 was suspended in 9% aqueous sodium hydrogen carbonate solution (56 ml), and dioxane (12 ml) solution of N- (benzyloxycarbonyloxy) succinate (2.3 g) was cooled under ice cooling. Was added dropwise and stirred for 3 hours while gradually returning to room temperature. The reaction solution was diluted with acetic acid ethyl ester, washed with water, 10% citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (3.8 g).
[1238]
[1239] Reference Example 168 (3S, 4S) -3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] -5-hydroxyglycylic acid ethyl ester (low polarity) Compound) and (3R, 4S) -3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] -5-hydroxyglycylic acid ethyl ester (high polar compound)
[1240]
[1241] To the methylene chloride (100 ml) solution of the compound (30 g) obtained in Reference Example 167, trifluoroacetic acid (100 ml) was added dropwise under ice-cooling, and stirred for 3 hours while gradually returning to room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in methylene chloride (100 ml). A solution of methylene chloride (100 ml) of triethylamine (20 ml) and dicarbon-di-tert-butyl (19 g) was added dropwise to the solution under ice cooling, followed by stirring for 4 hours while gradually returning to room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 2: 1) to give the titled low polar compound (7.6 g) and the title high polar compound (10 g).
[1242] Low Polar Compounds:
[1243]
[1244] High Polar Compounds:
[1245]
[1246] Reference Example 169 Methanesulfonic Acid (3R, 4S) -4-[(methylsulfonyl) oxy] tetrahydro-3-furanyl ester
[1247]
[1248] To the methylene chloride (50 ml) solution of 1,4-anhydroerythritol (5.0 g) was added dropwise triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) under ice-cooling in order, and under ice-cooling 10 Stirred for a minute. The reaction solution was diluted with methylene chloride and washed with 10% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (9.2 g).
[1249]
[1250] Reference Example 170 (3R, 4S) -3,4-diazidetetrahydrofuran
[1251]
[1252] The compound (9.2 g) obtained in the reference example 169 was dissolved in N, N-dimethylformamide (50 ml), sodium azide (18 g) was added, and it stirred for 18 hours by heating at 100 degreeC. The reaction solution was diluted with acetic acid ethyl ester and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (3.8 g).
[1253]
[1254] Reference Example 171 (3R, 4S) -tetrahydro-3,4-furandiamine dihydrochloride
[1255]
[1256] The compound (3.8 g) obtained in Reference Example 170 was dissolved in ethanol (50 ml), 10% palladium carbon (1.0 g) was added, and the mixture was stirred for 18 hours under a hydrogen atmosphere. Insolubles were filtered off through a pad of celite and the filtrate was concentrated under reduced pressure. Ethanol hydrochloric acid solution was added to the obtained residue to make a hydrochloride, and then recrystallized from a mixed solvent of ethanol and diethyl ether to obtain the title compound (2.0 g).
[1257]
[1258] Reference Example 172 N-[(3R ^* , 4S ^* )-4-aminotetrahydro-3-furanyl] -5-chloroindole-2-carboxamide
[1259]
[1260] To a N, N-dimethylformamide (10 ml) solution of the compound (0.5 g) obtained in Reference Example 171, 5-chloroindole-2-carboxylic acid (0.29 g) and 1-hydroxybenzotriazole ( 0.2 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.6 g) were added sequentially and stirred at 50 degreeC for 1 day. The residue obtained by concentrating the reaction solution was diluted with a mixed solvent of chloroform: methanol (9: 1), and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain the title compound (0.2 g).
[1261]
[1262] Reference Example 173 (4R) -4-[(E) -3-ethoxy-3-oxo-1-propenyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester
[1263]
[1264] In the same manner as in Reference Example 164, the title compound was obtained from (4S) -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester.
[1265]
[1266] Reference Example 174 (4R) -4- [1- (benzylamino) -3-ethoxy-3-oxopropyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert -Butyl ester
[1267]
[1268] In the same manner as in Reference Example 165, the title compound was obtained from the compound obtained in Reference Example 173.
[1269]
[1270] Reference Example 175 (4R) -4- (1-{[(5-chloroindol-2-yl) carbonyl] amino} -3-ethoxy-3-oxopropyl) -2,2-dimethyl-1 , 3-oxazolidine-3-carboxylic acid tert-butyl ester
[1271]
[1272] In the same manner as in Reference Example 166, the compound obtained in Reference Example 174 was subjected to catalytic reduction to remove the benzyl group, and then in the same manner as in Reference Example 172 to condense with 5-chloroindole-2-carboxylic acid to obtain the title compound.
[1273]
[1274] Reference Example 176 (3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl Ester (low polar compound) and (3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-ylcarbamic acid tert -Butyl ester (high polar compound)
[1275]
[1276] To the ethanol (20 ml) solution of the compound (1.0 g) obtained in Reference Example 175, 1 N sodium hydroxide solution (4.0 ml) was added and stirred for 4 hours. Citric acid was added to the reaction solution, the mixture was adjusted to pH 4.0 and extracted with acetic acid ethyl ester. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (50 ml), toluenesulfonic acid monohydrate (0.1 g) was added, and the mixture was stirred for 18 hours. The reaction solution was diluted with acetic acid ethyl ester and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1) to give the titled low polar compound (0.3 g) and high polar compound (0.3 g). Got.
[1277] Low Polar Compounds:
[1278]
[1279] High Polar Compounds:
[1280]
[1281] Reference Example 177 1,1,3-trioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
[1282]
[1283] A tetrahydrofuran (900 ml) solution of N-tert-butoxycarbonyl-L-methionine sulfonemethyl ester (60.2 g) was cooled to -78 ° C and 0.5 M potassium bis (trimethylsilyl) amide (toluene solution, 900 ml) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours and at room temperature for 4 hours and half. Aqueous 1 M ammonium chloride solution was added and stirred. After the reaction solution was separated, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting solid was collected by filtration to give the title compound (12.4 g). The separated aqueous layer was extracted twice with ethyl acetate, the organic layers were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. Further, the aqueous layers used for washing were combined, extracted again with acetic acid ethyl ester, washed with saturated brine and dried over anhydrous magnesium sulfate. The combined ethyl acetate extracts were dried and concentrated under reduced pressure to afford the title compound (27.7 g) (total amount of title compound: 40.1 g).
[1284]
[1285] Reference Example 178 (3R ^* , 4R ^* )-3-hydroxy-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
[1286]
[1287] Sodium borohydride (2.17 g) was added to a methanol (200 ml) suspension of the compound (10.1 g) obtained in Reference Example 177, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. After adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution to the residue, the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (9.96 g).
[1288]
[1289] Reference Example 179 (3R ^* , 4R ^* )-3-Amino-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester (low polar compound) and (3R ^* , 4S ^* )-3-Amino-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester (high polar compound)
[1290]
[1291] Diethyl azodicarboxylic acid (6.96 g) was added to a tetrahydrofuran (150 ml) solution of the compound (9.66 g) and triphenylphosphine (10.5 g) obtained in Reference Example 178, followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the resulting solid was collected by filtration. The solid collected by filtration was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 7: 3) to tert 1,1-dioxo-1,2,3,4-tetrahydrothiopyran-4-ylcarbamic acid tert. A mixture (7.25 g) comprising -butyl ester was obtained as a colorless solid. Further, the mother liquor was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 7: 3) to give 1,1-dioxo-1,2,3,4-tetrahydrothiopyran. A mixture (9.18 g) comprising -4-ylcarbamic acid tert-butyl ester was obtained as a colorless solid (total amount: 16.4 g). The resulting mixture was dissolved in dioxane (60 ml), and 28% aqueous ammonia (60 ml) was added and stirred for half an hour at 60 ° C. in a sealed tube. After cooling, the reaction solution was concentrated under reduced pressure. The dioxane was distilled off and extracted five times with methylene chloride. The organic layers were combined and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methylene chloride: methanol = 96: 4) to obtain the title low polar compound (2.31 g) and high polar compound (4.31 g).
[1292] Low Polar Compounds:
[1293]
[1294] High Polar Compounds:
[1295]
[1296] Reference Example 180 (2S, 3S) -2,3-bis (methoxymethoxy) -1,4-butanediol
[1297]
[1298] To a mixed solution of diethyl L-tartrate (8.6 g), diisopropylethylamine (40 ml) and methylene chloride (40 ml), chloromethyl methyl ether (4.8 ml) was added dropwise under ice-cooling, and gradually added to room temperature. It stirred for 18 hours, returning. The residue obtained by concentrating the reaction solution was diluted with acetic acid ethyl ester, and washed with 10% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran. The solution was added dropwise to tetrahydrofuran suspension of lithium aluminum hydride (2.2 g) under ice cooling, followed by stirring for 2 hours under ice cooling. Under ice-cooling, 10% aqueous sodium hydrogen sulfate solution was carefully added, stirred for 1 hour, diluted with saturated brine and extracted with ethyl acetate. After drying the obtained organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (3.0 g).
[1299]
[1300] Reference Example 181 (3S, 4S) -3, 4-bis (methoxymethoxy) tetrahydrofuran
[1301]
[1302] Diethyl azodicarboxylic acid (2.64 ml) was added to a mixed solution of the compound obtained in Reference Example 180 (3.0 g), triphenylphosphine (4.5 g), tetrahydrofuran (10 ml) and toluene (40 ml). It was added dropwise and stirred at room temperature for 4 days. The reaction solution was concentrated, and a mixed solvent (160 ml) made of hexane: diethyl ether (1: 1) was added thereto, stirred for 3 hours, and the precipitated insoluble matter was filtered out. The filtrate was concentrated and the residue obtained was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 4: 1) to give the title compound (1.95 g).
[1303]
[1304] Reference Example 182 (3S, 4S) Tetrahydro-3,4-furandiol
[1305]
[1306] To the methanol (6.0 ml) solution of the compound (1.95 g) obtained in Reference Example 181, concentrated hydrochloric acid (2.1 ml) was added and stirred for 18 hours. The reaction solution was concentrated, the obtained residue was diluted with chloroform, dried over potassium carbonate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.52 g).
[1307]
[1308] Reference Example 183 (3S, 4S) Tetrahydro-3,4-furandiamine
[1309]
[1310] The title compound was obtained in the same manner as the method described in Reference Examples 169 to 171 from the compound obtained in Reference Example 182.
[1311]
[1312] Reference Example 184 (2R, 3R) -2,3-bis (methoxymethoxy) -1,4-butanediol
[1313]
[1314] In the same manner as in Reference Example 180, the title compound was obtained from diethyl D-tartarate.
[1315] ¹ H-NMR: consistent with Reference Example 180 being an enantiomer.
[1316] Reference Example 185 (3R, 4R) -3, 4-bis (methoxymethoxy) tetrahydrofuran
[1317]
[1318] In the same manner as in Reference Example 181, the title compound was obtained from the compound obtained in Reference Example 184.
[1319] ¹ H-NMR: consistent with Reference Example 181 which is an enantiomer.
[1320] Reference Example 186 (3R, 4R) Tetrahydro-3,4-furandiol
[1321]
[1322] In the same manner as in Reference Example 182, the title compound was obtained from the compound obtained in Reference Example 185.
[1323] ¹ H-NMR: consistent with Reference Example 182 which is an enantiomer.
[1324] Reference Example 187 (3R, 4R) Tetrahydro-3,4-furandiamine
[1325]
[1326] In the same manner as in Reference Example 183, the title compound was obtained from the compound obtained in Reference Example 186.
[1327] ¹ H-NMR: consistent with Reference Example 183 which is an enantiomer.
[1328] Reference Example 188 (3R, 4R) -1-Benzyl-3,4-dihydroxy-2,5-pyrrolidinedione
[1329]
[1330] L-tartaric acid (30 g) and benzylamine (22 ml) were added to xylene (150 ml) and heated to reflux at 150 ° C. for 3 hours using a Deanstark dehydrator. After cooling the reaction solution overnight, the crystals were collected by filtration and washed with acetone. The resulting crude product was recrystallized from ethanol to obtain the title compound (23.2 g).
[1331]
[1332] Reference Example 189 (3S, 4S) -1-Benzyl-3, 4-pyrrolidinediol
[1333]
[1334] Compound (11 g) obtained in Reference Example 188 was dissolved in tetrahydrofuran (110 ml), and lithium aluminum hydride (5.69 g) was added little by little under ice-cooling. It heated up to room temperature and heated to reflux overnight for 1 hour. After allowing to cool, ice-cooled the mixture, followed by addition of water (5.7 ml), 15% aqueous sodium hydroxide solution (5.7 ml), and water (17.1 ml), and the mixture was returned to room temperature and stirred for 1 hour. The precipitate was filtered through Celite filtration, the mother liquor was concentrated, and then recrystallized with acetic acid ethyl ester to obtain the title compound (6.35 g).
[1335]
[1336] Reference Example 190 Methanesulfonic Acid (3S, 4S) -1-Benzyl-4-[(methylsulfonyl) oxy] pyrrolidinyl Ester
[1337]
[1338] In the same manner as in Reference Example 169, the title compound was obtained from the compound obtained in Reference Example 189.
[1339]
[1340] Reference Example 191 (3S, 4S) -3,4-bis [(methylsulfonyl) oxy] -1-pyrrolidinecarboxylic acid tert-butyl ester
[1341]
[1342] The compound (1.57 g) obtained in Reference Example 190 was dissolved in 1,2-dichloroethane (16 ml), and chloroformic acid 1-chloroethyl (0.73 ml) was added thereto, followed by heating to reflux for 4 hours. After distilling off the solvent under reduced pressure, methanol (16 ml) was added to the obtained residue, the mixture was heated to reflux for 1 hour, cooled and concentrated, and the crystals were collected by filtration with acetic acid ethyl ester (3S, 4S) -3,4-bis [ (Methylsulfonyl) oxy] pyrrolidine hydrochloride (1.30 g) was obtained as colorless crystals. Di-tert-butyl dicarbonate (1.15 ml) was added to the obtained methylene chloride (26 ml) solution of hydrochloride and triethylamine (1.40 ml), and the mixture was stirred overnight at room temperature. After concentration, the mixture was diluted with acetic acid ethyl ester, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 1) to obtain the title compound (1.40 g).
[1343]
[1344] Reference Example 192 (3R, 4R) -3, 4-diazide-1-pyrrolidinecarboxylic acid tert-butyl ester
[1345]
[1346] In the same manner as in Reference Example 170, the title compound was obtained from the compound obtained in Reference Example 191.
[1347]
[1348] Reference Example 193 (3R, 4R) -3-Amino-4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid tert-butyl ester
[1349]
[1350] The title compound was obtained from the compound obtained in Reference Example 192 in the same manner as the methods described in Reference Examples 171 and 172.
[1351]
[1352] Reference Example 194 (3S) -5-Oxotetrahydro-3-furanylcarbamic acid tert-butyl ester
[1353]
[1354] To a tetrahydrofuran (20 ml) solution of (3S)-(-)-tetrahydro-5-oxo-3-furanylcarbamic acid benzyl ester (3.3 g), di-tert-butyl dicarbonate (4.1 g) and 10% palladium carbon (0.4 g) was added and stirred for 1 day under hydrogen atmosphere. The insolubles were removed by filtration through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 4: 1) to obtain the title compound (1.5 g).
[1355]
[1356] Reference Example 195 (3S, 4S) -4-Azide-5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester
[1357]
[1358] To a tetrahydrofuran (20 ml) solution of the compound (0.87 g) obtained in Reference Example 194, 1 M lithium bis (trimethylsilyl) amide (tetrahydrofuran solution, 8.65 ml) was added dropwise at -78 ° C and stirred for 30 minutes. . Subsequently, a tetrahydrofuran (10 ml) solution of p-toluenesulfonyl azide (1.02 g) was added and stirred for 5 minutes, followed by addition of trimethylchlorosilane (1.7 ml), followed by stirring for 2 hours while gradually returning to room temperature. The reaction solution was diluted with diethyl ether, washed with 10% aqueous hydrochloric acid solution, 5% saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (0.62 g).
[1359]
[1360] Reference Example 196 (3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester
[1361]
[1362] In the same manner as described in Reference Examples 90 and 91, the title compound was obtained from the compound obtained in Reference Example 195.
[1363]
[1364] Reference Example 197 (3S, 4S) -4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester
[1365]
[1366] In the same manner as in Reference Example 90, (3S, 4S) -4-amino-5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester was obtained from the compound obtained in Reference Example 195, followed by reaction of Reference Example 91 According to the conditions, the compound obtained in Reference Example 10 was reacted to obtain the title compound.
[1367]
[1368] Reference Example 198 2-[((3S) -3-[(tert-butoxycarbonyl) amino] -2-{[(5-chloroindol-2-yl) carbonyl] amino} -4-hydride Oxybutanoyl) amino] acetic acid ethyl ester
[1369]
[1370] Compound (0.4 g), glycine ethyl ester hydrochloride (1.0 g) and triethylamine (1.0 ml) obtained in Reference Example 196 were added to ethanol (20 ml) and stirred by heating at 60 ° C for 18 hours. The reaction was diluted with chloroform and washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to obtain the title compound (0.31 g).
[1371]
[1372] Reference Example 199 2-((4R) -4-amino-3-{[(5-chloroindol-2-yl) carbonyl] amino} -2-oxopyrrolidin-1-yl) acetate ethyl ester Hydrochloride
[1373]
[1374] Using the reaction conditions described in Reference Example 181, the compound obtained in Reference Example 198 was converted to a pyrrolidone derivative, and then the tert-butoxycarbonyl group was removed in the same manner as in Reference Example 69 to obtain the title compound.
[1375]
[1376] Reference Example 200 (3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-methyl-5-oxopyrrolidin-3-ylcarbamic acid tert- Butyl ester
[1377]
[1378] In the same manner as in Reference Example 198, the compound obtained in the reaction of the compound obtained in Reference Example 196 with methylamine (40% methanol solution) was treated under the same conditions as in Reference Example 181 to obtain the title compound.
[1379]
[1380] Reference Example 201 N-[(3S, 4R) -4-Amino-1-methyl-2-oxopyrrolidin-3-yl] -5-chloroindole-2-carboxamide
[1381]
[1382] In the same manner as in Reference Example 69, the compound obtained in Reference Example 200 was treated to obtain the title compound.
[1383]
[1384] Reference Example 202 3,6-dihydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester
[1385]
[1386] Di-tert-butyl dicarbonate (6.55 g) was added to a mixture of 1,2,3,6-tetrahydropyridine (2.50 g) and 10% aqueous sodium carbonate solution (3.0 ml), followed by stirring at room temperature for 20 hours. Water was added to the reaction solution, followed by extraction with acetic acid ethyl ester. The organic layer was washed sequentially with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (5.08 g).
[1387]
[1388] Reference Example 203 (3R ^* , 4S ^* )-3,4-dihydroxy-1-piperidinecarboxylic acid tert-butyl ester
[1389]
[1390] The compound obtained in Reference Example 202 (18.45 g) was dissolved in acetonitrile (200 ml), and water (38 ml), 0.039 mol aqueous osmium tetraoxide solution (82 ml), N-methylmorpholine N-oxide (23.13 g ) Was added and stirred at room temperature for 17 hours. Excess oxidant was treated with saturated aqueous sodium sulfite solution and extracted with ethyl acetate. The organic layer was washed with water, 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 1: 3) to obtain the title compound (15.0 g).
[1391]
[1392] Reference Example 204 (3R ^* , 4S ^* )-3,4-bis [(methylsulfonyl) oxy] -1-piperidinecarboxylic acid tert-butyl ester
[1393]
[1394] In the same manner as in Reference Example 169, the title compound was obtained from the compound obtained in Reference Example 203.
[1395]
[1396] Reference Example 205 (3R ^* , 4S ^* )-3,4-diazide-1-piperidinecarboxylic acid tert-butyl ester
[1397]
[1398] In the same manner as in Reference Example 170, the title compound was obtained from the compound obtained in Reference Example 204.
[1399]
[1400] Reference Example 206 (3R ^* , 4S ^* )-3,4-diamino-1-piperidinecarboxylic acid tert-butyl ester
[1401]
[1402] In the same manner as in Reference Example 171, the title compound was obtained from the compound obtained in Reference Example 205.
[1403]
[1404] Reference Example 207 (3R ^* , 4S ^* )-3-amino-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-piperidinecarboxylic acid tert-butyl ester
[1405]
[1406] The compound (3.23 g) obtained in Reference Example 206 was dissolved in N, N-dimethylformamide (100 ml), triethylamine (2.08 ml) and the compound (3.80 g) obtained in Reference Example 52 were added thereto for 3 days at room temperature. Stirred. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 to 10: 1) to obtain the title compound (2.70 g).
[1407]
[1408] Reference Example 208 (3R ^* , 4S ^* )-3-amino-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Carbonyl] amino} -1-piperidinecarboxylic acid t-butyl ester
[1409]
[1410] The compound (3.23 g) obtained in Reference Example 206 was dissolved in N, N-dimethylformamide (100 ml), and triethylamine (2.08 ml) was added. Subsequently, the compound (3.83 g) obtained in Reference Example 149 was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated by silica gel column chromatography (methylene chloride: methanol = 10: 1 to 5: 1) to obtain the title compound (2.27 g).
[1411]
[1412] Reference Example 209 (3R ^* , 4S ^* )-3-amino-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1-piperidinecarboxylic acid tert-butyl ester
[1413]
[1414] In the same manner as in Reference Example 172, the title compound was obtained from the compound obtained in Reference Example 206 and 5-fluoroindole-2-carboxylic acid.
[1415]
[1416] Reference Example 210 (3S, 4R) -5-Azide-3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] gylic acid ethyl ester
[1417]
[1418] To a methylene chloride (100 ml) solution of (3S, 4S) -compound (low polar compound) (7.1 g) obtained in Reference Example 168, triethylamine (4.80 ml) and methanesulfonyl chloride (1.55 ml) were cooled under ice-cooling. It dripped in order and stirred for 30 minutes under ice-cooling. The reaction solution was diluted with chloroform and washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a methanesulfonyl compound (9.20 g). The resulting mixed solution of methanesulfonyl, sodium azide (5.64 g) and N, N-dimethylformamide (100 ml) was stirred at 80 ° C for 20 hours. The reaction solution was diluted with acetic acid ethyl ester and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (5.42 g).
[1419]
[1420] Reference Example 211 (4S, 5R) -5-[(tert-Butoxycarbonyl) amino] -2-oxopiperidin-4-ylcarbamic acid benzyl ester
[1421]
[1422] To a mixture of ethanol (150 ml) and tetrahydrofuran (10.0 ml) of the compound (5.42 g) obtained in Reference Example 210 was added Lindla catalyst (2.71 g) and stirred under a hydrogen atmosphere for 3 hours. The mixture was stirred for 14 hours under nitrogen. The insolubles were removed by filtration through a celite pad, the filtrate was concentrated under reduced pressure, and the obtained residue was made into tetrahydrofuran (30 ml) solution, triethylamine (3.0 ml) was added, and stirring was carried out at room temperature for 1.5 hours. It was done. The reaction solution was diluted with ethyl acetate and washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 25: 1) to obtain the title compound (2.50 g).
[1423]
[1424] Reference Example 212 (3R, 4S) -3-[(tert-butoxycarbonyl) amino] piperidin-4-ylcarbamic acid benzyl ester
[1425]
[1426] To a tetrahydrofuran (70 ml) solution of the compound (2.49 g) obtained in Reference Example 211, 1 mol of a borane tetrahydrofuran complex (tetrahydrofuran solution, 34.0 ml) was added dropwise under ice cooling, and gradually returned to room temperature. Stirred for time. Methanol (100 ml) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Ethanol (45 ml), water (5 ml) and triethylamine (10 ml) were added to the obtained residue, and heating and refluxing were performed for 24 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol: water = 7: 3: 1, lower layer) to obtain the title compound (1.61 g).
[1427]
[1428] Reference Example 213 (3R, 4S) -1-acetyl-4-{[(benzyloxy) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester
[1429]
[1430] The compound obtained in Reference Example 212 was reacted with acetyl chloride in the presence of triethylamine in methylene chloride to obtain the title compound.
[1431]
[1432] Reference Example 214 (3R, 4S) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester
[1433]
[1434] 10% palladium carbon (532 mg) was added to an ethanol (50 ml) solution of the compound (745 mg) obtained in Reference Example 213, and stirred for 16 hours at room temperature under a hydrogen atmosphere. After removing the insolubles by celite filtration, the filtrate was concentrated under reduced pressure. The obtained residue was treated with 5-chloroindole-2-carboxylic acid (467 mg) in the same manner as in Reference Example 68 to obtain the title compound (650 mg).
[1435]
[1436] Reference Example 215 (3R, 4R) -5-Azide-3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] gylic acid ethyl ester
[1437]
[1438] In the same manner as in Reference Example 210, the title compound was obtained from the (3R, 4S) -compound (high polar compound) obtained in Reference Example 168.
[1439]
[1440] Reference Example 216 (4R, 5R) -5-[(tert-Butoxycarbonyl) amino] -2-oxopiperidin-4-ylcarbamic acid benzyl ester
[1441]
[1442] The compound obtained in Reference Example 215 was treated in the same manner as Reference Example 211 to obtain the title compound.
[1443]
[1444] Reference Example 217 (3R, 4R) -3-[(tert-butoxycarbonyl) amino] piperidin-4-ylcarbamic acid benzyl ester
[1445]
[1446] The compound obtained in Reference Example 216 was treated in the same manner as Reference Example 212 to obtain the title compound.
[1447]
[1448] Reference Example 218 (3R, 4R) -1-acetyl-4-{[(benzyloxy) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester
[1449]
[1450] The compound obtained in Reference Example 217 was treated in the same manner as Reference Example 213 to obtain the title compound.
[1451]
[1452] Reference Example 219 (3R, 4R) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-ylcarbamic acid tert-butyl ester
[1453]
[1454] The compound obtained in Reference Example 218 was treated in the same manner as Reference Example 214 to obtain the title compound.
[1455]
[1456] Reference Example 220 (3R, 4S) -3-[(tert-butoxycarbonyl) amino] -1- (2-methoxyacetyl) piperidin-4-ylcarbamic acid benzyl ester
[1457]
[1458] The title compound was obtained in the same manner as the Reference Example 213 from the compound obtained in Reference Example 212 and methoxyacetyl chloride.
[1459]
[1460] Reference Example 221 (3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester
[1461]
[1462] In the same manner as in Reference Example 214, the title compound was obtained from the compound obtained in Reference Example 220.
[1463]
[1464] Reference Example 222 (3R, 4R) -3-[(tert-butoxycarbonyl) amino] -1- (2-methoxyacetyl) piperidin-4-ylcarbamic acid benzyl ester
[1465]
[1466] In the same manner as in Reference Example 213, the title compound was obtained from the compound obtained in Reference Example 217 and methoxyacetyl chloride.
[1467]
[1468] Reference Example 223 (3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester
[1469]
[1470] In the same manner as in Reference Example 214, the title compound was obtained from the compound obtained in Reference Example 222 and 5-chloroindole-2-carboxylic acid.
[1471]
[1472] Reference Example 224 (3R, 4S) -3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] -5-{[tert-butyl (diphenyl) Silyl] oxy} yl acetic acid ethyl ester
[1473]
[1474] To a (3R, 4S) -compound (high polar compound) (0.74 g) of N, N-dimethylformamide (30 ml) obtained in Reference Example 168, triethylamine (0.47 ml) and imidazole (0.19) under ice-cooling. g) and tert-butylchlorodiphenylsilane (0.7 ml) were added sequentially and stirred for 4 days while gradually returning to room temperature. The reaction solution was diluted with acetic acid ethyl ester, washed with 10% aqueous citric acid solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound (0.85 g).
[1475]
[1476] Reference Example 225 (3R, 4S) -4-[(tert-Butoxycarbonyl) amino] -5-{[tert-butyl (diphenyl) silyl] oxy} -3-{[(5-chloroindole -2-yl) carbonyl] amino} yl acetic acid ethyl ester
[1477]
[1478] In the same manner as in Reference Example 214, the benzyloxycarbonyl group of the compound obtained in Reference Example 224 was removed, and then condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.
[1479]
[1480] Reference Example 226 (3R ^* , 4R ^* )-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] Amino} -1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
[1481]
[1482] In the same manner as in Reference Example 68, the title compound was obtained from the (3R ^* , 4R ^* )-compound (low polar compound) obtained in Reference Example 179 and the compound obtained in Reference Example 10.
[1483]
[1484] Reference Example 227 N- (3R ^* , 4R ^* )-4-amino-1,1-dioxohexahydro-1-thiopyran-3-yl] -5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[1485]
[1486] The compound obtained in Reference Example 226 was treated in the same manner as Reference Example 69 to obtain the title compound.
[1487]
[1488] Reference Example 228 (3R ^* , 4R ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4-yl Carbamic acid tert-butyl ester
[1489]
[1490] In the same manner as in Reference Example 68, the title compound was obtained from (3R ^* , 4R ^* )-compound (low polar compound) and 5-chloroindole-2-carboxylic acid obtained in Reference Example 179.
[1491]
[1492] Reference Example 229 N-[(3R ^* , 4R ^* )-4-amino-1,1-dioxohexahydro-1-thiopyran-3-yl] -5-chloroindole-2-carboxamide hydrochloride
[1493]
[1494] The compound obtained in Reference Example 228 was treated in the same manner as Reference Example 69 to obtain the title compound.
[1495]
[1496] Reference Example 230 (3R ^* , 4S ^* )-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] Amino} -1,1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester
[1497]
[1498] In the same manner as in Reference Example 98, the title compound was obtained from the (3R ^* , 4S ^* )-compound (high polar compound) obtained in Reference Example 179 and the compound obtained in Reference Example 10.
[1499]
[1500] Reference Example 231 N-[(3R ^* , 4S ^* )-4-amino-1,1-dioxohexahydro-1-thiopyran-3-yl] -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[1501]
[1502] The compound obtained in Reference Example 230 was treated in the same manner as Reference Example 69 to obtain the title compound.
[1503]
[1504] Reference Example 232 (3R ^* , 4R ^* )-3-{[(5-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran-4- Ilcarbamic acid tert-butyl ester
[1505]
[1506] In the same manner as in Reference Example 68, the title compound was obtained from the (3R ^* , 4R ^* )-compound (low polar compound) and 5-fluoroindole-2-carboxylic acid obtained in Reference Example 179.
[1507]
[1508] Reference Example 233 N-[(3R ^* , 4R ^* )-4-amino-1,1-dioxohexahydro-1-thiopyran-3-yl] -5-fluoroindole-2-carboxamide Hydrochloride
[1509]
[1510] The compound obtained in Reference Example 232 was treated in the same manner as Reference Example 69 to obtain the title compound.
[1511]
[1512] REFERENCE EXAMPLE 234 (3R) -3-{[(benzyloxy) carbonyl] amino} -4-[(tert-butoxycarbonyl) amino] -5-oxogilacetic acid ethyl ester
[1513]
[1514] Sulfur trioxide complex salt (1.5) at room temperature in a mixed solvent of (3R, 4S) -compound (high polar compound) (0.5 g), dimethyl sulfoxide (6.8 ml) and triethylamine (2.6 ml) obtained in Reference Example 168. g) was added slowly and stirred for 20 minutes. The reaction solution was poured into water, extracted with ethyl acetate, and the resulting organic layer was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (0.51 g).
[1515]
[1516] Reference Example 235 (4R) -5-[(tert-butoxycarbonyl) amino] -1-methyl-2-oxopiperidin-4-ylcarbamic acid benzyl ester
[1517]
[1518] To ethanol (10 ml) solution of the compound (0.51 g) obtained in Reference Example 234, acetic acid (0.27 ml) and 2 M methylamine (tetrahydrofuran solution, 1.0 ml) were added sequentially under ice cooling, gradually returning to room temperature. After stirring for 1 hour, sodium cyanoborohydride (0.15 g) was added and the mixture was stirred for 18 hours. The reaction solution was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was dissolved in toluene (20 ml). Triethylamine (2 ml) was added to the solution, the mixture was heated to reflux for 2 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give the title compound (0.28). g) was obtained.
[1519]
[1520] Reference Example 236 (4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-methyl-6-oxopiperidin-3-ylcarbamic acid tert-butyl ester
[1521]
[1522] In the same manner as in Reference Example 214, the title compound was obtained from the compound obtained in Reference Example 235 and 5-chloroindole-2-carboxylic acid.
[1523]
[1524] Reference Example 237 4- (pyridin-4-yl) benzoic acid hydrochloride
[1525]
[1526] 4-bromopyridine hydrochloride (11.7 g) and 4-carboxyphenylboronic acid (10.0 g) are dissolved in a mixed solvent of toluene (250 ml) -water (250 ml), and tetrakis (triphenylphosphine) palladium ( 0) (5.0 g) and anhydrous sodium carbonate (25.4 g) were added in this order and heated and refluxed at 120 degreeC for 19 hours. After cooling to room temperature, acetic acid ethyl ester was added, extraction was performed with water, and concentrated hydrochloric acid was added to the aqueous layer to make acidic. The aqueous layer was washed with acetic acid ethyl ester, the aqueous layer was concentrated and the precipitated solid was collected by filtration to give the title compound (8.37 g).
[1527]
[1528] Reference Example 238 4- (Pyridin-4-yl) Benzoic Acid Methyl Ester
[1529]
[1530] The compound (12.4 g) obtained in Reference Example 237 was dissolved in methanol (200 ml), concentrated sulfuric acid (5 ml) was added thereto, and the mixture was heated to reflux for 3 hours. After the reaction was completed, the solvent was distilled off, and a saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off, hexane was added to the residue, and the solid was obtained to obtain the title compound (9.86 g).
[1531]
[1532] Reference Example 239 4- [4- (methoxycarbonyl) phenyl] pyridine N-oxide
[1533]
[1534] The compound (1.49 g) obtained in the reference example 238 was dissolved in methylene chloride (30 ml), 70% m-chloro perbenzoic acid (3.46 g) was added, and it stirred at room temperature for 1 hour. An aqueous sodium sulfite solution was added to the mixture, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (1.33 g).
[1535]
[1536] Reference Example 240 4- (4-carboxyphenyl) pyridine N-oxide
[1537]
[1538] The compound (802 mg) obtained in Reference Example 239 was dissolved in dioxane (20 ml), 1 N sodium hydroxide solution (5 ml) was added thereto, and the mixture was refluxed for 1 hour, followed by stirring at room temperature for 2 hours. 1N aqueous hydrochloric acid solution (5 ml) was added to neutralize. Further, water (5 ml) was added to the resulting precipitate, which was collected by filtration to obtain the title compound (627 mg).
[1539]
[1540] Reference Example 241 2- (4-carboxyphenyl) -1-pyridine N-oxide
[1541]
[1542] The title compound was obtained in the same manner as Reference Examples 237, 238, 239, and 240 from 2-bromopyridine.
[1543]
[1544] Reference Example 242 2- (4-Chloroanilino) -2-oxoacetic acid ethyl ester
[1545]
[1546] To a solution of 4-chloroaniline (1.16 g) and methylene chloride (26 ml), triethylamine (1.52 ml) and chlorooxoacetic acid ethyl ester (1.11 ml) were sequentially added under ice cooling, followed by stirring at room temperature for 14 hours. After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution, the organic layer was washed with 10% citric acid solution and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and then hexane was added to the residue to precipitate crystals, filtered and collected to dryness to give the title compound (1.89 g).
[1547]
[1548] Reference Example 243 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid methyl ester
[1549]
[1550] 2-amino-5-chloropyridine (1.16 g) and triethylamine (1.51 ml) were dissolved in methylene chloride (26 ml), and chlorooxoacetic acid ethyl ester (1.10 ml) was added under ice cooling, followed by stirring at room temperature for 14 hours. . After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution and separating the solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 1). The resulting pale yellow solid was dissolved in methanol (20 ml) and stirred at 50 ° C. for 11 hours. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and dried to obtain the title compound (0.43 g).
[1551]
[1552] Reference Example 244 (1S) -3-cyclohexene-1-carboxylic acid
[1553]
[1554] (R)-(+)-α-methylbenzylamine salt of (1S) -3-cyclohexene-1-carboxylic acid (J. Am. Chem. Soc., 1978, 100, 5199-5203) (95.0 g) was dissolved in acetic acid ethyl ester (1.6 l) and 2N hydrochloric acid (1.6 l), the organic layer was aliquoted, the aqueous layer was extracted with acetic acid ethyl ester (500 ml × 2 times), and the organic layers were combined and saturated brine. (300 ml × 2 times) and the organic layer was aliquoted. After the aqueous layer was extracted with ethyl acetate (200 ml), the organic layer was washed with saturated brine (100 ml), the combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (48.3 g).
[1555] [a] ²⁵ _D = −104 ° (c = 1, chloroform).
[1556]
[1557] Reference Example 245 (1S, 4S, 5S) -4-iodine-6-oxabicyclo [3.2.1] octane-7-one
[1558]
[1559] To a mixture of the compound obtained in Reference Example 244 (48.0 g), methylene chloride (580 ml), potassium iodide (82.1 g), sodium bicarbonate (42.0 g) and water (530 ml), iodine (125.4) at an internal temperature of 5 ° C g) was added and stirred at room temperature for 3 hours. After adding 1 N aqueous sodium thiosulfate solution (800 ml) to the reaction solution, the mixture was extracted with methylene chloride (1 L, 500 ml), and the organic layer was washed with aqueous sodium bicarbonate solution (300 ml), water (500 ml) and saturated brine (300). ml), dried over anhydrous magnesium sulfate, and concentrated. The precipitated crystals were collected by filtration, washed with hexane and dried to obtain the title compound (89.5 g).
[1560] Melting point: 130-131 ° C.
[1561] [α] ²⁵ _D = -41 ° (c = 1, chloroform).
[1562]
[1563] Reference Example 246 (1S, 3S, 6R) -7-Oxabicyclo [4.1.0] heptane-3-carboxylic acid ethyl ester
[1564]
[1565] To the ethanol (810 ml) suspension of the compound (89.3 g) obtained in Reference Example 245 was added a 2 N aqueous sodium hydroxide solution (213 ml) while stirring at room temperature, followed by stirring for 3 hours. The reaction solution was concentrated under reduced pressure over a bath temperature of 35 ° C., and water (500 ml) was added to the obtained oil, and extracted with methylene chloride (500 ml and 300 ml). The organic layer was washed with water (300 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane: ethyl acetate = 85:15) to obtain the title compound (41.3 g).
[1566] [a] ²⁵ _D = −58 ° (c = 1, chloroform).
[1567]
[1568] Reference Example 247 (1S, 3R, 4R) -3-Azide-4-hydroxycyclohexanecarboxylic acid ethyl ester
[1569]
[1570] A mixture of compound (41.0 g), N, N-dimethylformamide (300 ml), ammonium chloride (19.3 g) and sodium azide (23.5 g) obtained in Reference Example 246 was stirred at 76 ° C for 13 hours. The insolubles were collected by filtration, and the filtrate was concentrated under reduced pressure without solidifying, and the filtered and collected material was added to the residue and dissolved in water (500 ml). Extracted with acetic acid ethyl ester (500 ml, 300 ml), washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the title compound (51.5 g).
[1571] [a] ²⁵ _D = + 8 ° (c = 1, chloroform).
[1572]
[1573] Reference Example 248 (1S, 3R, 4R) -3-[(tert-butoxycarbonyl) amino] -4-hydroxycyclohexanecarboxylic acid ethyl ester
[1574]
[1575] A mixture of the compound obtained in Reference Example 247 (51.2 g), di-tert-butyldicarbonate (68.1 g), 5% palladium carbon (5.0 g) and acetic acid ethyl ester (1000 ml) was subjected to hydrogen pressure (7 kg / cm 2). Stir overnight at room temperature. The reaction solution was filtered and concentrated to obtain an oily product, which was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-&gt; 3: 1). Crystallization from hexanes gave the title compound (46.9 g). The mother liquor was further purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give the title compound (6.74 g).
[1576] [α] ²⁵ _D = + 25 ° (c = 1, chloroform).
[1577]
[1578] Reference Example 249 (1S, 3R, 4S) -4-azide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[1579]
[1580] To a solution of compound (53.5 g), methylene chloride (500 ml) and triethylamine (130 ml) obtained in Reference Example 248, methanesulfonyl chloride (42 ml) was added over 20 minutes at -10 ° C to -15 ° C. It dripped. It took 2 hours, it heated up to room temperature and stirred for 2 hours. 0.5N hydrochloric acid (800 ml) was added dropwise to the reaction solution at 0 ° C to make acid, and extracted with methylene chloride (500 ml, 300 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystal was dissolved in N, N-dimethylformamide (335 ml), sodium azide (60.5 g) was added, and the mixture was stirred at 67 to 75 ° C for 16 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to distill 250 ml of the solvent. The residue and the filtered material were combined and dissolved in water (500 ml) and extracted with acetic acid ethyl ester (1 l and 300 ml). The organic layer was washed with saturated brine (400 ml, 200 ml), dried over anhydrous magnesium sulfate, and then concentrated to obtain a crystal obtained by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (18.4 g). Got.
[1581] [α] ²⁵ _D = + 62 ° (c = 1, chloroform).
[1582]
[1583] Reference Example 250 (1S, 3R, 4S) -4-Azide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid
[1584]
[1585] Lithium hydroxide (102 mg) and water (5 ml) were added to a tetrahydrofuran (25 ml) solution of the compound (1.0 g) obtained in Reference Example 249, followed by stirring for 17 hours, followed by further addition of lithium hydroxide (50 mg). It was added and stirred for 4 hours. 1N aqueous hydrochloric acid solution (6.3 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure to obtain the title compound (980 mg).
[1586]
[1587] Reference Example 251 (1R, 2S, 5S) -2-Azide-5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester
[1588]
[1589] Compound (4.77 g) obtained in Reference Example 250 was dissolved in methylene chloride (150 ml), and dimethylamine hydrochloride (3.26 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.60 g) , 1-hydroxybenzotriazole monohydrate (3.24 g) and N-methylmorpholine (8.09 g) were added, and the mixture was stirred at room temperature for 18 hours. After saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, the organic layer was dried and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 50) to obtain the title compound (4.90 g).
[1590]
[1591] Reference Example 252 N-{(1R, 2S, 5S) -2-Azide-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothia Solo [5,4-c] pyridine-2-carboxamide
[1592]
[1593] The compound (9.13 g) obtained in Reference Example 251 was dissolved in methylene chloride (100 ml), ethanol chloride solution (100 ml) was added, and the mixture was stirred at room temperature for 1 minute. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in N, N-dimethylformamide (200 ml), the compound (7.75 g) obtained in Reference Example 10, 1-hydroxybenzotriazole monohydrate (4.47 g), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.2 g) and triethylamine (2.02 ml) were added, and the mixture was stirred overnight at room temperature. Furthermore, the compound (2.38g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.60g) obtained by the reference example 10 were added, and it stirred for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was separated by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution, and the obtained organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to obtain the title compound (7.38 g).
[1594]
[1595] Reference Example 253 N-{(1R, 2S, 5S) -2-Amino-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[1596]
[1597] 10% palladium carbon (6.0 g) was added to a methanol (300 ml) solution of the compound (9.0 g) obtained in Reference Example 252, and the mixture was stirred vigorously at room temperature for 11 hours at 4 atmospheres of hydrogen. The catalyst was filtered off and the filtrate was concentrated to give the title compound (7.67 g).
[1598]
[1599] Reference Example 254 2- (4-Fluoroanilino) -2-oxoacetic acid methyl ester
[1600]
[1601] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-fluoroaniline and chlorooxoacetic acid methyl ester.
[1602]
[1603] Reference Example 255 2- (4-Bromoanilino) -2-oxoacetic acid methyl ester
[1604]
[1605] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-bromoaniline and chlorooxoacetic acid methyl ester.
[1606]
[1607] Reference Example 256 2- (4-Chloro-2-methylanilino) -2-oxoacetic acid methyl ester
[1608]
[1609] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-chloro-2-methylaniline and chlorooxoacetic acid methyl ester.
[1610]
[1611] Reference Example 257 2-[(4-chloro-3-methylanilino) -2-oxoacetic acid methyl ester
[1612]
[1613] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-chloro-3-methylaniline and chlorooxoacetic acid methyl ester. ¹ H-NMR
[1614]
[1615] Reference Example 258 2- (4-Chloro-2-fluoroanilino) -2-oxoacetic acid methyl ester
[1616]
[1617] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-chloro-2-fluoroaniline and chlorooxoacetic acid methyl ester.
[1618]
[1619] Reference Example 259 2- (2,4-Difluoroanilino) -2-oxoacetic acid methyl ester
[1620]
[1621] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 2,4-difluoroaniline and chlorooxoacetic acid methyl ester.
[1622]
[1623] Reference Example 260 2- (3,4-Difluoroanilino) -2-oxoacetic acid methyl ester
[1624]
[1625] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 3,4-difluoroaniline and chlorooxoacetic acid methyl ester.
[1626]
[1627] Reference Example 261 2-Oxo-2- (pyridin-4-ylamino) acetic acid methyl ester
[1628]
[1629] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-aminopyridine and chlorooxoacetic acid methyl ester.
[1630]
[1631] Reference Example 262 2-[(5-bromopyridin-2-yl) amino] -2-oxoacetic acid methyl ester
[1632]
[1633] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 2-amino-5-bromopyridine and chlorooxoacetic acid methyl ester.
[1634]
[1635] Reference Example 263 2-[(6-chloropyridin-3-yl) amino] -2-oxoacetic acid ethyl ester
[1636]
[1637] 5-amino-2-chloropyridine (386 mg) was dissolved in N, N-dimethylformamide (8 ml), 2-ethoxy-2-oxoacetate potassium salt (469 mg), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (863 mg) and 1-hydroxybenzotriazole monohydrate (203 mg) were added and stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, followed by separating liquid by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution, and then drying the organic layer over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and then purified by silica gel flash column chromatography (hexane: acetic acid ethyl ester = 2: 1) to give a residue (200 mg) containing the title compound.
[1638]
[1639] Reference Example 264 2-[(6-chloropyridazin-3-yl) amino] -2-oxoacetic acid methyl ester
[1640]
[1641] 3-amino-6-chloropyridazine (516 mg) was dissolved in pyridine (26 ml), and triethylamine (665 μl) and chlorooxoacetic acid methyl ester (441 μl) were added sequentially in ice-cooling at room temperature for 14 hours. Stirred. Water was added to the reaction solution to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (748 mg).
[1642]
[1643] Reference Example 265 2-[(5-chlorothiazol-2-yl) amino] -2-oxoacetic acid methyl ester
[1644]
[1645] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 2-amino-5-chlorothiazole and chlorooxoacetic acid methyl ester.
[1646]
[1647] Reference Example 266 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid lithium salt
[1648]
[1649] To a tetrahydrofuran (20 ml) solution of the compound (1.12 g) obtained in Reference Example 243, water (5.0 ml) and lithium hydroxide (128 mg) were added at room temperature and stirred for 5 hours. The solvent was distilled off under reduced pressure, hexane (30 ml) was added to the obtained white solid, stirred for 30 minutes, the solid was collected by filtration, and dried to obtain the title compound (1.02 g).
[1650]
[1651] Reference Example 267 2- (4-Chloroanilino) acetic acid ethyl ester
[1652]
[1653] 4-chloroaniline (2.0 g) was dissolved in acetonitrile (20 ml), bromoacetic acid ethyl ester (2.1 g) and potassium carbonate (2.2 g) were added and stirred at 60 ° C for 2 days. The reaction solution was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: chloroform = 2: 1) to obtain the title compound (2.3 g).
[1654]
[1655] Reference Example 268 2- (4-Chloro-2-fluoroanilino) acetic acid ethyl ester
[1656]
[1657] In the same manner as in the method described in Reference Example 267, the title compound was obtained from 4-chloro-2-fluoroaniline and bromoacetic acid ethyl ester.
[1658]
[1659] Reference Example 269 2-[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] -2-oxoacetic acid ethyl ester
[1660]
[1661] The compound (1.5 g) obtained in Reference Example 253 was dissolved in N, N-dimethylformamide (15 ml), and 2-ethoxy-2-oxoacetate potassium salt (962 mg) and 1- (3-dimethylaminopropyl ) -3-Ethylcarbodiimide hydrochloride (1.18 g) and 1-hydroxybenzotriazole monohydrate (277 mg) were added, and it stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure, and an aqueous saturated sodium bicarbonate solution and methylene chloride were added to the residue and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 47: 3) to obtain the title compound (1.13 g).
[1662]
[1663] Reference Example 270 2-[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] -2-oxoacetate
[1664]
[1665] The compound (1.13 g) obtained in Reference Example 269 was dissolved in tetrahydrofuran (20 ml), methanol (10 ml) and water (10 ml), and lithium hydroxide (58 mg) was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to give the title compound (1.10 g).
[1666]
[1667] Reference Example 271 N-{(1R, 2S, 5S) -2-azide-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxamide
[1668]
[1669] The title compound was obtained from the compound obtained in Reference Example 293 and the compound obtained in Reference Example 251 in the same manner as the method described in Reference Example 252.
[1670]
[1671] Reference Example 272 N-{(1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-5,6-dihydro-4H-pyrrolo [ 3,4-d] thiazole-2-carboxamide
[1672]
[1673] In the same manner as described in Reference Example 253, the title compound was obtained from the compound obtained in Reference Example 271.
[1674]
[1675] Reference Example 273 5-Chloro-4-fluoroindole-2-carboxylic acid methyl ester
[1676]
[1677] Under argon atmosphere, ethanol (100 ml) was added to sodium hydride (containing 60%, 4.7 g) at 0 ° C. and stirred for 10 minutes. 2-nitropropane (11 ml) was added to the reaction solution, followed by stirring for 10 minutes, followed by addition of 1- (bromomethyl) -3-chloro-2-fluorobenzene (10 g), followed by stirring at room temperature for 3.5 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water, and the organic layer was washed sequentially with 1N aqueous sodium hydroxide solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate ethyl hexane: hexane = 3: 7) to give crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oily compound. Under argon atmosphere, methanol (20 ml) was added to sodium hydride (containing 60%, 1.6 g) at 0 ° C. and stirred for 10 minutes. The reaction solution was cooled to −20 ° C., and a solution of crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and methanol (10 ml) of 2-azide acetic acid methyl ester (5.0 g) was added within 20 minutes. The reaction solution was heated to 0 ° C., stirred for 2.5 hours, and water (40 ml) was added. The reaction solution was concentrated under reduced pressure, and the residue was extracted with methylene chloride acetate ethyl ester mixture. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (toluene: hexane = 3: 17) to prepare 2-azide-3-[(3-chloro-2-fluoro) phenyl] acrylic acid methyl ester (2.6 g). ) This was dissolved in xylene (50 ml) and stirred at 130-140 ° C. for 3 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (methylene chloride), and then crystallized with diethyl ether hexane to obtain the title compound (440 mg).
[1678]
[1679] Reference Example 274 5-Chloro-4-fluoroindole-2-carboxylic acid
[1680]
[1681] The compound (440 mg) obtained in the reference example 273 was dissolved in tetrahydrofuran (10 ml), the aqueous solution of lithium hydroxide (160 mg) (5 ml) was added, and it stirred at room temperature for 3 hours. An aqueous solution of lithium hydroxide (240 mg) (5 ml) was added to the reaction mixture, which was then stirred at room temperature for another 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was neutralized with 1N aqueous hydrochloric acid solution and extracted three times with acetic acid ethyl ester. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (390 mg).
[1682]
[1683] Reference Example 275 1-benzyl-5-chloroindole-2-carboxylic acid ethyl ester
[1684]
[1685] 5-Chloroindole-2-carboxylic acid ethyl ester (1.4 g) was dissolved in N, N-dimethylformamide (30 ml), potassium carbonate (2.9 g) and benzyl chloride (2.4 ml) were added, and the bath temperature was 100 ° C. The mixture was heated and stirred for 1.5 hours at. The reaction solution was concentrated under reduced pressure, and the residue was poured into iced water and extracted with acetic acid ethyl ester. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 19), and crystallized from diethyl ether-hexane to obtain the title compound (1.6 g).
[1686]
[1687] Reference Example 276 1-benzyl-5-chloro-3-fluoroindole-2-carboxylic acid ethyl ester
[1688]
[1689] To the methylene chloride solution (30 ml) of the compound (2.2 g) obtained in Reference Example 275, 1-fluoro-2,6-dichloropyridinium triflate (4.4 g) was added and heated to reflux for 3 days. The reaction solution was partitioned between acetic acid ethyl ester and water, and the aqueous layer was extracted with acetic acid ethyl ester. The organic layers were combined, washed sequentially with 1N hydrochloric acid, water, and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate ethyl hexane: hexane = 1:24) to obtain the title compound (2.8 g). A portion of this was purified by preparative silica gel thin layer chromatography to obtain the title compound.
[1690]
[1691] Reference Example 277 5-Chloro-3-fluoroindole-2-carboxylic acid ethyl ester
[1692]
[1693] The crude compound (1.4 g) obtained in Reference Example 276 was dissolved in anisole (30 ml), and aluminum chloride (2.9 g) was added in small portions under ice-cooling. The reaction solution was stirred at room temperature for 30 minutes, and further, aluminum chloride (2.9 g) was added and stirred for 18 hours. Aluminum chloride (8.0 g) was added to the reaction solution, stirred for 5 hours, and water was added thereto. The reaction solution was extracted with acetic acid ethyl ester, and the combined organic layers were washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride) to give the title compound (470 mg).
[1694]
[1695] Reference Example 278 5-Chloro-3-fluoroindole-2-carboxylic acid
[1696]
[1697] The title compound was obtained from the compound obtained in Reference Example 277 in the same manner as in Reference Example 274.
[1698]
[1699] Reference Example 279 (1R, 2S, 5S)-{[(5-chloro-3-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarba Hydrochloric acid tert-butyl ester
[1700]
[1701] In the same manner as in Reference Example 97, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 278.
[1702]
[1703] Reference Example 280 3-Bromo-5-chloroindole-2-carboxylic acid ethyl ester
[1704]
[1705] To N, N-dimethylformamide (10 ml) solution of 5-chloroindole-2-carboxylic acid ethyl ester (500 mg) was added N-bromosuccinimide (440 mg) under ice cooling. The reaction solution was stirred at room temperature for 18 hours and the solvent was distilled off under reduced pressure. The residue was partitioned between acetic acid ethyl ester and water, and the aqueous layer was extracted with acetic acid ethyl ester. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate ethyl acetate: hexane = 1: 9), and the white powder obtained was washed with hexane to obtain the title compound (680 mg).
[1706]
[1707] Reference Example 281 3-Bromo-5-chloroindole-2-carboxylic acid
[1708]
[1709] The title compound was obtained from the compound obtained in Reference Example 280 in the same manner as in Reference Example 274.
[1710]
[1711] Reference Example 282 (1R, 2S, 5S) -2-{[(3-bromo-5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl Carbamic acid tert-butyl ester
[1712]
[1713] In the same manner as in Reference Example 97, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 281.
[1714]
[1715] Reference Example 283 3-Chloro-5-fluoroindole-2-carboxylic acid ethyl ester
[1716]
[1717] 5-Fluoroindole-2-carboxylic acid ethyl ester (2.0 g) was dissolved in N, N-dimethylformamide (20 ml) and N, N- of N-chlorosuccinimide (1.4 g) under ice-cooling. A dimethylformamide (10 ml) solution was added dropwise and stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 5: 1) to obtain the title compound (1.9 g).
[1718]
[1719] Reference Example 284 3-Chloro-5-fluoroindole-2-carboxylic acid
[1720]
[1721] The title compound was obtained from the compound obtained in Reference Example 283 in the same manner as in Reference Example 274.
[1722]
[1723] Reference Example 285 5-Chloro-3-formylindole-2-carboxylic acid ethyl ester
[1724]
[1725] Phosphorous oxychloride (2.0 ml) was added to N-methylformanilide (2.9 g), followed by stirring for 15 minutes, followed by 1,2-dichloroethane (50 ml) and 5-chloroindole-2-carboxylic acid ethyl ester (4.0 g). ) Was added and heated to reflux for 1 hour. Under ice-cooling, the reaction solution was poured into an aqueous solution of sodium acetate (14 g) (28 ml), stirred for 18 hours, and the insolubles were collected by filtration. This was washed sequentially with water and diethyl ether to give the title compound (3.56 g).
[1726]
[1727] Reference Example 286 5-Chloro-3-formylindole-2-carboxylic acid
[1728]
[1729] The compound (1.0 g) obtained in Reference Example 285 was dissolved in ethanol (10 ml), 1 N sodium hydroxide solution (10 ml) was added dropwise, and the mixture was heated and stirred at 50 ° C for 2 hours. An aqueous solution of 1 N hydrochloric acid (11 ml) was added to the reaction solution, followed by stirring. The precipitated insoluble matter was collected by filtration to obtain the title compound (0.86 g).
[1730]
[1731] Reference Example 287 5-Chloro-2-ethoxycarbonylindole-3-carboxylic acid
[1732]
[1733] Compound (1.5 g) and sulfamic acid (1.7 g) obtained in Reference Example 286 were dissolved in tert-butanol (30 ml) -water (30 ml), sodium chlorite (1.6 g) was added thereto, and the mixture was stirred for 8 hours. The reaction solution was diluted with water and extracted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixed solvent of isopropyl ether-hexane to obtain the title compound (0.7 g).
[1734]
[1735] Reference Example 288 5-Chloro-3-[(dimethylamino) carbonyl] indole-2-carboxylic acid ethyl ester
[1736]
[1737] The compound (0.7 g) obtained in Reference Example 287 was dissolved in N, N-dimethylformamide (10 ml), and dimethylamine hydrochloride (0.26 g), 1-hydroxybenzotriazole monohydrate (0.43 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.0 g) was added and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed sequentially with 1 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixed solvent of isopropyl ether-hexane to obtain the title compound (0.6 g).
[1738]
[1739] Reference Example 289 5-Chloro-3-[(dimethylamino) carbonyl] indole-2-carboxylic acid
[1740]
[1741] The title compound was obtained from the compound obtained in Reference Example 288 in the same manner as in Reference Example 286.
[1742]
[1743] Reference Example 290 5- (phenylsulfonyl) -5,6-dihydro-4H-pyrrolo [3,4-d] thiazole
[1744]
[1745] Benzenesulfonamide (638 mg) and 4,5-bis (bromomethyl) thiazole (M. Al. Hariri, O. Galley, F. Pautet, H. Fillion, Eur. J. Org. Chem. 1998) under ice cooling , 593-594.) (1.10 g) was dissolved in N, N-dimethylformamide (10 ml), sodium hydride (60% oily, 357 mg) was added in one portion and stirred at room temperature for 3 hours. Water and methylene chloride were added, the mixture was separated, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and purified by silica gel column chromatography (methylene chloride: ethyl acetate ethyl acetate = 9: 1) to obtain the title compound (137 mg).
[1746]
[1747] Reference Example 291 5,6-Dihydro-4H-pyrrolo [3,4-d] thiazole dibromide
[1748]
[1749] A mixture of the compound obtained in Reference Example 290 (800 mg), phenol (800 μl) and 47% aqueous hydrobromic acid solution (5.00 ml) was heated to reflux for 2 hours. After cooling to room temperature, ethyl acetate and water were added for separation, and the aqueous layer was distilled off under reduced pressure. Acetic acid ethyl ester was added to the residue, and the precipitates were collected by filtration and dried to obtain the title compound (521 mg).
[1750]
[1751] Reference Example 292 5-Methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole
[1752]
[1753] A title compound was obtained from the compound obtained in Reference Example 291 in the same manner as the method described in Reference Example 9.
[1754]
[1755] Reference Example 293 5-Methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxylic acid lithium salt
[1756]
[1757] In the same manner as described in Reference Example 5, the title compound was obtained from the compound obtained in Reference Example 292.
[1758]
[1759] Reference Example 294 (1R, 2S, 5S) -2-[(6-Chloro-2-naphthoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester
[1760]
[1761] The title compound from the compound obtained in Reference Example 144 and 6-chloronaphthalene-2-carboxylic acid (Eur. J. Chem-Chim. Ther., 1984, Volume 19, pages 205-214) in the same manner as Reference Example 97 Got.
[1762]
[1763] Reference Example 295 (E) -3- (morpholin-4-yl) -2-acrylic acid ethyl ester
[1764]
[1765] Propionic acid ethyl ester (2.0 ml) was dissolved in methylene chloride (20 ml), and morpholine (1.70 ml) was added dropwise under ice-cooling. After stirring for 1 hour at room temperature, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to obtain the title compound (3.72 g).
[1766]
[1767] Reference Example 296 3-Chlorobenzenediazonium Tetrafluoroborate
[1768]
[1769] 3-chloroaniline (2.0 g) was dissolved in a mixed solvent of water (30 ml) and concentrated hydrochloric acid (3.5 ml), and sodium nitrite (1.30 g) was added thereto under ice cooling, followed by stirring for 10 minutes. Concentrated hydrochloric acid (5.3 ml) and sodium tetrafluoroborate (6.90 g) were added, the mixture was stirred for 30 minutes under ice cooling, and the precipitates were collected by filtration, washed with water, methanol and diethyl ether to obtain the title compound (2.63 g). This was used for the next reaction.
[1770] Reference Example 297 7-Chlorocinnoline-3-carboxylic acid ethyl ester
[1771]
[1772] The compound (1.45 g) obtained in Reference Example 295 was dissolved in acetonitrile (100 ml), the compound (1.73 g) obtained in Reference Example 296 was added thereto, stirred at room temperature for 1 hour, and heated to reflux for 7 days. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride → methylene chloride: acetic acid ethyl ester = 10: 1, followed by hexane: acetic acid ethyl ester = 4: 1 → 1: 1) to give the title compound (0.25 g). )
[1773]
[1774] Reference Example 298 7-chlorocinnoline-3-carboxylic acid
[1775]
[1776] In the same manner as in Reference Example 286, the title compound was obtained from the compound obtained in Reference Example 297.
[1777]
[1778] Reference Example 299 (1R, 2S, 5S) -2-{[(7-Chlorocinolin-3-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert -Butyl ester
[1779]
[1780] In the same manner as in Reference Example 97, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 298.
[1781]
[1782] Reference Example 300 (1R, 2S, 5S) -2-{[(5-chloro-lH-benzimidazol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl Carbamic acid tert-butyl ester
[1783]
[1784] 10% palladium carbon (50 mg) was added to a tetrahydrofuran (5.0 ml) solution of the compound (235 mg) obtained in Reference Example 143, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give 5-chlorobenzimidazole-2-carboxylic acid (Bull. Chem. Soc. Jpn., 1989, Vol. 62, p. 2668) (165 mg) N To a solution of, N-dimethylformamide (5.0 ml), 1-hydroxybenzotriazole monohydrate (100 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (171 mg) were added to room temperature. It was added at and stirred for 4 days. After concentrating the reaction mixture, methylene chloride, aqueous sodium hydrogen carbonate solution and water were added to the mixture, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 10: 1) to give the title compound (250 mg).
[1785]
[1786] Reference Example 301 3- (4-Fluorophenyl) -2-{[(4-methylphenyl) sulfonyl] amino} propionic acid methyl ester
[1787]
[1788] 2-amino-3- (4-fluorophenyl) propionic acid methyl ester (2.01 g), p-toluenesulfonyl chloride (2.25 g) and 4-dimethylaminopyridine (309 mg) were dissolved in chloroform (30 ml) And pyridine (3.0 ml) was added, and it heated and refluxed for 4.5 hours. Further p-toluenesulfonyl chloride (2.20 g) was added, and the mixture was heated to reflux for 3.5 hours. The reaction solution was poured into ice and 1N hydrochloric acid (17 ml), followed by separation. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-2: 1) to obtain the title compound (2.89 g).
[1789]
[1790] Reference Example 302 7-Fluoro-2-[(4-methylphenyl) sulfonyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester
[1791]
[1792] Compound (1.50 g) and paraformaldehyde (207 mg) obtained in Reference Example 301 were dissolved in chloroform (40 ml) and substituted with argon. Then trifluoroborane-diethyl ether complex (1.20 ml) was added, and it stirred at room temperature for 7.5 hours. The reaction solution was poured into ice and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 1) to obtain the title compound (1.45 g).
[1793]
[1794] Reference Example 303 7-Fluoroisoquinoline-3-carboxylic acid methyl ester
[1795]
[1796] The compound (1.45 g) obtained in Reference Example 302 was dissolved in N, N-dimethylformamide (40 ml). Oxygen was introduced into the reaction solution and stirred at 100 ° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was added with saturated aqueous sodium hydrogen carbonate solution and methylene chloride, and the organic layer was washed with 10% citric acid solution and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 1: 1) to obtain the title compound (0.59 g).
[1797]
[1798] Reference Example 304 7-Fluoroisoquinoline-3-carboxylic Acid Hydrochloride
[1799]
[1800] The compound (1.45 g) obtained in Reference Example 303 was dissolved in concentrated hydrochloric acid (18 ml) and heated to reflux for 2.5 hours. The reaction solution was cooled, precipitates were collected by filtration, washed with water and dried to obtain the title compound (0.46 g).
[1801]
[1802] Reference Example 305 7-Chloro-2H-chromen-3-carboxylic acid ethyl ester
[1803]
[1804] 4-chloro-2-hydroxybenzaldehyde (Acta. Chem. Scand., 1999, Vol. 53, p. 258) (510 mg) was dissolved in tetrahydrofuran (40 ml) and sodium hydride (60% oily, 157). mg) was added and stirred at room temperature for 2 hours. To the reaction solution was added 2-diethylphosphonoacrylic acid ethyl ester (J. Org. Chem. 1978, Vol. 43, p. 1256) (769 mg) of tetrahydrofuran solution (10 ml) and stirred at room temperature for 2 hours. Heated to reflux overnight. After cooling the reaction solution to room temperature, water and diethyl ether were added to separate the solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 10: 1) to give the title compound (247 mg).
[1805]
[1806] Reference Example 306 7-Chloro-2H-chromen-3-carboxylic Acid
[1807]
[1808] The title compound was obtained from the compound obtained in Reference Example 305 in the same manner as in Reference Example 274.
[1809]
[1810] Reference Example 307 (1R, 2S, 5S) -2-{[(E) -3- (4-chlorophenyl) -2-propenyl] amino} -5-[(dimethylamino) carbonyl] cyclo Hexylcarbamic acid tert-butyl ester
[1811]
[1812] In the same manner as in Reference Example 97, the title compound was obtained from the compound obtained in Reference Example 144 and 4-chloro cinnamic acid.
[1813]
[1814] Reference Example 308 6-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid methyl ester
[1815]
[1816] Acetylenedicarboxylic acid dimethyl ester (13.5 ml) was added to a methanol (150 ml) solution of 4-chloroaniline (12.76 g), and the mixture was heated to reflux for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in diphenyl ether (70 ml) and stirred with heating at 240 ° C. for 4 hours. After cooling the reaction solution, a mixed solvent of hexane and diethyl ether was added, and the precipitated crystals were collected by filtration and washed to obtain the title compound (11.09 g).
[1817]
[1818] Reference Example 309 6-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
[1819]
[1820] The title compound was obtained from the compound obtained in Reference Example 308 in the same manner as in Reference Example 286.
[1821]
[1822] Reference Example 310 (1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert- Butyl ester
[1823]
[1824] To a tetrahydrofuran (40 ml) solution of the compound (5.00 g) obtained in Reference Example 97, water (10 ml) and lithium hydroxide (263 mg) were added and stirred overnight at room temperature. 1-hydroxybenzotriazole monohydrate (1.75 g), 1, in an N, N-dimethylformamide (100 ml) solution of dimethylamine hydrochloride (1.85 g) and the residue obtained by filtration and concentrating the filtrate. -(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.32 g) and diisopropylethylamine (11.3 ml) were added at room temperature and stirred for 2 days. After the reaction mixture was concentrated, methylene chloride, aqueous sodium hydrogen carbonate solution and water were added to separate the mixture, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: acetone = 2: 1 → 1: 1) to obtain the title compound (4.59 g).
[1825]
[1826] Reference Example 311 (1R, 2S, 5S) -2-{[(5-Fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert -Butyl ester
[1827]
[1828] 1) (1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4 from the compound obtained in Reference Example 96 and 5-fluoroindole-2-carboxylic acid as in Reference Example 91; -{[(5-fluoroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester was obtained.
[1829]
[1830] 2) The title compound was obtained from the compound in the same manner as in Reference Example 310.
[1831]
[1832] Reference Example 312 2-Amino-6,6-dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid ethyl ester
[1833]
[1834] Copper argon (I) (918 mg) was suspended in tetrahydrofuran (50 ml) and cooled to -20 ° C under argon, and n-butyllithium (1.56 hexane solution, 6.41 ml) was added dropwise over 5 minutes. The mixture was stirred at -20 ° C for 30 minutes. After cooling this reaction liquid to -50 degreeC, diisobutyl aluminum hydride (1.00 mol hexane solution) was dripped over 20 minutes, and it stirred at -50 degreeC for 1 hour. 2,2-Dimethyl-5-oxo-5,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester (Helv. Chim. Acta, 1998, 81, 303) (986) Tetrahydrofuran (5 ml) solution containing mg) was added dropwise over 5 minutes and stirred at -50 ° C for 2 hours. After raising the temperature to -20 ° C, bromine (4.90 ml) was added dropwise at once and at -20 ° C. Stir for 30 minutes. Water and ethyl acetate were added to the reaction mixture for separation. The organic layer was washed with saturated aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was dissolved in N, N-dimethylformamide (10 ml), thiourea (760 mg) was added, and the mixture was stirred overnight at 50 ° C. After distilling off the solvent, methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (acetic acid ethyl ester: hexane = 4: 1) to give the title compound (412 mg).
[1835]
[1836] Reference Example 313 2-Bromo-6,6-dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid ethyl ester
[1837]
[1838] Copper (II) bromide (431 mg) was suspended in acetonitrile (8 ml), and tert-butyl nitrite (249 mg) was added dropwise at room temperature. The acetonitrile solution (8 ml) of the compound (412 mg) obtained in Reference Example 312 was added to the reaction solution under ice cooling, and the temperature was raised to 50 ° C and stirred for 15 minutes. The solvent was distilled off, and the residue was separated by adding diethyl ether and 10% hydrochloric acid, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain the title compound (151 mg).
[1839]
[1840] Reference Example 314 6,6-dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid ethyl ester
[1841]
[1842] To the diethyl ether solution (5 ml) of the compound (432 mg) obtained in Reference Example 313 was added n-butyllithium (1.56 hexane solution, 1.04 ml) at -78 ° C and stirred at -78 ° C for 30 minutes. Water and diethyl ether were added to the reaction mixture, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (307 mg).
[1843]
[1844] Reference Example 315 6,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine
[1845]
[1846] The compound (307 mg) obtained in Reference Example 314 was dissolved in a mixed solvent of water (5 ml), ethanol (5 ml) and dioxane (5 ml), and lithium hydroxide (598 mg) was added to the reaction solution and heated for 7 days. It was refluxed. After leaving to room temperature, water and methylene chloride were added and liquid-separated, and the aqueous layer was further extracted 6 times with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound (207 mg).
[1847]
[1848] Reference Example 316 6,6-dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester
[1849]
[1850] The compound (207 mg) obtained in Reference Example 315 was dissolved in methylene chloride (5 ml), and di-tert-butyldicarbonate (404 mg) and 4- (N, N-dimethylamino) pyridine (151 mg) were added thereto. Stir at room temperature for 2 hours. Further di-tert-butyldicarbonate (404 mg) was added and stirred overnight at room temperature, again di-tert-butyldicarbonate (1.00 g) was added and stirred for 1 hour. Methylene chloride and an aqueous 10% hydrochloric acid solution were added and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 4: 1) to give the title compound (95.4 mg).
[1851]
[1852] Reference Example 317 4-Chloro-5- (1,3-dioxolan-2-yl) thiazole-2-carboxylic acid lithium salt
[1853]
[1854] 2,4-dichlorothiazole-5-carbaldehyde ethyleneacetal (J. Chem. Soc. Perkin Trans. 1, 1992, page 973) (2.26 g) was dissolved in tetrahydrofuran (15 ml) and dried. After cooling with ice-acetone, n-butyllithium (1.5 ml hexane solution, 6.8 ml) was added thereto, stirred for 20 minutes, and carbon dioxide gas was introduced at the same temperature. The mixture was gradually warmed up to room temperature over 1.5 hours, concentrated under reduced pressure, powdered by addition of hexane, collected by filtration, suspended in ethyl acetate, and filtered again to obtain the title compound (1.65 g).
[1855] Reference Example 318 4-Chloro-5- (1,3-dioxolan-2-yl) thiazole-2-carboxylic acid ethyl ester
[1856]
[1857] Compound (242 mg) and ethanol (0.2 ml) obtained in Reference Example 317 were dissolved in N, N-dimethylformamide (2 ml), and 1-hydroxybenzotriazole monohydrate (136 mg) and 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250 mg) was added and stirred overnight at room temperature. The solvent was concentrated under reduced pressure, and diethyl ether and diluted hydrochloric acid were added to separate an organic layer. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (170 mg).
[1858]
[1859] Reference Example 319 4-Chloro-5-formylthiazole-2-carboxylic acid ethyl ester
[1860]
[1861] The compound (132 mg) obtained in the reference example 318 was dissolved in diethyl ether (5 ml), 20% hydrochloric acid aqueous solution (0.3 ml) was added, and it stirred at room temperature for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (110 mg).
[1862]
[1863] Reference Example 320 4-Azide-5-Formylthiazole-2-Carboxylic Acid Ethyl Ester
[1864]
[1865] The compound (5.15 g) obtained in the reference example 319 was dissolved in dimethyl sulfoxide (30 ml), sodium azide (1.52 g) was added, and it stirred at room temperature for 2.5 hours. Ice water was added to the reaction solution, followed by extraction with diethyl ether, washing with water twice, and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to obtain the title compound (1.78 g).
[1866]
[1867] Reference Example 321 6-Methyl-6,7-dihydrothiazolo [4,5-d] pyrimidine-2-carboxylic acid ethyl ester
[1868]
[1869] The compound (1.56 g) obtained in Reference Example 320 was dissolved in methylene chloride (20 ml), acetic acid (2 ml), methylamine (2-degree tetrahydrofuran solution, 21 ml) and sodium triacetoxyborohydride (2.98 g) ) Was added and stirred. After 1 hour, sodium triacetoxy borohydride (2.98 g) was added, and stirring was continued for 4.5 hours. An aqueous solution of 0.5 N sodium hydroxide (100 ml) was added to the reaction solution, which was made alkaline, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a brown oil (1.43 g). This oily substance was dissolved in ethanol (50 ml), 10% palladium carbon (2.0 g) was added, and hydrogenation was performed at room temperature and normal pressure. After 2.5 hours, the catalyst was filtered off and the filtrate was concentrated to dissolve the residue in methylene chloride (30 ml), trimethyl ortho formate (0.7 ml) and boron trifluoride-diethyl ether complex (0.3 ml) were added to room temperature. Stir at 15 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with methylene chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3) to obtain the title compound (100 mg).
[1870]
[1871] Reference Example 322 6-Methyl-6,7-dihydrothiazolo [4,5-d] pyrimidine-2-carboxylic acid lithium salt
[1872]
[1873] The compound (463 mg) obtained in the reference example 321 was dissolved in tetrahydrofuran (20 ml), lithium hydroxide (54.1 mg) and water (4 ml) were added, and it stirred at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure and dried with a vacuum pump to give the title compound (460 mg).
[1874]
[1875] Reference Example 323 (1R, 2S, 5S) -2-Azide-5-{[ethyl (methyl) amino] carbonyl} cyclohexylcarbamic acid tert-butyl ester
[1876]
[1877] The title compound was obtained by condensation of the compound obtained in Reference Example 250 with ethylmethylamine.
[1878]
[1879] Reference Example 324 (1R, 2S, 5S) -2-{[(7-chloroisoquinolin-3-yl) carbonyl] amino} -5-{[ethyl (methyl) amino] carbonyl} cyclohexylcar Bamic acid tert-butyl ester
[1880]
[1881] The compound (1.44 g) obtained in Reference Example 323 was dissolved in methanol (20 ml), 10% palladium carbon (150 mg) was added, and the mixture was stirred under a hydrogen stream. After 24 hours, the catalyst was filtered off and the solvent was concentrated under reduced pressure to give a colorless oil that was used as such in the next reaction.
[1882] The oily substance was dissolved in methylene chloride (30 ml), and the compound (850 mg) obtained in Reference Example 57, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.27 g), 1-hydrate Roxybenzotriazole monohydrate (900 mg) and N-methylmorpholine (1.34 g) were added and stirred at room temperature. After 17 hours, methylene chloride and saturated sodium hydrogen carbonate solution were added to the reaction mixture for separation. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography (methanol: methylene chloride = 1: 50) to give the title compound (1.61 g).
[1883]
[1884] Reference Example 325 N-((1S, 2R, 4S) -2-amino-4-[(7-chloroisoquinolin-3-yl) carbonyl] -4-{[ethyl (methyl) amino] carbonyl } Cyclohexyl) -7-chloroisoquinoline-3-carboxamide
[1885]
[1886] The compound (1.60 g) obtained in the reference example 324 was dissolved in the ethanol hydrochloride solution (25 ml), and it stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was separated by adding methylene chloride and 1 N sodium hydroxide solution. The aqueous layer was extracted with methylene chloride, the combined organic layers were dried over potassium carbonate and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the precipitate was collected by filtration to obtain the title compound (1.22 g).
[1887]
[1888] Reference Example 326 (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[tert-butyl (diphenyl) silyl] oxy} cyclohexanecarboxylic acid Ethyl ester
[1889]
[1890] The compound (28.0 g) obtained in Reference Example 88 was dissolved in N, N-dimethylformamide (500 ml), and tert-butyldiphenylsilyl chloride (63.5 ml) and imidazole (19.9 g) were added. After stirring at room temperature for 10 hours, acetic acid ethyl ester and water were added and the mixture was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed twice with water. After drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 1: 0 → 47: 3) to give 0.4 mg of N, N-dimethylformamide in the title compound. (52.5 g) was obtained.
[1891]
[1892] Reference Example 327 (1R ^* , 2R ^* , 5S ^* )-2-{[tert-butyl (diphenyl) silyl] oxy} -5- (hydroxymethyl) cyclohexanecarbamic acid tert-butyl ester
[1893]
[1894] Suspend lithium aluminum hydride (7.11 g) in dry diethyl ether (100 ml) at 0 ° C. under argon substitution, and diethyl ether solution (500 ml) of the compound (52.5 g) obtained in Reference Example 326 over 30 minutes. It dripped. After stirring at 0 degreeC for 30 minutes, methanol (100 ml) was dripped at the reaction liquid. The resulting slurry was filtered off with celite, the filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 3: 1) to give the title compound (29.6 g).
[1895]
[1896] Reference Example 328 Methanesulfonic Acid ((1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[tert-butyl (diphenyl) silyl] oxy} cyclo Hexyl) methyl ester
[1897]
[1898] The compound (29.5 g) obtained in Reference Example 327 was dissolved in methylene chloride (200 ml) and pyridine (20 ml), methanesulfonyl chloride (9.5 ml) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for separation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed twice with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 2: 1) to obtain the title compound (29.8 g).
[1899]
[1900] Reference Example 329 (1R ^* , 2R ^* , 5S ^* )-2-{[tert-butyl (diphenyl) silyl] oxy} -5- (cyanomethyl) cyclohexanecarbamic acid tert-butyl ester
[1901]
[1902] The compound (29.8 g) obtained in the reference example 328 was dissolved in N, N-dimethylformamide (400 ml), sodium cyanide (3.64 g) was added, and it stirred at 80 degreeC for 11 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution and the mixture was separated. The organic layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 5: 1) to obtain the title compound (20.6 g).
[1903]
[1904] Reference Example 330 (1R ^* , 2R ^* , 5S ^* )-2-{[tert-butyl (diphenyl) silyl] oxy} -5- (2-oxoethyl) cyclohexanecarbamic acid tert-butyl ester
[1905]
[1906] The compound (2.00 g) obtained in Reference Example 329 was dissolved in anhydrous methylene chloride (20 ml), substituted with argon, and cooled to -78 ° C. Diisobutyl aluminum hydride (0.95 M hexane solution, 8.55 ml) was dripped here, and it heated up to room temperature and stirred for 3 hours. The reaction solution was cooled to 0 ° C. and methanol (10 ml) was added dropwise. The resulting slurry was filtered off with celite, the filtrate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 1: 0 → 49: 1) to give the title compound (1.45 g).
[1907]
[1908] Reference Example 331 2-((1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl) amino] -4-{[tert-butyl (diphenyl) silyl] oxy} cyclohexyl Acetic acid
[1909]
[1910] The compound (8.40 g) obtained in Reference Example 330 was dissolved in a mixed solvent of water (33 ml) and tert-butanol (120 ml), 2-methyl-2-butene (8.08 ml) and sodium dihydrogen phosphate dihydrate ( 2.64 g) and sodium chlorite (3.45 g) were added, and it stirred at room temperature for 1.5 hours. Methylene chloride and water were added to the reaction mixture, and the aqueous layer was adjusted to pH 4 with 1N aqueous hydrochloric acid. The solution was separated and extracted twice with methylene chloride from the aqueous layer. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: acetic acid ethyl ester = 2: 1 → 1: 1) to give the title compound (7.62 g).
[1911]
[1912] [Reference Example 332] (1R ^* , 2R ^* , 5S ^* )-2-{[tert-butyl (diphenyl) silyl] oxy} -5- [2- (dimethylamino) -2-oxoethyl] cyclohexanecarb Bamic acid tert-butyl ester
[1913]
[1914] The compound (7.62 g) obtained in Reference Example 331 was dissolved in N, N-dimethylformamide (150 ml), and dimethylamine hydrochloride (6.07 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride (8.56 g), 1-hydroxybenzotriazole monohydrate (1.01 g) and triethylamine (10.3 ml) were added and the mixture was stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and the residue was separated by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with methylene chloride, and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 1: 1). The solvent was distilled off, and hexane was added, and the white precipitate produced by filtration was collected to obtain the title compound (6.42 g).
[1915]
[1916] Reference Example 333 (1R ^* , 2R ^* , 5S ^* )-5- [2- (dimethylamino) -2-oxoethyl] -2-hydroxycyclohexanecarbamic acid tert-butyl ester
[1917]
[1918] The compound (6.36 g) obtained in Reference Example 332 was dissolved in tetrahydrofuran (50 ml), tetrabutylammonium fluoride (1 N. tetrahydrofuran solution, 17.85 ml) was added, and stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride: methanol = 24: 1) to obtain the title compound (3.49 g).
[1919]
[1920] Reference Example 334 Methanesulfonic Acid (1R ^* , 2R ^* , 4S ^* )-2-[(tert-butoxycarbonyl) amino] -4- [2- (dimethylamino) -2-oxoethyl] cyclohexyl ester
[1921]
[1922] The compound (8.05 mg) obtained in Reference Example 333 was dissolved in methylene chloride (50 ml), cooled to -78 ° C under argon atmosphere, and methanesulfonyl chloride (2.70 ml) was added dropwise. It heated up at 0 degreeC, stirred for 30 minutes, and stirred at room temperature for 2 hours. Water was added to the reaction solution to separate the solution, and the mixture was extracted with methylene chloride. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: acetic acid ethyl ester = 1: 1 → 0: 1) to obtain the title compound (3.63 g).
[1923]
[1924] Reference Example 335 (1R ^* , 2S ^* , 5S ^* )-2-azide-5- [2- (dimethylamino) -2-oxoethyl] cyclohexanecarbamic acid tert-butyl ester
[1925]
[1926] The compound (3.62 g) obtained in the reference example 334 was dissolved in N, N-dimethylformamide (20 ml), sodium azide (3.11 g) was added, and it stirred at 75 degreeC for 17 hours. The reaction solution was poured into a mixture of water and ethyl acetate and separated. The organic layer was extracted twice with ethyl acetate, and the combined organic layers were washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (acetic acid ethyl ester) to obtain the title compound (1.30 g).
[1927]
[1928] Reference Example 336 N-{(1R ^* , 2S ^* , 4R ^* )-2-amino-4- [2- (dimethylamino) -2-oxoethyl] cyclohexyl} -5-chloroindole-2-car Copyamide hydrochloride
[1929]
[1930] After the catalytic reduction of the compound obtained in Reference Example 335 in the same manner as in Reference Example 324, the product obtained by condensation with 5-chloroindole-2-carboxylic acid was treated in the same manner as in Reference Example 69 to obtain the title compound.
[1931]
[1932] Reference Example 337 (1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexanecarbamic acid tert-butyl ester
[1933]
[1934] The title compound was obtained from the compound obtained in Reference Example 97 in the same manner as in 2) of Reference Example 129.
[1935] Reference Example 338 Methanesulfonic Acid ((1S, 3R, 4S) -3-[(tert-butoxycarbonyl) amino] -4-{[(5-chloroindol-2-yl) carbonyl] amino} Cyclohexyl) methyl ester
[1936]
[1937] Compound (500 mg) and triethylamine (329 ml) obtained in Reference Example 337 were suspended in tetrahydrofuran (8 ml) -methylene chloride (8 ml) and cooled to -78 ° C. After dropping methanesulfonyl chloride (138 ml) into this solution, the liquid temperature was gradually raised to -5 ° C and stirred at the same temperature for 15 hours. The reaction solution was concentrated, water was added to the residue, and extracted three times with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (654 mg).
[1938]
[1939] Reference Example 339 (1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfanyl) methyl] cyclohexanecarbamic acid tert- Butyl ester
[1940]
[1941] The compound (654 mg) obtained in Reference Example 338 was dissolved in N, N-dimethylformamide (8 ml), 15% aqueous sodium thiomethoxide solution (1.8 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted three times with acetic acid ethyl ester. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to give the title compound (492 mg).
[1942]
[1943] Reference Example 340 (1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfonyl) methyl] cyclohexanecarbamic acid tert- Butyl ester
[1944]
[1945] The compound (300 mg) obtained in Reference Example 339 was dissolved in methylene chloride (10 ml), and m-chloroperbenzoic acid (70%, 400 mg) was added under stirring at 0 ° C. After stirring for 1 hour as it was, the reaction solution was poured into water and extracted three times with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1), followed by separation with an aqueous saturated sodium bicarbonate solution and acetic acid ethyl ester, and the organic layer was concentrated to give the title compound (254 mg).
[1946]
[1947] Reference Example 341 (5-Chlorothien-3-yl) Methanol
[1948]
[1949] 5-chlorothiophene-3-carboxylic acid (Monatsh. Chem., 1989, Vol. 120, p. 53) (6.93 g) was dissolved in tetrahydrofuran (750 ml), triethylamine (27.3 ml), Ethyl chloroformate (18.7 ml) was added and the mixture was stirred for 2 and a half hours at room temperature. Furthermore, the aqueous solution (41 ml) of sodium borohydride (19.3g) was dripped over 10 minutes, and it stirred at room temperature for 18.5 hours. Acetic acid was added to the reaction solution to make it acidic, and then the solvent was distilled off under reduced pressure. Water and methylene chloride were added to the residue, followed by separation. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate ethyl hexane: 1: 4) to obtain the title compound (5.17 g).
[1950]
[1951] Reference Example 342 5-Chlorothiophene-3-carbaldehyde
[1952]
[1953] The compound (5.17 g) obtained in Reference Example 341 was dissolved in methylene chloride (400 ml), manganese dioxide (51.3 g) was added, and the mixture was stirred at room temperature for 15 hours. After filtering the reaction solution, the solvent was distilled off under reduced pressure to obtain the title compound (2.84 g).
[1954]
[1955] Reference Example 343 2-Azide-3- (5-chlorothien-3-yl) acrylic acid ethyl ester
[1956]
[1957] After adding ethanol (15 ml) to 20% sodium ethoxide ethanol solution (10.7 ml) and cooling to 0 ° C., a mixture of the compound (1.01 g) obtained in Reference Example 342 and azide acetic acid ethyl ester (3.55 g) was prepared. It dripped over 30 minutes, and stirred at 0 degreeC for 3 hours. Aqueous solution of cooled ammonium chloride was added to the reaction mixture, and extracted three times with diethyl ether. The organic layers were combined and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1:49) to give the title compound (1.04 g).
[1958]
[1959] Reference Example 344 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester
[1960]
[1961] The compound (0.97 g) obtained in Reference Example 343 was dissolved in xylene (20 ml) and heated to reflux for 30 minutes. After cooling, the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (0.608 g).
[1962]
[1963] Reference Example 345 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid
[1964]
[1965] The title compound was obtained from the compound obtained in Reference Example 344 in the same manner as in Reference Example 274.
[1966]
[1967] Reference Example 346 1-Chloro-4- (2,2-dibromovinyl) benzene
[1968]
[1969] 4-chlorobenzaldehyde (2.81 g) was dissolved in methylene chloride (300 ml), carbon tetrabromide (13.3 g) and triphenylphosphine (21.0 g) were added, and the mixture was stirred at room temperature for 90 minutes. After the precipitated insolubles were filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the title compound (5.54 g).
[1970]
[1971] Reference Example 347 3- (4-Chlorophenyl) -2-propioic acid
[1972]
[1973] The compound (1.0 g) obtained in Reference Example 346 was dissolved in tetrahydrofuran (30 ml), and n-butyllithium (1.59 prescribed hexane solution, 4.46 ml) was added dropwise at -78 ° C under an argon stream. It heated up to and stirred for 1 hour. The reaction solution was again cooled to -78 ° C, stirred for 2 minutes under a carbon dioxide gas stream, and then heated to room temperature. The reaction solution was concentrated under reduced pressure, and then, saturated saline and acetic acid ethyl ester were added to the residue. 3N hydrochloric acid was added to the aqueous layer to make it acidic, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (453 mg).
[1974]
[1975] Reference Example 348 6-Chloro-4-oxo-1,4-dihydroquinazolin-2-carboxylic acid ethyl ester
[1976]
[1977] To a pyridine (15 ml) solution of 2-amino-5-chlorobenzamide (2.50 g) was added oxoacetic acid ethyl ester (2.0 ml) and stirred at room temperature for 18 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in acetic acid (50 ml), acetic anhydride (5.0 ml) was added, and the mixture was heated to reflux for 16 hours. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and the precipitated crystals were filtered, collected and washed to obtain the title compound (2.71 g).
[1978]
[1979] Reference Example 349 6-Chloro-4-oxo-1,4-dihydroquinazolin-2-carboxylic acid
[1980]
[1981] Lithium hydroxide (263 mg) was added to a mixed solution of water (5 ml) -tetrahydrofuran (15 ml) of the compound (1.26 g) obtained in Reference Example 348, and the mixture was stirred at room temperature for 18 hours. The reaction solution was neutralized with 1N hydrochloric acid (11 ml) under ice cooling and stirred for 1 hour. The precipitated crystals were filtered, collected and washed to obtain the title compound (0.96 g).
[1982]
[1983] Reference Example 350 2-Chloro-N- (4-chlorophenyl) acetamide
[1984]
[1985] p-chloroaniline (3.82 g) was dissolved in acetic acid ethyl ester (30 ml), and chloroacetyl chloride (2.39 ml) was added at room temperature, followed by stirring for 1 hour. The reaction solution was heated and stirred at 60 ° C. for 3.5 hours, and the precipitated crystals were collected by filtration to obtain the title compound (4.78 g). In addition, the filtrate was concentrated to about 1/4, and the precipitated crystals were filtered and collected to obtain the title compound (1.01 g).
[1986]
[1987] Reference Example 351 S- [2- (4-chloroanilino) -2-oxoethyl] sodium thiosulfate
[1988]
[1989] The compound (5.79 g) obtained in Reference Example 350 was dissolved in ethanol (140 ml), and an aqueous solution of sodium thiosulfate pentahydrate (7.04 g) (140 ml) was added at a time under stirring at 70 ° C, and the mixture was heated to reflux for 1.5 hours. The reaction solution was concentrated to about 1/10, and the precipitated powder was filtered and collected to obtain the title compound (8.20 g).
[1990]
[1991] Reference Example 352 2-Chloro-N- (5-chloropyridin-2-yl) acetamide hydrochloride
[1992]
[1993] 2-amino-5-chloropyridine (3.85 g) was dissolved in acetic acid ethyl ester (60 ml), and chloroacetyl chloride (2.39 ml) was added at room temperature, followed by stirring for 1 hour. The reaction solution was heated and stirred at 60 ° C. for 30 minutes, and then chloroacetyl chloride (0.5 ml) was added thereto, followed by further stirring at 60 ° C. for 1 hour. The precipitated powder was collected by filtration to give the title compound (6.18 g).
[1994]
[1995] Reference Example 353 S- {2-[(5-chloropyridin-2-yl) amino] -2-oxoethyl} sodium thiosulfate
[1996]
[1997] A solution (130 ml) in which sodium thiosulfate pentahydrate (6.35 g) and sodium hydrogencarbonate (2.15 g) was dissolved in a solution obtained by dissolving the compound (6.18 g) obtained in Reference Example 352 in ethanol (130 ml) was stirred at 80 ° C. At one time, the mixture was heated to reflux for 2 hours at an external temperature of 110 캜. Concentrated to dryness under reduced pressure, ethanol (500 ml) was added to the residue, and the mixture was extracted twice by heating. The extract was concentrated to about 1/20, diethyl ether was added, and the precipitated insoluble matter was collected by filtration to obtain the title compound (6.65 g).
[1998]
[1999] Reference Example 354 N-{(1R, 2S, 5S) -2-[(2-chloroacetyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2000]
[2001] The compound (100 mg) obtained in Reference Example 253 was dissolved in ethyl acetate (10 ml), and chloroacetyl chloride (21.6 µl) was added thereto, followed by heating and stirring at 60 ° C for 30 minutes. After cooling, the insolubles were collected by filtration, dissolved in methylene chloride-methanol, and the solvent was distilled off under reduced pressure to obtain the title compound (112 mg).
[2002]
[2003] Reference Example 355 S- {2-[((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) amino] -2-oxoethyl} sodium sulfate
[2004]
[2005] The solution obtained in Reference Example 354 (106 mg) was dissolved in ethanol (1.5 ml), and an aqueous solution (1.5 ml) in which sodium thiosulfate pentahydrate (55 mg) and sodium hydrogencarbonate (18.6 mg) was dissolved at a time at 90 ° C was stirred. It was heated to reflux for 1 hour. Concentrated to dryness under reduced pressure, ethanol (10 ml) was added to the residue, and the mixture was extracted during heating. The extract was concentrated to about 1/2, isopropyl ether (10 ml) was added, and the precipitated insoluble was filtered and collected to obtain the title compound (72 mg).
[2006]
[2007] Reference Example 356 2-[(5-chlorothien-2-yl) amino] -2-oxoacetic acid methyl ester
[2008]
[2009] Triethylamine (1.25 ml) and azididiphenylphosphoryl (1.55 ml) were added to a toluene (20 ml) suspension of 5-chlorothiophene-2-carboxylic acid (0.99 g), followed by stirring at 80 ° C for 1 hour. After cooling the reaction solution to room temperature, tert-butanol (2 ml) was added thereto, and the mixture was heated to reflux for 19 hours. The reaction solution was concentrated under reduced pressure, methylene chloride (200 ml) was added to the obtained residue, and the mixture was washed with distilled water, 10% citric acid solution, distilled water, saturated sodium bicarbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 4: 1) to give 5-chloro-2-thienylcarbamic acid tert-butyl ester (1.05 g).
[2010]
[2011] The above product (1.87 g) was added to 4N dioxane hydrochloride solution (40 ml) and stirred at room temperature for 4 hours, and then the solvent was distilled off under reduced pressure. The residue was suspended in tetrahydrofuran (50 ml), sodium ice carbonate (2.02 g) and chlorooxoacetic acid methyl ester (0.883 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, water and methylene chloride were added to the residue, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and the solvent was distilled off to obtain the title compound (1.44 g).
[2012]
[2013] Reference Example 357 2-[(5-fluoropyridin-2-yl) amino] -2-oxoacetic acid methyl ester
[2014]
[2015] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 2-amino-5-fluoropyridine and chlorooxoacetic acid methyl ester.
[2016]
[2017] Reference Example 358 2- [4-Chloro-2- (trifluoromethyl) anilino] -2-oxoacetic acid methyl ester
[2018]
[2019] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-chloro-2-trifluoroaniline and chlorooxoacetic acid methyl ester.
[2020]
[2021] Reference Example 359 2- [4-Chloro-2- (trifluoromethyl) anilino] -2-oxoacetic acid
[2022]
[2023] Lithium hydroxide (28 mg) was added to a tetrahydrofuran (7 ml) -water (3 ml) mixed solution of the compound (297 mg) obtained in Reference Example 358, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (8 ml) and methylene chloride (20 ml) were added to the reaction solvent to carry out a liquid separation operation. After drying the obtained organic layer with anhydrous sodium sulfate, the solvent was distilled off and dried under reduced pressure to obtain the title compound (291 mg).
[2024]
[2025] Reference Example 360 5-Chloro-N, N-dimethyl-2-nitrobenzamide
[2026]
[2027] In the same manner as in Reference Example 143, 5-chloro-2-nitrobenzoic acid and dimethylamine were condensed to obtain the title compound.
[2028]
[2029] Reference Example 361 2-Amino-5-chloro-N, N-dimethylbenzamide
[2030]
[2031] To a mixture of N, N-dimethylformamide (80 ml) -water (40 ml) of the compound (2.8 g) obtained in Reference Example 360 was added iron (III) hexahydrate (9.93 g) and zinc powder (8.01 g). Heated to reflux for 20 minutes. The reaction solution was filtered through Celite 545, ethyl acetate (200 ml) was added to the filtrate, and separation was performed. The aqueous layer was washed with acetic acid ethyl ester (100 ml × 2), and the combined organic layers were washed with distilled water (100 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was treated by silica gel column chromatography (methylene chloride: hexane = 1: 1 → 1: 0 → methanol: methylene chloride = 1: 100) to give the title compound (2.41 g).
[2032]
[2033] Reference Example 362 2- {4-Chloro-2-[(dimethylamino) carbonyl] anilino} -2-oxoacetic acid methyl ester
[2034]
[2035] The title compound was obtained from the compound obtained in Reference Example 361 and the chlorooxoacetic acid methyl ester in the same manner as the method described in Reference Example 242.
[2036]
[2037] Reference Example 363 4-Chloro-2-methoxyaniline
[2038]
[2039] In the same manner as described in Reference Example 361, the title compound was obtained from 5-chloro-2-nitroanisole.
[2040]
[2041] Reference Example 364 2- (4-Chloro-2-methoxyanilino) -2-oxoacetic acid methyl ester
[2042]
[2043] In the same manner as in the method described in Reference Example 242, the title compound was obtained from the compound obtained in Reference Example 363 and the chlorooxoacetic acid methyl ester.
[2044]
[2045] Reference Example 365 2- (4-Chloroanilino) -2- (hydroxyimino) acetic acid ethyl ester
[2046]
[2047] 4-chloroaniline (3.03 g) and 2-chloro- in the same manner as described in Gilchrist, TL; Peek, ME; Rees, CW; J. Chem. Soc. Chem. Commun., 1975, 913. The title compound was obtained from 2-hydroxyiminoacetic acid ethyl ester.
[2048]
[2049] Reference Example 366 (1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2- (hydroxyimino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclo Hexylcarbamic acid tert-butyl ester
[2050]
[2051] To the ethanol (5.0 ml) solution of the compound (350 mg) obtained in Reference Example 365, the compound (597 mg) obtained in Reference Example 144 was added and stirred at 70 ° C for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (methylene chloride: methanol = 30: 1) to obtain the title compound (180 mg).
[2052]
[2053] Reference Example 367 (3R, 4S) -4-{[2- (4-chloroanilino) -2-oxoacetyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcar Bamic acid tert-butyl ester
[2054]
[2055] The title compound was obtained in the same manner as the method described in Reference Example 214 from the compound obtained in Reference Example 374 and the compound obtained in Reference Example 220.
[2056]
[2057] Reference Example 368 (3R, 4S) -4-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -1- (2-methoxyacetyl) piperi Din-3-ylcarbamic acid tert-butyl ester
[2058]
[2059] The title compound was obtained in the same manner as the method described in Reference Example 214 from the compound obtained in Reference Example 266 and the compound obtained in Reference Example 220.
[2060]
[2061] Reference Example 369 (3R, 4S) -4-({2-[(5-bromopyridin-2-yl) amino] -2-oxoacetyl} amino) -1- (2-methoxyacetyl) pi Ferridin-3-ylcarbamic acid tert-butyl ester
[2062]
[2063] The title compound was obtained in the same manner as the method described in Reference Example 214 from the compound obtained in Reference Example 375 and the compound obtained in Reference Example 220.
[2064]
[2065] Reference Example 370 3- (4-Chloroanilino) -3-oxopropionic acid ethyl ester
[2066]
[2067] To a solution of 4-chloroaniline (2.0 g) in N, N-dimethylformamide (20 ml), ethyl potassium malonate (3.2 g), 1-hydroxybenzotriazole (2.1 g) and 1- (3) at room temperature -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.5 g) was added sequentially, and it stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, 10% citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (4.0 g).
[2068]
[2069] Reference Example 371 3- (4-Chloroanilino) -3-oxopropionic acid
[2070]
[2071] To the ethanol (10 ml) solution of compound (1.0 g) obtained in Reference Example 370 was added dropwise 1 N aqueous sodium hydroxide solution (10 ml) at room temperature, followed by stirring for 2 hours. An aqueous solution of 1 N hydrochloric acid (10 ml) was added to the reaction mixture, followed by stirring. The precipitated insoluble matter was collected by filtration to obtain the title compound (0.5 g).
[2072]
[2073] Reference Example 372 3- (3-Chloroanilino) -3-oxopropionic acid ethyl ester
[2074]
[2075] In the same manner as in the method described in Reference Example 370, the title compound was obtained by condensation of 3-chloroaniline and potassium potassium malonate.
[2076]
[2077] Reference Example 373 3- (3-Chloroanilino) -3-oxopropionic acid
[2078]
[2079] The title compound was obtained from the compound obtained in Reference Example 372 in the same manner as the method described in Reference Example 371.
[2080]
[2081] Reference Example 374 2- (4-Chloroanilino) -2-oxoacetic acid
[2082]
[2083] In the same manner as described in Reference Example 359, the title compound was obtained from the compound obtained in Reference Example 242.
[2084]
[2085] Reference Example 375 2-[(5-bromopyridin-2-yl) amino] -2-oxoacetic acid
[2086]
[2087] The title compound was obtained from the compound obtained in Reference Example 262 in the same manner as the method described in Reference Example 359.
[2088]
[2089] Reference Example 376 4-Chloro-3-fluorobenzoic acid
[2090]
[2091] Sodium chlorite (17 g) was added to a mixed solution of 4-chloro-3-fluorobenzaldehyde (10 g), amide sulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice-cooling. Small portions were added and stirred for 4 days while slowly returning to room temperature. The reaction solution was diluted with acetic acid ethyl ester and washed with water, 1N aqueous hydrochloric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g).
[2092]
[2093] Reference Example 377 2- (4-Chloro-3-fluoroanilino) -2-oxoacetic acid methyl ester
[2094]
[2095] The title compound was obtained by condensing the compound obtained in Reference Example 376 with the chlorooxoacetic acid methyl ester after Curtius transfer reaction in the same manner as the method described in Reference Example 356.
[2096]
[2097] Reference Example 378 2- (4-Chloro-3-fluoroanilino) -2-oxoacetic acid
[2098]
[2099] In the same manner as described in Reference Example 359, the title compound was obtained from the compound obtained in Reference Example 377.
[2100]
[2101] Reference Example 379 3- (4-Chlorophenyl) -3-oxopropionic acid ethyl ester
[2102]
[2103] To ethyl acetate (100 ml) suspension of ethyl potassium malonate (8.2 g) was added triethylamine (17 ml) and magnesium chloride (5.5 g) under ice cooling, followed by stirring for 18 hours while slowly returning to room temperature. Meanwhile, a suspension of 4-chlorobenzoic acid (5.0 g), thionyl chloride (12 ml), N, N-dimethylformamide (1 drop) and toluene (100 ml) was heated to reflux for 1 hour, and the reaction solution was concentrated. It was. The obtained residue was dissolved in ethyl acetate, added dropwise to the reaction solution under ice-cooling, and stirred for 18 hours while gradually returning to room temperature. 10% citric acid aqueous solution was added to the reaction solution, the mixture was stirred for 30 minutes, and the organic layer was separated. The organic layer obtained was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (6.4 g).
[2104]
[2105] Reference Example 380 3- (4-Chlorophenyl) -3-hydroxypropionic acid ethyl ester
[2106]
[2107] To a tetrahydrofuran (10 ml) solution of the compound (1.0 g) obtained in Example 379, sodium borohydride (0.2 g) was added in small portions under ice cooling, followed by stirring for 2 hours while gradually returning to room temperature. Aqueous 10% citric acid solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (0.56 g).
[2108]
[2109] Reference Example 381 3- (4-Chlorophenyl) -3-hydroxypropionic acid
[2110]
[2111] The title compound was obtained from the compound obtained in Reference Example 380 in the same manner as the method described in Reference Example 359.
[2112]
[2113] Reference Example 382 (1R, 2S, 5S) -2-{[3- (4-chlorophenyl) -3-hydroxypropanoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcar Bamic acid tert-butyl ester
[2114]
[2115] In the same manner as described in Reference Example 91, the title compound was obtained by condensing the compound obtained in Reference Example 144 and the compound obtained in Reference Example 381.
[2116]
[2117] Reference Example 383 (1R, 2S, 5S) -2-{[3- (4-chlorophenyl) -3-oxopropanoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarba Hydrochloric acid tert-butyl ester
[2118]
[2119] Manganese dioxide (0.47 g) was added to a 1,4-dioxane (20 ml) solution of the compound (0.5 g) obtained in Reference Example 382, and the mixture was stirred for 4 days. The insolubles were filtered off through a pad of celite and the filtrate obtained was concentrated under reduced pressure to afford the title compound (0.46 g).
[2120]
[2121] Reference Example 384 (1S, 3R, 4R) -4-Azide-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[2122]
[2123] The title compound was obtained from the compound obtained in Reference Example 248 in the same manner as the method described in Reference Example 249.
[2124] [α] _D ²⁵ + 62 ° (c = 1, chloroform)
[2125]
[2126] Reference Example 385 (1R, 2R, 5S) -2-Azide-5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester
[2127]
[2128] In the same manner as described in Reference Example 250 and Reference 251, the title compound was obtained from the compound obtained in Reference Example 384.
[2129]
[2130] Reference Example 386 (1R, 2R, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(dimethylamino) carbonyl ] Cyclohexylcarbamic acid tert-butyl ester
[2131]
[2132] The title compound was obtained by converting the azide group of the compound obtained in Reference Example 385 with an amino group in the same manner as in Reference Example 90, and then condensing with the compound obtained in Reference Example 266 in the same manner as in Reference Example 91.
[2133]
[2134] Reference Example 387 N-{(1R, 2R, 5S) -2-azide-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothia Solo [5,4-c] pyridine-2-carboxamide
[2135]
[2136] The title compound was obtained from the compound obtained in Reference Example 385 and the compound obtained in Reference Example 10 in the same manner as the method described in Reference Example 252.
[2137]
[2138] Reference Example 388 4-[(2-methoxy-2-oxoacetyl) amino] piperidine-1-carboxylic acid tert-butyl ester
[2139]
[2140] In the same manner as in the method described in Reference Example 242, the title compound was obtained from (4-amino-N-tert-butoxycarbonyl) piperidine and chlorooxoacetic acid methyl ester.
[2141]
[2142] Reference Example 389 4-{[2-({(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} amino) -2-oxoacetyl] amino} piperidine-1-carboxylic acid tert-butyl ester
[2143]
[2144] In the same manner as described in Reference Example 191, the title compound was obtained from the compound obtained in Reference Example 310 and the compound obtained in Reference Example 388.
[2145]
[2146] Reference Example 390 2-[(5-chloropyridin-2-yl) (methyl) amino] -2-oxoacetic acid methyl ester
[2147]
[2148] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 5-chloro-N-methyl-2-pyridinamine and chlorooxoacetic acid methyl ester.
[2149]
[2150] Reference Example 391 2-[(5-chloro-pyrimidin-2-yl) amino] -2-oxoacetic acid methyl ester
[2151]
[2152] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 2-amino-5-chloropyrimidine and chlorooxoacetic acid methyl ester.
[2153]
[2154] Reference Example 392 N-((1R, 2S, 5S) -2-azide-5-{[ethyl (methyl) amino] carbonyl} cyclohexyl) -5-methyl-5,6-dihydro-4H -Pyrrolo [3,4-d] thiazole-2-carboxamide
[2155]
[2156] In the same manner as described in Reference Example 252, the title compound was obtained from the compound obtained in Reference Example 323 and the compound obtained in Reference Example 293.
[2157]
[2158] Reference Example 393 2- (4-Chloro-3-methoxyanilino) -2-oxoacetic acid methyl ester
[2159]
[2160] 2-Chloro-5-nitroanisole was reduced in the same manner as in Reference Example 361 to obtain an amino substance, and then condensed with chlorooxoacetic acid methyl ester in the same manner as in Reference Example 242 to obtain the title compound. .
[2161]
[2162] Reference Example 394 2- (4-Chloro-3-methoxyanilino) -2-oxoacetic acid
[2163]
[2164] The title compound was obtained by hydrolyzing the compound obtained in Reference Example 393 in the same manner as in Reference Example 359.
[2165]
[2166] Reference Example 395 N ¹ -{(1S, 2R, 4S) -2-amino-4-[(dimethylamino) carbonyl] cyclohexyl} -N ^2- (4-chloro-3-methoxyphenyl) ethane Diamide
[2167]
[2168] Condensation of the compound obtained in Reference Example 144 and the compound obtained in Reference Example 394 in the same manner as in Reference Example 97, followed by treatment with hydrochloric acid in the same manner as in Reference Example 69, followed by neutralization with an aqueous solution of 1 N sodium hydroxide The title compound was obtained.
[2169]
[2170] Reference Example 396 2- (4-ethynylanilino) -2-oxoacetic acid methyl ester
[2171]
[2172] In the same manner as in the method described in Reference Example 242, the title compound was obtained from 4-ethynylaniline and chlorooxoacetic acid methyl ester.
[2173]
[2174] Reference Example 397 2- (4-ethynylanilino) -2-oxoacetic acid sodium salt
[2175]
[2176] In the same manner as described in Reference Example 266, the title compound was obtained by hydrolyzing the compound obtained in Reference Example 396 with sodium hydroxide.
[2177]
[2178] Reference Example 398 2-[(5-chloropyrazin-2-yl) amino] -2-oxoacetic acid methyl ester
[2179]
[2180] 2-amino-5-chloropyrazine and chlorooxoacetic acid synthesized according to the method described in Reference Example 242 (Sato, Nobuhiro et al., J. Heterocycl. Chem. 1982, 19 (3), 673-4) The title compound was obtained from methyl ester.
[2181]
[2182] Reference Example 399 2-[(5-chloropyrazin-2-yl) amino] -2-oxoacetic acid
[2183]
[2184] The title compound was obtained from the compound obtained in Reference Example 398 in the same manner as the method described in Reference Example 359.
[2185]
[2186] Reference Example 400 2- (4-Chloro-3-nitroanilino) -2-oxoacetic acid
[2187]
[2188] In the same manner as described in Reference Example 242, 4-chloro-3-nitroaniline and chlorooxoacetic acid methyl ester were condensed, and then hydrolyzed in the same manner as in Reference Example 359 to obtain the title compound.
[2189]
[2190] Reference Example 401 2- (4-Chloro-2-nitroanilino) -2-oxoacetic acid sodium salt
[2191]
[2192] Condensation of 4-chloro-2-nitroaniline and chlorooxoacetic acid methyl ester in the same manner as in Reference Example 242, the residue obtained by hydrolysis in the same manner as in Reference Example 266 was dissolved in methanol, and 1 Precipitated sodium hydroxide solution was added to the resulting precipitate, which was collected by filtration to obtain the title compound.
[2193]
[2194] Reference Example 402 6-Chloro-4-methyl-3-pyridinamine
[2195]
[2196] 2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in ethanol (5 ml), and a catalytic amount of Rain nickel was added and stirred for 9 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 2) to give the title compound (113 mg).
[2197]
[2198] [Referential Example 403] N ¹ - (2- amino-phenyl) -N ² - (4- chlorophenyl) ethane diamide
[2199]
[2200] The title compound was obtained by condensing the compound obtained in Reference Example 374 with 1,2-benzenediamine in the same manner as in Reference Example 59.
[2201]
[2202] REFERENCE EXAMPLE 404 N-((1R, 2S, 5S) -2-azide-5-{[ethyl (methyl) amino] carbonyl} cyclohexyl) -5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2203]
[2204] In the same manner as in Reference Example 252, the compound obtained in Reference Example 323 was treated with hydrochloric acid, deprotected, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[2205]
[2206] Reference Example 405 2- (4-Chlorophenyl) -1-hydrazinecarboxylic acid phenyl ester
[2207]
[2208] (4-chlorophenyl) hydrazine hydrochloride (3.00 g) was dissolved in tetrahydrofuran (50 ml), diethyl ether (50 ml) and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer, and then dried over anhydrous sodium sulfate and concentrated. (4-Chlorophenyl) hydrazine was obtained as a brown solid. When this was dissolved in benzene (15 ml) and heated to reflux, a benzene (8.0 ml) solution of diphenyl carbonate (5.22 g) was added dropwise over 30 minutes. After refluxing for 19 hours, the mixture was cooled to room temperature, concentrated, and then suspension was ultrasonically added with benzene (15 ml), hexane (50 ml) was added thereto, stirred for 30 minutes, and the insolubles were collected by filtration and dried to obtain the title compound ( 1.05 g) was obtained.
[2209]
[2210] Reference Example 406 5-tert-Butoxycarbonyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxylic acid lithium salt
[2211]
[2212] The title compound was obtained from the compound obtained in Reference Example 33 in the same manner as the method described in Reference Example 10.
[2213]
[2214] Reference Example 407 1-hydroxycyclopropanecarboxylic acid benzyl ester
[2215]
[2216] Triethylamine (1.0 ml) and benzyl bromide (650 µl) were added to a tetrahydrofuran (3.0 ml) solution of 1-hydroxycyclopropanecarboxylic acid (409 mg), followed by stirring at room temperature for 23 hours. Methylene chloride and 1 N hydrochloric acid aqueous solution were added to the reaction solution to prepare two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 4: 1) to give the title compound (607 mg). Got.
[2217]
[2218] Reference Example 408 1-methoxycyclopropanecarboxylic acid benzyl ester
[2219]
[2220] To a tetrahydrofuran (5.0 ml) solution of the compound (600 mg) obtained in Reference Example 407, 60% aqueous sodium hydride (345 mg) and methyl iodide (900 µl) were added and refluxed for 28 hours. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction solution to prepare two layers. The organic layer was washed with saturated brine and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate ethyl ester = 10: 1) to give the title compound (340 mg).
[2221]
[2222] Reference Example 409 1-methoxycyclopropanecarboxylic acid
[2223]
[2224] The title compound was obtained from the compound obtained in Reference Example 408 in the same manner as the method described in Reference Example 152.
[2225]
[2226] Reference Example 410 (3R, 4S) -4-{[(7-Chloroisoquinolin-3-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarba Hydrochloric acid tert-butyl ester
[2227]
[2228] The title compound was obtained from the compound obtained in Reference Example 220 and the compound obtained in Reference Example 57 in the same manner as the method described in Reference Example 214.
[2229]
[2230] Reference Example 411 (3R, 4S) -4-{[2- (4-Chloro-3-fluoroanilino) -2-oxoacetyl] amino} -1- (2-methoxyacetyl) piperidine 3-ylcarbamic acid tert-butyl ester
[2231]
[2232] In the same manner as in the method described in Reference Example 214, the title compound was obtained by condensing the compound obtained in Reference Example 220 and the compound obtained in Reference Example 377.
[2233]
[2234] Reference Example 412 (3R, 4S) -4-({2-[(5-chloro-2-thienyl) amino] -2-oxoacetyl} amino) -1- (2-methoxyacetyl) piperi Din-3-ylcarbamic acid tert-butyl ester
[2235]
[2236] The title compound was obtained from the lithium salt of the carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 220 and the compound obtained in Reference Example 356 in the same manner as the method described in Reference Example 214.
[2237]
[2238] Reference Example 413 5-Methyl-5H-pyrrolo [3,4-d] thiazolo-2-carboxylic acid ethyl ester
[2239]
[2240] 1) 2-Tioxoacetic acid ethyl ester (26.75 g) was added to an ethanol (250 ml) solution of 3-bromo-2-butanone (26.36 g), and the mixture was refluxed for 14 hours. The reaction solution was cooled, concentrated under reduced pressure, and ethyl acetate and saturated brine were added to the residue, thereby preparing two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 6: 1) to give 4,5-dimethylthiazole-2-carboxylic acid ethyl ester (19.53 g).
[2241]
[2242] 2) N-bromosuccinimide (62.42 g) and 2,2'-azobisisobutyronitrile (227 mg) were added to 1,2-dichloroethane (500 ml) solution of the above product (19.53 g). It was refluxed for 42 hours. After cooling the reaction solution, water and methylene chloride were added to make two layers. The organic layer was washed with saturated brine and concentrated under reduced pressure to give a crude product (40.54 g) as a dark brown oil. Triethylamine (8.0 ml) and 2 mol methylamine tetrahydrofuran solution (11.0 ml) were added to the acetonitrile solution (400 ml) of the obtained crude product (8.41 g) at room temperature, and stirred for 3 days at room temperature. The reaction solution was concentrated under reduced pressure, and methylene chloride and saturated brine were added to the residue, thereby preparing two layers. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 3: 1) to give the title compound (270 mg).
[2243]
[2244] Reference Example 414 6-Chloro-4-oxo-4H-chromen-2-carboxylic Acid Ethyl Ester
[2245]
[2246] Under argon substitution, oily about 60% sodium hydride (1.68 g) was added to ethanol (10 ml) and stirred for 10 minutes at room temperature. After adding oxalic acid diethyl ester (3.36 ml), ethanol solution (20 ml) of 5'-chloro-2'-hydroxyacetophenone (2.82 g) was added dropwise, and ethanol (40 ml) was added and refluxed for 1 hour 30 minutes. The mixture was stirred at 50 ° C. for 14 hours. Concentrated sulfuric acid (1.5 ml) and ethanol (10 ml) were added to the mixed solution, and the mixture was refluxed for 4 hours. After cooling, the mixture was concentrated under reduced pressure to reduce the solvent in half, and toluene and monobasic sodium hydroxide solution (15 ml) were added to the concentrate. Extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid ethyl ester = 7: 1), and the obtained solid was washed with hexane to obtain the title compound (1.20 g).
[2247]
[2248] Reference Example 415 6-Chloro-4-oxo-4H-chromen-2-carboxylic acid
[2249]
[2250] The title compound was obtained from the compound obtained in Reference Example 414 in the same manner as the method described in Reference Example 359.
[2251]
[2252] Reference Example 416 (1S, 3R, 4S) -4-Amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester
[2253]
[2254] In the same manner as described in Reference Example 90, the title compound was obtained from the compound obtained in Reference Example 249.
[2255]
[2256] Reference Example 417 (1R, 2S, 5S) -2-{[(6-chloro-4-oxo-4H-chromen-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexylcarbamic acid tert-butyl ester
[2257]
[2258] N, N-dimethylformamide (0.02 ml) was added to a thionyl chloride (2.0 ml) solution of the compound (213 mg) obtained in Reference Example 415, and the mixture was refluxed for 15 minutes. The reaction solution was concentrated under reduced pressure, triethylamine (500 µl) and the compound obtained in Reference Example 144 (294 mg) were added as a tetrahydrofuran (4.0 ml) solution, followed by stirring at room temperature for 15 minutes. Ethyl acetate and 10% aqueous citric acid solution were added to the reaction solution to prepare two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1) to give the title compound (230 mg).
[2259]
[2260] Reference Example 418 (3R, 4S) -4-{[(7-Chlorocinolin-3-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-ylcarba Hydrochloric acid tert-butyl ester
[2261]
[2262] The title compound was obtained from the lithium salt of the carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 220 and the ester described in Reference Example 297 in the same manner as the method described in Reference Example 214.
[2263]
[2264] Reference Example 419 (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(dimethylamino) carbonyl ] Cyclohexylcarbamic acid tert-butyl ester
[2265]
[2266] In the same manner as described in Reference Example 68, the compound obtained in Reference Example 144 and the compound obtained in Reference Example 266 were condensed to obtain the title compound.
[2267]
[2268] [Referential Example ^{420] N 1 - {(1S} , 2R, 4S) -2- amino-4 - [(dimethylamino) carbonyl] cyclohexyl} -N ² - (5- chloropyridin-2-yl) ethane Dia Mead hydrochloride
[2269]
[2270] In the same manner as described in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 419.
[2271]
[2272] Reference Example 421 2-[({(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} amino) carbonyl] -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester
[2273]
[2274] The compound obtained in Reference Example 420 and 5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid (WO94 / 21599) were prepared. Condensation gave the title compound.
[2275]
[2276] Reference Example 422 2-Chloro-N- (4-fluorophenyl) acetamide
[2277]
[2278] In the same manner as described in Reference Example 350, the title compound was obtained from p-fluoroaniline.
[2279]
[2280] Reference Example 423 S- [2- (4-fluoroanilino) -2-oxoethyl] sodium thiosulfate
[2281]
[2282] In the same manner as described in Reference Example 351, the title compound was obtained from the compound obtained in Reference Example 422.
[2283]
[2284] Reference Example 424 (1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-{[2- (4-fluoroanilino) -2-oxoethanethioyl] amino} cyclohexyl Carbamic acid tert-butyl ester
[2285]
[2286] Compound (1.1 g) obtained in Reference Example 144 and compound (1.24 g) obtained in Reference Example 423 were dissolved in N-methylmorpholine (20 ml), and the bath temperature was raised from room temperature to 140 ° C. over 15 minutes at the same temperature. The mixture was heated and stirred for 15 minutes. After allowing to cool, ice water was added to the reaction solution, and insoluble materials were collected by filtration. It was purified by silica gel column chromatography (methylene chloride: methanol = 200: 1 → 197: 3) to obtain the title compound (1.43 g).
[2287]
[2288] Reference Example 425 2-Chloro-N- (5-fluoropyridin-2-yl) acetamide hydrochloride
[2289]
[2290] In the same manner as described in Reference Example 352, the title compound was obtained from 2-amino-5-fluoropyridine.
[2291]
[2292] Reference Example 426 S- {2-[(5-fluoropyridin-2-yl) amino] -2-oxoethyl} sodium sulfate
[2293]
[2294] The title compound was obtained from the compound obtained in Reference Example 425 in the same manner as the method described in Reference Example 353.
[2295]
[2296] Reference Example 427 (1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoropyridin-2-yl) amino] -2-oxoethanethi Oil} amino) cyclohexylcarbamic acid tert-butyl ester
[2297]
[2298] The pyridine (70 ml) solution of the compound (1.20 g) obtained in Reference Example 144 was heated to 120 ° C, the compound (2.42 g) obtained in Reference Example 426 was added thereto, stirred for 30 minutes, cooled to room temperature, and the solvent was distilled off under reduced pressure. It was. Methylene chloride (100 ml), saturated aqueous sodium hydrogencarbonate solution (100 ml), and water (50 ml) were added to the obtained residue, followed by separating an aqueous layer. The aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: tetrahydrofuran = 1: 1). The resulting solid was slurried with isopropyl ether (40 ml) for 1 hour, filtered and combined to give the title compound (920 mg).
[2299]
[2300] Reference Example 428 (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethioyl} amino) -5-[(dimethylamino) Carbonyl] cyclohexylcarbamic acid tert-butyl ester
[2301]
[2302] In the same manner as described in Reference Example 427, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 353.
[2303]
[2304] Reference Example 429 2-Chloro-4,5,6,7-tetrahydrobenzothiazole-6-ylformamide
[2305]
[2306] 2-chloro-5-oxo-4,5,6,7-tetrahydrobenzo [d] thiazole (Helv. Cim. Acta., 1994, Vol. 77, p. 1256) (4.53 g) methanol (200 ml) Ammonium acetate (18.58 g) and sodium cyanoborohydride (10.68 g) were added to the solution, and the mixture was heated to reflux. After 19 hours, hydrochloric acid was added to decompose the excess reagents, and the reaction solution was concentrated under reduced pressure, made alkaline with 1N sodium hydroxide aqueous solution, and then separated by adding methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was treated by silica gel column chromatography (methylene chloride: methanol = 20: 1), and the solvent was distilled off to obtain a pale yellow oil (2.42 g). This oily substance was dissolved in methylene chloride (100 ml), formic acid (530 µl), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.68 g), and 1-hydroxybenzotriazole ( 2.60 g) and N-methylmorpholine (3.88 g) were added and stirred at room temperature. After 20 hours, methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, and the obtained residue was treated with silica gel column chromatography (methylene chloride: methanol = 20: 1) to obtain the title compound (2.21).
[2307]
[2308] Reference Example 430 N- (2-Chloro-4,5,6,7-tetrahydrobenzothiazol-6-yl) -N-methylcarbamic acid tert-butyl ester
[2309]
[2310] To a tetrahydrofuran (50 ml) solution of the compound (2.11 g) obtained in Reference Example 429, 1 M borane-tetrahydrofuran complex tetrahydrofuran solution (14.6 ml) was added and heated to reflux. After 15 hours, 1M borane-tetrahydrofuran complex tetrahydrofuran solution (6.0 ml) was added and heated to reflux. After 4 hours, ethanol (10 ml) and 1N hydrochloric acid (15 ml) were added and heated to reflux. After 3 hours, the reaction solution was concentrated under reduced pressure, an aqueous solution of 1 N sodium hydroxide and methylene chloride were added thereto, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (50 ml), triethylamine (1.28 g) and di-tert-butyldicarbonate (2.21 g) were added and stirred at room temperature. After 30 minutes, methylene chloride and monobasic hydrochloric acid were added and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was treated by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (2.26 g).
[2311]
[2312] Reference Example 431 N- (2-[({(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5 -[(Dimethylamino) carbonyl] cyclohexyl} amino) carbonyl] -4,5,6,7-tetrahydrobenzothiazol-6-yl) -N-methylcarbamic acid tert-butyl ester
[2313]
[2314] To the diethyl ether (10 ml) -tetrahydrofuran (5 ml) solution of the compound (1.0 g) obtained in Reference Example 430, cooled to -78 ° C, and 1.6 rt tert-butyllithium pentane solution (3.1 ml) was added thereto. After stirring for 20 minutes, carbon dioxide gas was introduced for 20 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure to give 6-[(tert-butoxycarbonyl) (methyl) amino] -4,5,6,7-tetrahydrobenzothiazole-2-carboxylic acid lithium salt. .
[2315] Lithium carboxylate (350.2 mg), 1- (3-dimethylaminopropyl) -3- obtained by the above reaction in a N, N-dimethylformamide (20 ml) solution of the compound (490.5 mg) obtained in Reference Example 420. Ethylcarbodiimide hydrochloride (287.6 mg), 1-hydroxybenzotriazole (202.7 mg) and N-methylmorpholine (0.319 ml) were added and stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, water and methylene chloride were added to the residue, the mixture was separated, and the organic layer was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine in that order. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methylene chloride: methanol = 40: 1 → 20: 1) to obtain the title compound (323.9 mg).
[2316]
[2317] Reference Example 432 N-{(1S, 2R, 4S) -2-amino-4-[(dimethylamino) carbonyl] cyclohexyl} -5-chloroindole-2-carboxamide hydrochloride
[2318]
[2319] In the same manner as in Reference Example 69, the compound obtained in Reference Example 310 was deprotected to obtain the title compound.
[2320]
[2321] Reference Example 433 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetate
[2322]
[2323] To a tetrahydrofuran (2000 ml) suspension of 2-amino-5-chloropyridine (100 g) and sodium bicarbonate (78.4 g), chlorooxoacetic acid methyl ester (78.7 ml) was added dropwise at 0 ° C, and at room temperature for 2 hours. Stirred. The reaction solution was added to a mixture of diethyl ether (2000 ml), ammonium chloride (62.4 g) and water (1000 ml) under stirring, followed by separating an aqueous layer with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and dried to obtain 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid methyl ester (162 g). To a solution of tetrahydrofuran (1800 ml) of this ester (160 g) was added water (450 ml) and lithium hydroxide (18.2 g). After stirring for 2 hours at room temperature, the solvent was distilled off under reduced pressure, and hexane (3000 ml) was added to the obtained residue, followed by stirring for 3 hours. The solid was collected by filtration and dried, acetonitrile (1000 ml) was added to the obtained solid (190 g), followed by stirring for 1 hour. The resulting solid was collected by filtration, washed with diethyl ether (500 ml) and dried to obtain the title compound. (158 g) was obtained.
[2324]
[2325] Reference Example 434 (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5-[(dimethylamino) carbonyl ] Cyclohexylcarbamic acid tert-butyl ester
[2326]
[2327] In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 433.
[2328]
[2329] [Referential Example ^{435] N 1 - {(1S} , 2R, 4S) -2- amino-4 - [(dimethylamino) carbonyl] cyclohexyl} -N ² - (5- chloropyridin-2-yl) ethane Dia Mead hydrochloride
[2330]
[2331] In the same manner as in Reference Example 69, the title compound was obtained from the compound obtained in Reference Example 434.
[2332]
[2333] Example 1 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopropyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2334]
[2335] 1-hydroxybenzotriazole monohydrate (71 mg) in a solution of the compound obtained in Reference Example 59 (108 mg) and the compound obtained in Reference Example 10 (124 mg) in N, N-dimethylformamide (3 ml). And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 mg) were added at room temperature and stirred for 8 days. The reaction solution was concentrated under reduced pressure using a vacuum pump, and then water (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) were added and extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 10: 1). To the obtained amorphous material was added 1N ethanol hydrochloride solution, methylene chloride and methanol, followed by concentration to give the title compound (72 mg).
[2336]
[2337] Example 2 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclobutyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2338]
[2339] Compound (117 mg) obtained in Reference Example 60 was dissolved in N, N-dimethylformamide (5 ml), and compound (136 mg) and 1- (3-dimethylaminopropyl) -3-ethyl obtained in Reference Example 10. Carbodiimide hydrochloride (255 mg) and 1-hydroxybenzotriazole monohydrate (90 mg) were added, the mixture was stirred overnight at room temperature, and then the solvent was distilled off using a vacuum pump, and the residue was methylene chloride and saturated carbonic acid. An aqueous sodium hydrogen solution was added to the solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 7: 93). Acetic acid ethyl ester and monobasic ethanol hydrochloride solution were added to the obtained compound to make acid, and the solvent was concentrated under reduced pressure. Acetic acid ethyl ester was added again, and the resulting precipitate was collected by filtration and dried to give the title compound (56 mg).
[2340]
[2341] Example 3 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2342]
[2343] The compound obtained in Reference Example 62 (120 mg) was dissolved in N, N-dimethylformamide (5 ml), 5-chloroindole-2-carboxylic acid (80 mg), 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (98 mg), 1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine (141 μl) were added and stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was separated by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7), and methylene chloride (5 ml) and 1 N-ethanol hydrochloric acid solution (282 µl) were added to the pale yellow solid obtained. Acetic acid ethyl ester was added, the solvent was concentrated under reduced pressure, and the resulting precipitate was collected by filtration to obtain the title compound (109 mg).
[2344]
[2345] Example 4 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) sulfonyl] amino} cyclohexyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2346]
[2347] The compound (400 mg) obtained in Reference Example 67 was suspended in methylene chloride (10 ml), and triethylamine (0.514 ml) and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (Japanese Patent Laid-Open) 2000-119253) (319 mg) was added and stirred at room temperature for 15 minutes. Water was added to the reaction solution to carry out a liquid separation operation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a pale yellow foamy material. This was dissolved in tetrahydrofuran (3 ml), methanol (2 ml) and 1N sodium hydroxide aqueous solution (1.5 ml) were added and heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and methylene chloride and 1 N hydrochloric acid aqueous solution were added to the residue to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3). To the obtained product was added 1N hydrochloric acid (1 ml) and concentrated under reduced pressure to give the title compound (108 mg).
[2348]
[2349] Example 5 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2350]
[2351] The compound obtained in Reference Example 65 (300 mg) was dissolved in N, N-dimethylformamide (20 ml), 5-chloroindole-2-carboxylic acid (109 mg) and 1-hydroxybenzotriazole monohydrate. (9 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (321 mg) and triethylamine (0.232 ml) were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure using a vacuum pump, and methylene chloride and water were added to the residue to carry out a liquid separation operation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain a colorless foamy material. To this was added 1 N hydrochloric acid (1 ml) and concentrated under reduced pressure to afford the title compound (203 mg).
[2352]
[2353] Example 6 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2354]
[2355] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 67 and 5-chloroindole-2-carboxylic acid.
[2356]
[2357] Example 7 N-{(1R ^* , 2S ^* )-2-[(6-chloro-2-naphthoyl) amino] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothia Solo [5,4-c] pyridine-2-carboxamide hydrochloride
[2358]
[2359] Compound (275 mg) obtained in Reference Example 67 in the same manner as in Example 5, 6-chloronaphthalene-2-carboxylic acid (Eur. J. Chem. Chim. Ther., 1984, Volume 19, pages 205-214 ) (148 mg), triethylamine (0.298 ml) and 1-hydroxybenzotriazole monohydrate (11 mg) are dissolved in N, N-dimethylformamide (20 ml) and 1- (3-dimethylamino The title compound (186 mg) was obtained by reaction by adding propyl) -3-ethylcarbodiimide hydrochloride (412 mg).
[2360]
[2361] Example 8 N-((1R ^* , 2R ^* )-2-{[(6-chloro-1-benzothiophen-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2362]
[2363] Compound (255 mg) obtained in Reference Example 65, 6-chlorobenzo [b] thiophene-2-carboxylic acid (JP-A 2000-119253) (141 mg) and triethyl in the same manner as in Example 5. Amine (0.276 ml) and 1-hydroxybenzotriazole monohydrate (10 mg) were dissolved in N, N-dimethylformamide (20 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodii Mid hydrochloride (382 mg) was added to the reaction to give the title compound (239 mg).
[2364]
[2365] Example 9 N-((1R ^* , 2R ^* )-2-{[(5-fluoroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2366]
[2367] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 65 and 5-fluoroindole-2-carboxylic acid.
[2368]
[2369] Example 10 N-((1R ^* , 2R ^* )-2-{[(5-chloro-6-fluoroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2370]
[2371] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 65 and the compound obtained in Reference Example 23.
[2372]
[2373] Example 11 N-((1R ^* , 2S ^* )-2-{[(5-bromoindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2374]
[2375] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 67 and 5-bromoindole-2-carboxylic acid.
[2376]
[2377] Example 12 N-((1R ^* , 2S ^* )-2-{[(5-ethynylindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2378]
[2379] Triethylamine (6 ml), N, N-dimethylformamide (5 ml), trimethyl in a tetrahydrofuran solution (2 ml) of the compound (300 mg) and triphenylphosphine (70 mg) obtained in Example 11 Silylacetylene (0.250 ml) and palladium acetate (20 mg) were added at room temperature. After stirring at 90 ° C. for 2 hours, the reaction solution was allowed to cool to room temperature, followed by addition of methylene chloride (20 ml) and saturated aqueous sodium hydrogen carbonate solution (30 ml). The aqueous layer was extracted with methylene chloride (3 × 10 ml), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by preparative silica gel thin layer chromatography (methylene chloride: acetone: methanol = 10: 10: 1) to give a colorless solid. This was dissolved in methanol (6 ml), potassium carbonate (120 mg) was added, and the mixture was stirred for 1 hour. Methylene chloride (20 ml) and water (20 ml) were added to the reaction mixture, and the aqueous layer was extracted with methylene chloride (2 x 15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (methylene chloride: acetone: methanol = 10: 10: 1), which was dissolved in water-methanol-methylene chloride and concentrated to give the title compound (72 mg).
[2380]
[2381] Example 13 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5,6-dimethyl-4,5,6 , 7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxamide hydrochloride
[2382]
[2383] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 51.
[2384]
[2385] Example 14 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxamide
[2386]
[2387] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 26.
[2388]
[2389] Example 15 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [4,5-c] pyridine-2-carboxamide hydrochloride
[2390]
[2391] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 29.
[2392]
[2393] Example 16 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7 Tetrahydrooxazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2394]
[2395] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 69 and the compound obtained in Reference Example 21.
[2396]
[2397] Example 17 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydrothier Furnace [3,2-c] pyridine-2-carboxamide hydrochloride
[2398]
[2399] 5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxyl with the compound obtained in Reference Example 71 in the same manner as in Example 2. The acid (WO94 / 21599) was condensed, treated with hydrochloric acid and deprotected to afford the title compound.
[2400]
[2401] Example 18 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7 Tetrahydrothieno [3,2-c] pyridine-2-carboxamide hydrochloride
[2402]
[2403] The compound (171 mg) obtained in Example 17 was suspended in methylene chloride (10 ml), triethylamine (0.104 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Acetic acid (0.059 ml) was added to the reaction solution, followed by 35% formalin (0.070 ml) and sodium triacetoxy borohydride (118 mg), followed by stirring at room temperature for 30 minutes. An aqueous sodium hydroxide solution (3 ml) was added to the reaction solution, followed by water separation. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 3) to obtain a colorless foamy material. This was suspended in 1N hydrochloric acid and concentrated under reduced pressure to give the title compound (85 mg).
[2404]
[2405] Example 19 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -6- (dimethylamino) -4,5, 6,7-tetrahydrobenzothiazole-2-carboxamide hydrochloride
[2406]
[2407] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 31.
[2408]
[2409] Example 20 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (pyridin-4-yl) -4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2410]
[2411] To a tetrahydrofuran (3 ml) solution of the compound (204 mg) obtained in Reference Example 24 was added dropwise n-butyllithium (1.60 hexane solution, 0.704 ml) at -78 ° C and stirred at 0 ° C for 30 minutes. After cooling to −78 ° C., the temperature was raised to room temperature over 20 minutes while blowing carbon dioxide gas, and the reaction solution was concentrated under reduced pressure. To the obtained residue in N, N-dimethylformamide (6 ml) solution, the compound (400 mg) obtained in Reference Example 71, 1-hydroxybenzotriazole monohydrate (254 mg), and 1- (3-dimethylaminopropyl) 3-Ethylcarbodiimide hydrochloride (360 mg) and diisopropylamine (0.491 ml) were added at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and the residue was separated by adding methylene chloride (30 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and water (100 ml), and the aqueous layer was methylene chloride (4 x 15). ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 10: 1), which was dissolved in 1N aqueous hydrochloric acid solution-methanol-methylene chloride and concentrated to give the title compound (245 mg).
[2412]
[2413] Example 21 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cycloheptyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2414]
[2415] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 74 and the compound obtained in Reference Example 10.
[2416]
[2417] Example 22 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclooctyl) -5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2418]
[2419] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 78 and the compound obtained in Reference Example 10.
[2420]
[2421] Example 23 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -4,5,6,7-tetrahydrothia Solo [5,4-c] pyridine-2-carboxamide hydrochloride
[2422]
[2423] In the same manner as in Example 2, the product obtained by the reaction between the compound obtained in Reference Example 63 and the compound obtained in Reference Example 34 was subjected to hydrochloric acid treatment to obtain the title compound.
[2424]
[2425] Example 24 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5-isopropyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2426]
[2427] The compound (30 mg) obtained in Example 23 was suspended in methylene chloride (20 ml), triethylamine (260 µl) was added, and the mixture was stirred at room temperature for 15 minutes. Acetic acid (179 µl) and acetone (920 µl) were added to the reaction solution, and the mixture was stirred at room temperature for 2 minutes. Sodium triacetoxy borohydride (796 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. An aqueous sodium hydroxide solution (10 ml) was added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a colorless foamy material. This was dissolved in methylene chloride and 1N ethanol hydrochloride solution (1 ml) was added. The solution was concentrated under reduced pressure to give the title compound (205 mg).
[2428]
[2429] Example 25 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5-ethyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2430]
[2431] The compound (500 mg) obtained in Example 23 was dissolved in N, N-dimethylformamide (10 ml), triethylamine (576 µl) and ethyl iodide (329 µl) were added, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the insolubles were collected by filtration. This was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a light brown foamy material. It was suspended in 1N hydrochloric acid (2 ml) and the solution was concentrated under reduced pressure to give the title compound (180 mg).
[2432]
[2433] Example 26 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5- (1-methylcyclopropyl) -4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2434]
[2435] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 63 and the compound obtained in Reference Example 39.
[2436]
[2437] Example 27 N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4-methoxycyclopentyl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride (stereoisomer A and stereoisomer B)
[2438]
[2439] From the compound obtained in Reference Example 82 (a mixture of the stereoisomers in position 4) (268 mg), a mixture of stereoisomers A and B of the title compound was synthesized by condensation with the compound obtained in Reference Example 10 in the same manner as Example 2 After separation by silica gel column chromatography, hydrochloride was used to obtain stereoisomer A (75 mg) and stereoisomer B (70 mg) of the title compound.
[2440] Stereoisomer A:
[2441]
[2442] Stereoisomer B:
[2443]
[2444] Example 28 N-[(1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4- (hydroxymethyl) cyclopentyl] -5- ( 1,1-dimethyl-2-hydroxyethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride (stereoisomer A)
[2445]
[2446] 1) In the same manner as in Example 2, from the compound obtained in Reference Example 85 and the compound obtained in Reference Example 42, N-((1R ^* , 2R ^* )-4-[(benzyloxy) methyl] -2-{[( 5-chloroindol-2-yl) carbonyl] amino} cyclopentyl) -5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5,6 Stereoisomer A and stereoisomer B of, 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide were obtained.
[2447] Stereoisomer A:
[2448]
[2449] Stereoisomer B:
[2450]
[2451] 2) The stereoisomer A (288 mg) was suspended in methylene chloride (20 ml), dimethyl sulfide (1.15 ml) and anhydrous aluminum chloride (350 mg) were added thereto, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution (10 ml) was added to the reaction solution, followed by extraction with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 9: 1) to give 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethyl Ethyl) -N-[(1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4- (hydroxymethyl) cyclopentyl] -4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer A) (184 mg) was obtained.
[2452]
[2453] 3) The stereoisomer A (180 mg) obtained in 2) above was dissolved in 1N tetrabutylammonium fluoride tetrahydrofuran solution (2 ml) and stirred overnight at room temperature. Methylene chloride, monobasic sodium hydroxide aqueous solution, and sodium chloride were added to the reaction solution, and an organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 19: 1). The obtained powder was dissolved in methanol, 1N ethanol hydrochloride solution (229 µl) was added, ethyl acetate was added and the solvent was concentrated under reduced pressure to obtain the title compound (63 mg).
[2454]
[2455] Example 29 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,7,8,10-tetrahydro- 6H-pyrazolo [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxamide hydrochloride
[2456]
[2457] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 44.
[2458]
[2459] Example 30 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,6,7,8,9,11 Hexahydropyridazino [1,2-a] thiazolo [4,5-d] pyridazine-2-carboxamide hydrochloride
[2460]
[2461] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 46 and the compound obtained in Reference Example 71.
[2462]
[2463] Example 31 5-Chloro-N-{(1R ^* , 2S ^* )-2-[(5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-ylcarbonyl ) Amino] cyclohexyl} indole-2-carboxamide hydrochloride
[2464]
[2465] Under argon atmosphere, the compound (171 mg) obtained in Reference Example 33 was dissolved in diethyl ether (5 ml), and n-butyllithium (1.60 hexane solution, 385 µl) was added dropwise at -78 ° C. After stirring at −78 ° C. for 10 minutes, carbon dioxide gas was blown for 20 minutes and the temperature was raised to room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in N, N-dimethylformamide (10 ml), and the compound (184 mg) obtained in Reference Example 71 and 1-hydroxybenzotriazole monohydrate (76 mg) were obtained. And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (215 mg) were added and stirred at room temperature for 3 days. The reaction solution was concentrated, methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3: 97) to give ethanol hydrochloride solution (5 ml), and the mixture was stirred at room temperature for 1 hour to concentrate the reaction solution. The obtained residue was solidified by adding ethyl acetate, and the powder was collected by filtration to obtain the title compound (31 mg).
[2466]
[2467] Example 32 2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -5,7- Dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester
[2468]
[2469] The compound obtained in Reference Example 50 was hydrolyzed with lithium hydroxide and then reacted with the compound obtained in Reference Example 71 in the same manner as in Example 2 to obtain the title compound.
[2470]
[2471] Example 33 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -6-methyl-6,7-dihydro- 5H-pyrrolo [3,4-d] pyrimidine-2-carboxamide hydrochloride
[2472]
[2473] Trifluoroacetic acid (1 ml) was added to a solution obtained by dissolving the compound (34.0 mg) obtained in Example 32 in methylene chloride (1 ml) and stirred at room temperature for 1 hour. Concentrated under reduced pressure, the residue was dissolved in methylene chloride (1 ml), and triethylamine (17.6 µl), acetic acid (7.21 µl), 35% formalin (8.13 µl) and sodium hydride triacetoxyborate (20.1 mg) were added to room temperature. It was added at and stirred for 1 hour. Methylene chloride (10 ml) and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 7: 93), solidified by adding 1N ethanol hydrochloric acid solution and acetic acid ethyl ester, filtered and collected to obtain the title compound (8.00 mg). Got it.
[2474]
[2475] Example 34 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydrothia Solo [5,4-c] pyridine-2-carboxamide hydrochloride
[2476]
[2477] In the same manner as in Example 2, the product obtained by the reaction of the compound obtained in Reference Example 71 with the compound obtained in Reference Example 34 was subjected to hydrochloric acid treatment to obtain the title compound.
[2478]
[2479] Example 35 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (2-methoxyethyl) -4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2480]
[2481] In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and 2-methoxyethylbromide.
[2482]
[2483] Example 36 2- [2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -6 , 7-dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] acetic acid methyl ester hydrochloride
[2484]
[2485] In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and methyl bromoacetate.
[2486]
[2487] Example 37 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-isopropyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2488]
[2489] In the same manner as in Example 24, the title compound was obtained from the compound obtained in Example 34 and acetone.
[2490]
[2491] Example 38 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (tetrahydro-2H-pyran-4 -Yl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2492]
[2493] The title compound was obtained from the compound obtained in Example 34 and tetrahydro-4H-pyran-4-one in the same manner as in Example 24.
[2494]
[2495] Example 39 2- [2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -6 , 7-dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] ethylcarbamic acid tert-butyl ester
[2496]
[2497] In the same manner as in Example 24, the title compound was obtained from the compound obtained in Example 34 and N- (tert-butoxycarbonyl) aminoacetaldehyde (J. Org. Chem., 1988, Vol. 53, page 3457).
[2498]
[2499] Example 40 5- (2-aminoethyl) -N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2500]
[2501] The compound (450 mg) obtained in Example 39 was dissolved in methylene chloride (5 ml), ethanol hydrochloride solution (30 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (367 mg).
[2502]
[2503] Example 41 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- {2-[(methylsulfonyl) Amino] ethyl} -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2504]
[2505] The compound (110 mg) obtained in Example 40 was dissolved in pyridine (3 ml), methanesulfonyl chloride (30 µl) was added, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, a solution of methylene chloride: methanol = 85:15 and water were added to the residue, followed by a liquid separation operation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a pale yellow foamy material. This was suspended in 1N hydrochloric acid (0.3 ml) and the solution was concentrated under reduced pressure to give the title compound (63 mg).
[2506]
[2507] Example 42 2- [2-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} -6 , 7-dihydrothiazolo [5,4-c] pyridin-5 (4H) -yl] ethylcarbamic acid methyl ester hydrochloride
[2508]
[2509] The compound (144 mg) obtained in Example 40 was dissolved in pyridine (3 ml), triethylamine (138 µl) was added, followed by stirring at room temperature for 5 minutes. Triphosgene (49 mg) was added to tetrahydrofuran (1 ml) containing methanol (20 µl) to the solution, and the adjusted solution was added dropwise at room temperature, followed by stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methylene chloride: methanol = 9: 1, separated by addition of water, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a colorless foamy material. It was suspended in 1N hydrochloric acid (0.2 ml) and the solution was concentrated under reduced pressure to give the title compound (60 mg).
[2510]
[2511] Example 43 5- [2- (acetylamino) ethyl] -N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2512]
[2513] The compound (90 mg) obtained in Example 40 was dissolved in N, N-dimethylformamide (3 ml), triethylamine (65 µl) and acetic anhydride (22 µl) were added, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and methylene chloride and 0.3 N sodium hydroxide aqueous solution were added to the residue, followed by liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a colorless foamy material. It was suspended in 1N hydrochloric acid (0.3 ml) and the solution was concentrated under reduced pressure to give the title compound (73 mg).
[2514]
[2515] Example 44 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (2-hydroxyethyl) -4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2516]
[2517] In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and 2-bromoethanol.
[2518]
[2519] Example 45 5-Butyl-N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2520]
[2521] In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and 1-bromobutane.
[2522]
[2523] Example 46 5-acetyl-N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2524]
[2525] The compound (100 mg) obtained in Example 34 was dissolved in N, N-dimethylformamide (3 ml), triethylamine (84 µl) and acetic anhydride (29 µl) were added, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and methylene chloride and monobasic hydrochloric acid were added to the residue to carry out a liquid separation operation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain the title compound (86 mg).
[2526]
[2527] Example 47 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5- (methylsulfonyl) -4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2528]
[2529] The compound (100 mg) obtained in Example 34 was dissolved in pyridine (3 ml), triethylamine (168 µl) and methanesulfonyl chloride (48 µl) were added, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, methylene chloride and monobasic hydrochloric acid were added to the residue, an organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1) to obtain the title compound (79 mg).
[2530]
[2531] Example 48 5-Methyl-N-((1R ^* , 2S ^* )-2-{[(5-methylindol-2-yl) carbonyl] amino} cyclohexyl) -4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2532]
[2533] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 67 and 5-methylindole-2-carboxylic acid.
[2534]
[2535] Example 49 (1R ^* , 3S ^* , 4R ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester
[2536]
[2537] The compound (1.40 g) obtained in Reference Example 91 was suspended in ethanol (8 ml), an ethanol hydrochloride solution (10 ml) was added thereto, and the mixture was stirred for 12 hours. The solvent was distilled off under reduced pressure, and (1R ^* , 3S ^* , 4R ^* )-3-amino-4-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester hydrochloride ( 1.25 g) was obtained.
[2538] In the same manner as in Example 2, the title compound was obtained from the above product and the compound obtained in Reference Example 10.
[2539]
[2540] Example 50 (1S, 3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester
[2541]
[2542] The compound (4.2 g) obtained in Reference Example 97 was suspended in ethanol (25 ml), an ethanol hydrochloride solution (55 ml) was added thereto, and the mixture was stirred for 11 hours. The solvent was distilled off under reduced pressure to give a colorless solid (4.15 g).
[2543] The product (4.15 g) was dissolved in N, N-dimethylformamide (40 ml), and the compound (2.86 g) obtained in Reference Example 10 at room temperature, 1-hydroxybenzotriazole monohydrate (1.72 g), 1 -(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.15 g) was added and the mixture was stirred for 39 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain the title compound (1.71 g).
[2544] [α] _D -94 ° (c = 1.0, chloroform).
[2545] Example 51 (1R ^* , 3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester
[2546]
[2547] The compound obtained in Reference Example 107 was treated with the ethanol hydrochloride solution in the same manner as in Example 49, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[2548]
[2549] Example 52 (1R ^* , 3S ^* , 4R ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid ethyl ester
[2550]
[2551] In the same manner as in Example 49, the compound obtained in Reference Example 98 was treated with an ethanol hydrochloride solution, and then condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.
[2552]
[2553] Example 53 (1R ^* , 3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester hydrochloride
[2554]
[2555] In the same manner as in Example 49, the compound obtained in Reference Example 106 was treated with tetrahydrochloric acid dioxane solution, and then condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.
[2556]
[2557] Example 54 (1R, 3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid methyl ester
[2558]
[2559] In the same manner as in Example 49, the compound obtained in Reference Example 112 was treated with tetrahydrochloric acid dioxane solution, and then condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.
[2560]
[2561] Example 55 N-((1R ^* , 2S ^* , 5S ^* )-5- (aminocarbonyl) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl)- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2562]
[2563] In the same manner as in Example 49, the compound obtained in Reference Example 113 was treated with tetrahydrochloric acid dioxane solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[2564]
[2565] Example 56 (1R ^* , 3S ^* , 4R ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid
[2566]
[2567] The compound (916 mg) obtained in Example 49 was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (8 ml), and 1N sodium hydroxide solution (3.3 ml) was added at room temperature, followed by stirring at the same temperature for 12 hours. It was. After adding 1N ethanol hydrochloric acid solution (3.3 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and diethyl ether to obtain the title compound (712 mg).
[2568] Example 57 N-{(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclo Hexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2569]
[2570] To a chloroform suspension (10 ml) of a compound (168 mg) obtained in Example 56 was triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (53 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (75 mg) was added and the mixture was stirred for 72 hours. The solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7) to give a colorless solid (135 mg) suspended in ethanol (5 ml), and a 1N ethanol hydrochloride solution (0.5). ml) was added and stirred for 2 hours. The solvent was distilled off to give the title compound (112 mg).
[2571]
[2572] Example 58 (1S, 3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid
[2573]
[2574] The compound (1.6 g) obtained in Example 50 was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), and 1N sodium hydroxide solution (5.9 ml) was added at room temperature, followed by stirring at the same temperature for 12 hours. It was. After adding 1N hydrochloric acid (5.9 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and diethyl ether to obtain the title compound (1.19 g).
[2575] mp. 234-236 ° C.
[2576] [α] _D −57 ° (c = 1.0, methanol).
[2577] Example 59 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(cyclopropylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2578]
[2579] In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and cyclopropylamine.
[2580]
[2581] Example 60 N-[(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (pyrrolidin-1-ylcarbonyl) cyclo Hexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2582]
[2583] In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and pyrrolidine.
[2584]
[2585] Example 61 N-[(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (4-morpholinylcarbonyl) Cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2586]
[2587] In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 56 and morpholine.
[2588]
[2589] Example 62 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(ethylamino) carbonyl] cyclohexyl}- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2590]
[2591] The compound obtained in Example 58 (150 mg) was dissolved in N, N-dimethylformamide (3 ml), N-ethylamine hydrochloride (119 mg), 1-hydroxybenzotriazole monohydrate (79 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (112 mg) and triethylamine (326 µl) were added and the mixture was stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, an aqueous saturated sodium bicarbonate solution was added to the residue, followed by extraction with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3). The obtained solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (171 µl) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (74 mg).
[2592]
[2593] Example 63 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2594]
[2595] The compound obtained in Example 58 (900 mg) was dissolved in N, N-dimethylformamide (50 ml), dimethylamine hydrochloride (304 mg), 1-hydroxybenzotriazole monohydrate (262 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (369 mg) and diisopropylethylamine (1.83 ml) were added, and it stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, an aqueous saturated sodium bicarbonate solution was added to the residue, followed by extraction with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3). The obtained white solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (1.49 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (777 mg).
[2596] α _D = −53.9 ° (18 ° C., c = 0.505, methanol).
[2597]
[2598] Example 64 N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(2-methoxyethyl) (methyl) Amino] carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2599]
[2600] The title compound was obtained from the compound obtained in Example 58 in the same manner as in Example 57.
[2601]
[2602] Example 65 N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(2-hydroxyethyl) (methyl) Amino] carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2603]
[2604] The title compound was obtained from the compound obtained in Example 58 in the same manner as in Example 57.
[2605]
[2606] Example 66 N-((1R, 2S, 5S) -5- (1-azetidinylcarbonyl) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2607]
[2608] In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and azetidine hydrochloride.
[2609]
[2610] Example 67 N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(3S) -3-fluoropyrroli Diyl] carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2611]
[2612] In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and (S) -3-fluoropyrrolidine (Synlett., 1995, page 55).
[2613]
[2614] Example 68 (1R ^* , 3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexanecarboxylic acid lithium salt
[2615]
[2616] The compound (1.20 g) obtained in Example 51 was dissolved in tetrahydrofuran (32 ml), and lithium hydroxide (60.8 mg) and water (4 ml) were added sequentially under ice cooling, and it stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure to give the title compound (1.12 g).
[2617]
[2618] Example 69 N-{(1R ^* , 2S ^* , 4S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -4-[(dimethylamino) carbonyl] cyclo Hexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2619]
[2620] In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 68 and dimethylamine hydrochloride.
[2621]
[2622] Example 70 N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(3R) -3-hydroxypyrroli Diyl] carbonyl} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2623]
[2624] 1) The compound (1.18 g) obtained in Reference Example 58 was dissolved in methanol (12 ml), and 1 N hydrochloric acid (240 µl) and palladium hydroxide (221 mg) were added thereto to introduce hydrogen, followed by 4.5 hours of atmospheric pressure reduction at room temperature. It was done. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to give crude (3R) -3-{[tert-butyl (diphenyl) silyl] oxy} pyrrolidine hydrochloride (984 mg).
[2625] Product obtained (249 mg), compound obtained in Example 58 (295 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (126 mg) and 1-hydroxybenzotriazole monohydrate ( 87 mg) was dissolved in N, N-dimethylformamide (10 ml). Diisopropylethylamine (450 µl) was added dropwise under ice cooling, followed by stirring at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was added thereto with methylene chloride and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography (methanol: methylene chloride = 3: 97) to give N-((1R, 2S, 5S) -5-[((3R) -3-{[tert-butyl (diphenyl) silyl ] Oxy} pyrrolidinyl) carbonyl] -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (248 mg) was obtained.
[2626]
[2627] 2) The above product (240 mg) was dissolved in pyridine (10 ml), and hydrogen fluoride pyridine (3.0 ml) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 4.5 hours. Acetic acid ethyl ester (80 ml) was added to the reaction mixture under ice cooling, and the diluted reaction solution was poured into ice. Sodium hydrogencarbonate was added to this solution to make it alkaline, and the liquid separation operation was performed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography (methanol: methylene chloride = 1: 19 → 1: 9). The obtained crude product was dissolved in methylene chloride and methanol, and dried once by adding 1 N ethanol hydrochloric acid solution (225 µl), and solidified by adding methanol-diethyl ether to the residue to obtain the title compound (114 mg).
[2628]
[2629] Example 71 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5,5-dimethoxycyclohexyl) -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((1R ^* , 2S ^* )-2-{[(5-chloroindole-2- Yl) carbonyl] amino} -4,4-dimethoxycyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2630] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 118 and the compound obtained in Reference Example 10.
[2631]
[2632] Example 72 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-oxocyclohexyl) -5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carb Bonyl] amino} -4-oxocyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2633] The compound (100 mg) obtained in Example 71 was dissolved in chloroform (2 ml), trifluoroacetic acid (0.5 ml) and water (0.5 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. Saturated sodium hydrogen carbonate solution was added to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 19: 1). The resulting colorless solid was dissolved in methanol (4 ml), 1N ethanol hydrochloric acid solution (0.38 ml) was added, and the solvent was distilled off under reduced pressure to obtain the title compound (35 mg).
[2634]
[2635] Example 73 N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxyimino) cyclohexyl] -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-[(1R ^* , 2S ^* )-2-{[(5-chloroindole-2 -Yl) carbonyl] amino} -4- (hydroxyimino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2636] The compound (133 mg) obtained in Example 72 was dissolved in a mixed solvent of pyridine (8 ml) and methanol (8 ml), and hydroxylamine hydrochloride (30 mg) was added and stirred at room temperature for 3 days. The reaction solution was concentrated, water was added to the residue, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3-&gt; 17: 3) to obtain the title compound (131 mg).
[2637]
[2638] Example 74 N-((7R ^* , 8S ^* )-8-{[(5-chloroindol-2-yl) carbonyl] amino} -1,4-dioxaspiro [4,5] deck- 7-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((7R ^* , 8S ^* ) -7- { [(5-chloroindol-2-yl) carbonyl] amino} -1,4-dioxaspiro [4,5] deck-8-yl) -5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridine-2-carboxamide
[2639] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 120 and the compound obtained in Reference Example 10.
[2640]
[2641] Example 75 N-[(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (methoxyimino) cyclohexyl] -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-[(1R ^* , 2S ^* )-2-{[(5-chloroindole-2 -Yl) carbonyl] amino} -4- (methoxyimino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2642] 1) The compound (2.21 g) obtained in Example 124 was dissolved in methylene chloride (30 ml), trifluoroacetic acid (6 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, dried with a vacuum pump, dissolved in N, N-dimethylformamide (20 ml), 5-chloroindole-2-carboxylic acid (500 mg), 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (593 mg), 1-hydroxybenzotriazole monohydrate (473 mg) and N-methylmorpholine (2.8 ml) were added and stirred at room temperature for 10 hours. Furthermore, 5-chloroindole-2-carboxylic acid (242 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (237 mg) and 1-hydroxybenzotriazole monohydrate (189 mg) ) Was added and stirred for 4 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate, ethyl acetate, and tetrahydrofuran. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3 → 4: 1) to give N-[(1R ^* , 2S ^* )-2-amino-5- (methoxyimino) cyclohexyl] -5 -Chloroindole-2-carboxamide (368 mg) and N-[(1R ^* , 2S ^* )-2-amino-4- (methoxyimino) cyclohexyl] -5-chloroindole-2-carboxamide (300 mg) was obtained.
[2643] 2) N-[(1R ^* , 2S ^* )-2-amino-5- (methoxyimino) cyclohexyl] -5-chloroindole-2-carboxamide or N-[( 1R ^* , 2S ^* ) -2-amino-4- (methoxyimino) cyclohexyl] -5-chloroindole-2-carboxamide and the compound obtained in Reference Example 10, in the same manner as in Example 2, with the title compound. (Syn and anti isomer mixture of methoxyimino group moiety) were obtained.
[2644]
[2645] Example 76 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-hydroxycyclohexyl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer A) or N-((1R ^* , 2S ^* )-2-{[(5-chloroindole -2-yl) carbonyl] amino} -4-hydroxycyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide ( Stereoisomer A)
[2646] 1) The tert-butoxycarbonyl group of the (1R ^* , 2S ^* ) body (stereoisomer A) obtained in Reference Example 125 was removed in the same manner as in 1) of Example 75, and then 5-chloroindole-2-carboxylic acid and N-((1R ^* , 2S ^* )-2-amino-4-{[tert-butyl (diphenyl) silyl] oxy} cyclohexyl) -5-chloroindole-2-carboxamide (stereoisomer A ) And N-((1R ^* , 2S ^* )-2-amino-5-{[tert-butyl (diphenyl) silyl] oxy} cyclohexyl) -5-chloroindole-2-carboxamide (stereoisomer A )
[2647] 2) From the product and the compound obtained in Reference Example 10, N-((1R ^* , 2S ^* )-5-{[tert-butyl (diphenyl) silyl] oxy} -2- { [(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (Stereoisomer A) or N-((1R ^* , 2S ^* )-4-{[tert-butyl (diphenyl) silyl] oxy} -2-{[(5-chloroindol-2-yl) carbonyl] Amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (stereoisomer A) was obtained.
[2648]
[2649] 3) From the compound obtained in the above reaction, the title compound was obtained in the same manner as in 3) of Example 28.
[2650]
[2651] Example 77 N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-hydroxy-5-methylcyclohexyl) -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (isomer A1) or N-((1R ^* , 2S ^* )-2-{[(5 -Chloroindol-2-yl) carbonyl] amino} -4-hydroxy-4-methylcyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-carboxamide (isomer A2)
[2652] In the same manner as in Example 2, the title compound was obtained by reacting the compound obtained in Reference Example 128 with the compound obtained in Reference Example 10.
[2653] Isomer A1:
[2654]
[2655] Isomer A2:
[2656]
[2657] Example 78 N-[(1R ^* , 2R ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (hydroxymethyl) cyclohexyl]- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2658]
[2659] In the same manner as in Example 49, the compound obtained in Reference Example 129 was treated with an ethanol hydrochloride solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[2660]
[2661] Example 79 N-[(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- (methoxymethyl) cyclohexyl]- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2662]
[2663] In the same manner as in Example 49, the compound obtained in Reference Example 135 was treated with an ethanol hydrochloride solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[2664]
[2665] Example 80 N-((1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(methylsulfonyl) amino] Methyl} cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2666]
[2667] 1) The compound (437 mg) obtained in Reference Example 137 was dissolved in ethanol (5 ml), 4 dihydrochloric acid dioxane solution (5 ml) was added thereto, and the mixture was stirred for 13 hours. The solvent was distilled off and the residue was dissolved in N, N-dimethylformamide (10 ml), triethylamine (0.7 ml), the compound obtained in Reference Example 10 (300 mg), and 1-hydroxybenzotriazole monohydrate ( 162 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (230 mg) were added and the mixture was stirred for 13 hours. The solvent was concentrated under reduced pressure, water was added, extraction was performed with chloroform, and the organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3) to give N-((1R ^* , 2S ^* , 5S ^* )-5- (azidemethyl) -2- {[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carbox Mid (330 mg) was obtained.
[2668]
[2669] 2) The compound (300 mg) obtained by the above reaction was dissolved in ethanol (8 ml), and a catalytic amount of 10% palladium carbon was added, followed by stirring at room temperature under a hydrogen stream for 168 hours. The insolubles were filtered off and the solvent was distilled off to prepare crude N-((1R ^* , 2S ^* , 5S ^* )-5- (aminomethyl) -2-{[(5-chloroindol-2-yl) carbonyl] Amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (150 mg) is dissolved in chloroform (6 ml), Triethylamine (0.2 ml) and methanesulfonyl chloride (0.035 ml) were added under ice-cooling, and the mixture was stirred for 13 hours. The solvent was distilled off under reduced pressure, water was added, extraction was performed with chloroform, and the organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to obtain the title compound (56 mg).
[2670]
[2671] Example 81 N-{(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) methyl] cyclohexyl } -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide trifluoroacetate
[2672]
[2673] The title compound was obtained from the amine obtained in 2) of Example 80 in the same manner as in Example 24.
[2674]
[2675] Example 82 (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester (isomer B) and (3R ^* , 4S ^* )-3-{[(5 -Chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl ] Amino} cyclohexylcarbamic acid tert-butyl ester (isomer B)
[2676]
[2677] The compound (stereoisomer B) (1.79 g) obtained in Reference Example 140 was dissolved in tetrahydrofuran (36 ml), 10% palladium carbon (0.40 g) was added, and the mixture was stirred at room temperature for 20 hours under hydrogen stream. The catalyst was filtered off and the filtrate was concentrated under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (36 ml) and 5-chloroindole-2-carboxylic acid p-nitrophenol ester (2.02 g) was added thereto. Stir for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added, the insolubles were collected by filtration and washed with ethyl acetate to prepare the crude (3R ^* , 4S ^* )-3-amino-4-{[(5-chloro Indol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester (or (3R ^* , 4S ^* )-4-amino-3-{[(5-chloroindol-2-yl) carbonyl ] Amino} cyclohexylcarbamic acid tert-butyl ester) (isomer B1) (1.49) were obtained. The organic layer of the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1 → 10: 1) to give (3R ^* , 4S ^* )-4-amino-3-{[(5-chloro Indol-2-yl) carbonyl] amino} cyclohexylcarbamic acid tert-butyl ester (or (3R ^* , 4S ^* )-3-amino-4-{[(5-chloroindol-2-yl) carbonyl ] Amino} cyclohexylcarbamic acid tert-butyl ester) (isomer B2) (0.37 g) were obtained.
[2678] One of the title compounds was obtained from the compound obtained in Isomer B1 and Reference Example 10 in the same manner as in Example 2.
[2679]
[2680] Also in the same manner, another title compound was obtained from the above isomer B2.
[2681]
[2682] Example 83 N-((1R ^* , 2S ^* )-5-amino-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (or N-((1R ^* , 2S ^* )-4-amino-2-{[(5-chloroindole- 2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide) hydrochloride (stereoisomer B)
[2683]
[2684] In Example 82, the compound (stereoisomer B) (1.11 g) synthesized from Isomer B1 was suspended in methylene chloride (20 ml), an ethanol hydrochloride solution (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by gel filtration (Sephadex LH-20, methanol) to obtain the title compound (1.05 g).
[2685]
[2686] Example 84 N-{(1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfonyl) amino] cyclohexyl}- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-{(1R ^* , 2S ^* ) -2-{[(5-chloro Indol-2-yl) carbonyl] amino} -4-[(methylsulfonyl) amino] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-carboxamide (stereoisomer B)
[2687]
[2688] The compound (0.20 g) obtained in Example 83 was suspended in methylene chloride (7 ml), triethylamine (0.16 ml) and methanesulfonyl chloride (28 µl) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with methylene chloride, washed with aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1 → 15: 1) to give the title compound (67.9 mg).
[2689]
[2690] Example 85 N-((1R ^* , 2S ^* )-5- (acetylamino) -2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide or N-((1R ^* , 2S ^* )-4- (acetylamino) -2-{[( 5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (steric) Isomer B)
[2691]
[2692] The compound (stereoisomer B) (0.20 g) obtained in Example 83 was suspended in methylene chloride (7 ml), triethylamine (0.16 ml) and acetic anhydride (34 µl) were added, and the mixture was stirred at room temperature for 20 hours. Methylene chloride and aqueous sodium hydroxide solution were added to the reaction solution, and the insolubles were collected by filtration. The organic layer of the filtrate was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 15: 1-&gt; 10: 1) to obtain the title compound (0.12 g).
[2693]
[2694] Example 86 N-((1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-{[(methoxy (methyl) amino] carbonyl } Cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2695]
[2696] The compound obtained in Example 58 (250 mg) was dissolved in N, N-dimethylformamide (5 ml), and N, O-dimethylhydroxylamine hydrochloride (142 mg), 1- (3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (111 mg), 1-hydroxybenzotriazole monohydrate (89 mg) and N-methylmorpholine (213 ml) were added and stirred at room temperature for 19 hours. The reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3-&gt; 23: 2) to obtain a colorless amorphous solid (179 mg). This was dissolved in methanol-tetrahydrofuran, and 1N ethanol hydrochloric acid solution (960 ml) was added to obtain the title compound.
[2697]
[2698] Example 87 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(2,2-dimethylhydrazino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2699]
[2700] In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and N, N-dimethylhydrazine.
[2701]
[2702] Example 88 6-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -2-quinolinecarboxamide hydrochloride
[2703]
[2704] In the same manner as in Example 49, the compound obtained in Reference Example 145 was treated with an ethanol hydrochloride solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[2705]
[2706] Example 89 N-{(1R, 2S, 5S) -2-{[(5-chloro-4-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2707]
[2708] In the same manner as in Example 91, the compound obtained by the condensation of the compound obtained in Reference Example 144 with the compound obtained in Reference Example 274 was treated with dibasic acid hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound. .
[2709]
[2710] Example 90 7-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride
[2711]
[2712] In the same manner as in Example 49, the compound obtained in Reference Example 146 was treated with an ethanol hydrochloride solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[2713]
[2714] Example 91 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} tetrahydrofuran-3-yl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2715]
[2716] To a N, N-dimethylformamide (20 ml) solution of the compound (0.12 g) obtained in Example 172, the compound (0.1 g) obtained in Reference Example 10, 1-hydroxybenzotriazole monohydrate (78 mg), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.2 g) was added sequentially, and it stirred at room temperature for 1 day. The reaction solution was concentrated, and the obtained residue was diluted with chloroform: methanol (9: 1), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5) to obtain the free base of the title compound, and treated with ethanol hydrochloride solution to obtain the title compound (0.1 g).
[2717]
[2718] Example 92 N-((3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} tetrahydrofuran-3-yl) -5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2719]
[2720] The title compound was obtained from the compound obtained in Reference Example 183 by the method of Reference Example 172 and Example 91.
[2721]
[2722] Example 93 N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} tetrahydrofuran-3-yl) -5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2723]
[2724] The title compound was obtained from the compound obtained in Reference Example 187 by the method of Reference Example 172 and Example 91.
[2725] ¹ H-NMR and MS (FAB): Consistent with Example 92, which is an enantiomer.
[2726] Example 94 (3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid tert-butyl ester
[2727]
[2728] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 193 and the compound obtained in Reference Example 10.
[2729] Melting point: 190-192 ℃
[2730]
[2731] Example 95 N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidin-3-yl) -5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2732]
[2733] The compound (170 mg) obtained in Example 94 was dissolved in methylene chloride (3 ml), trifluoroacetic acid (2 ml) was added at room temperature, and the mixture was stirred for 1 hour. After concentration, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol: water = 7: 3: 1, lower layer), and methanol was added to the target compound to obtain the title compound (90 mg) as hydrochloride (NMR is a free base. Measured by).
[2734] Melting point: 248-250 ° C. (decomposition).
[2735]
[2736] Example 96 N-((3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -5-oxotetrahydrofuran-3-yl) -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2737]
[2738] The tert-butoxycarbonyl group of the compound obtained in Reference Example 196 was removed in the same manner as in Reference Example 69, and then reacted with the compound obtained in Reference Example 10 in the same manner as in Example 91 to obtain the title compound.
[2739]
[2740] Example 97 N-((3S, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -2-oxotetrahydrofuran-3-yl) -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2741]
[2742] The tert-butoxycarbonyl group of the compound obtained in Reference Example 197 was removed in the same manner as in Reference Example 69, and then reacted with 5-chloroindole-2-carboxylic acid in the same manner as in Example 91 to obtain the title compound.
[2743]
[2744] Example 98 (3S, 4R) -2- (3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -2-oxopyrrolidin-1-yl) acetic acid ethyl ester hydrochloride
[2745]
[2746] From the compound obtained in Reference Example 199 and the compound obtained in Reference Example 10, the title compound was obtained in the same manner as in Example 91 (NMR was determined by free base).
[2747]
[2748] Example 99 N-((3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-methyl-5-oxopyrrolidin-3-yl)- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2749]
[2750] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 201 and the compound obtained in Reference Example 10.
[2751]
[2752] Example 100 2-[((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) sulfonyl] acetic acid methyl ester
[2753]
[2754] The compound (230 mg) and triethylamine (0.10 ml) obtained in Example 95 were dissolved in methylene chloride (6.9 ml) and ice-cooled. Then methoxycarbonylmethanesulfonyl chloride (Synthesis, p. 321, 1975) (105 mg) was added and returned to room temperature and stirred overnight. Diluted with chloroform, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol = 20: 1), and then triturated with methanol-water to obtain the title compound (150 mg).
[2755]
[2756] Example 101 2-[((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) sulfonyl] acetic acid
[2757]
[2758] The compound (100 mg) obtained in Example 100 was dissolved in tetrahydrofuran (4 ml) -water (1 ml) and ice-cooled. Next, lithium hydroxide monohydrate (7.8 mg) was added, and the mixture was returned to room temperature and stirred for 4 hours. The mixture was neutralized with 1N aqueous hydrochloric acid, concentrated, and the precipitate was collected by filtration, washed with water and 50% ethanol, and dried at 50 ° C. under reduced pressure overnight to obtain the title compound (87 mg).
[2759]
[2760] Example 102 2-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) acetic acid methyl ester
[2761]
[2762] The compound (230 mg) and potassium carbonate (90 mg) obtained in Example 95 were dissolved in N, N-dimethylformamide (4.6 ml) and ice-cooled. Subsequently, bromoacetic acid methyl ester (0.062 ml) was added and stirred for 45 minutes. The reaction solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol = 10: 1), and then triturated with methanol-water to obtain the title compound (190 mg).
[2763]
[2764] Example 103 2-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) acetic acid
[2765]
[2766] The title compound was obtained in the same manner as Example 101 from the compound obtained in Example 102.
[2767]
[2768] Example 104 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid methyl ester
[2769]
[2770] The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 95 and 3-bromopropionic acid methyl ester.
[2771]
[2772] Example 105 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid
[2773]
[2774] The title compound was obtained in the same manner as Example 101 from the compound obtained in Example 104.
[2775]
[2776] Example 106 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) -3-oxopropionic acid ethyl ester
[2777]
[2778] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 95 and ethylmalonyl chloride.
[2779]
[2780] Example 107 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) -3-oxopropionic acid
[2781]
[2782] The title compound was obtained in the same manner as Example 101 from the compound obtained in Example 106.
[2783]
[2784] Example 108 1-[((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) methyl] cyclopropanecarboxylic acid methyl ester
[2785]
[2786] The title compound was obtained in the same manner as Example 102 from the compound obtained in Example 95 and 1- (bromomethyl) cyclopropanecarboxylic acid methyl ester.
[2787]
[2788] Example 109 1-[((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) methyl] cyclopropanecarboxylic acid
[2789]
[2790] The title compound was obtained in the same manner as Example 101 from the compound obtained in Example 108.
[2791]
[2792] Example 110 (3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6,7-tetra Hydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid tert-butyl ester
[2793]
[2794] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 193 and the compound obtained in Reference Example 148.
[2795]
[2796] Example 111 N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidin-3-yl) -5-isopropyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2797]
[2798] The title compound was obtained in the same manner as in Example 95 from the compound obtained in Example 110.
[2799]
[2800] Example 112 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid ethyl ester
[2801]
[2802] The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 111 and 3-bromopropionic acid ethyl ester.
[2803]
[2804] Example 113 3-((3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidin-1-yl) propionic acid
[2805]
[2806] The title compound was obtained in the same manner as Example 101 from the compound obtained in Example 112.
[2807]
[2808] Example 114 N-((3R, 4R) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} pyrrolidin-3-yl) -5-isopropyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2809]
[2810] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 111 and acetic anhydride.
[2811] Melting point: 254-258 ° C. (decomposition).
[2812]
[2813] Example 115 N-[(3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) pyrrolidin-3-yl]- 5-isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2814]
[2815] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 111 and methanesulfonyl chloride.
[2816] Melting point: 230-235 ° C. (decomposition).
[2817]
[2818] Example 116 (3R, 4R) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-isopropyl-4,5,6,7-tetra Hydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} pyrrolidine-1-carboxylic acid ethyl ester hydrochloride
[2819]
[2820] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 111 and ethyl chloroformate.
[2821] Melting point: 225-228 ° C. (decomposition).
[2822]
[2823] Example 117 (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester
[2824]
[2825] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 207 and the compound obtained in Reference Example 10.
[2826] Melting point: 152-154 ° C. (decomposition).
[2827]
[2828] Example 118 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride
[2829]
[2830] The title compound was obtained in the same manner as in Example 95 from the compound obtained in Example 117.
[2831] Melting point: 240-258 ° C. (decomposition).
[2832]
[2833] Example 119 (3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester
[2834]
[2835] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 208 and 5-chloroindole-2-carboxylic acid.
[2836] Melting point: 187-189 ° C. (decomposition).
[2837]
[2838] Example 120 N-((3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-4-yl) -5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride
[2839]
[2840] The title compound was obtained in the same manner as in Example 95 from the compound obtained in Example 119.
[2841] Melting point: 276-278 ° C. (decomposition).
[2842]
[2843] Example 121 (3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester
[2844]
[2845] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 209 and the compound obtained in Reference Example 10.
[2846]
[2847] Example 122 N-((3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride
[2848]
[2849] The title compound was obtained in the same manner as in Example 95 from the compound obtained in Example 121.
[2850] Melting point: 236-245 ° C. (decomposition).
[2851]
[2852] Example 123 N-((3R ^* , 4S ^* )-1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2853]
[2854] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and acetic anhydride.
[2855] Melting point: 215-225 ° C. (decomposition).
[2856]
[2857] Example 124 N-((3R ^* , 4S ^* )-1-acetyl-3-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-4-yl) -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2858]
[2859] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 120 and acetic anhydride.
[2860] Melting point: 225-250 ° C. (decomposition).
[2861]
[2862] Example 125 N-((3R ^* , 4S ^* )-1-acetyl-4-{[(5-fluoroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2863]
[2864] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 122 and acetic anhydride.
[2865] Melting point: 202 DEG C (decomposition).
[2866]
[2867] Example 126 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) piperidin-3-yl ] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2868]
[2869] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and methanesulfonyl chloride.
[2870] Melting point: 225-230 ° C. (decomposition).
[2871]
[2872] Example 127 N-[(3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) piperidin-4-yl ] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2873]
[2874] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 120 and methanesulfonyl chloride.
[2875] Melting point: 228-245 ° C. (decomposition).
[2876]
[2877] Example 128 N-[(3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1- (methylsulfonyl) piperazin-3-yl ] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2878]
[2879] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 122 and methanesulfonyl chloride.
[2880] Melting point: 216-250 ° C. (decomposition).
[2881]
[2882] Example 129 (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridine-2) carbonyl] amino} piperidine-1-carboxylic acid methyl ester hydrochloride
[2883]
[2884] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and methyl chloroformate.
[2885] Melting point: 248-253 ° C. (decomposition).
[2886]
[2887] Example 130 (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid ethyl ester hydrochloride
[2888]
[2889] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and ethyl chloroformate.
[2890] Melting point: 215-225 ° C. (decomposition).
[2891]
[2892] Example 131 (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid 2-methoxyethyl ester hydrochloride
[2893]
[2894] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and chloroformic acid 2-methoxyethyl ester.
[2895] Melting point: 224-226 ° C. (decomposition).
[2896]
[2897] Example 132 (3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -4-{[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid ethyl ester hydrochloride
[2898]
[2899] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 120 and ethyl chloroformate.
[2900] Melting point: 213-225 ° C. (decomposition).
[2901]
[2902] Example 133 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-propionylpiperidin-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2903]
[2904] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and propionyl chloride.
[2905] Melting point: 214-228 ° C. (decomposition).
[2906]
[2907] Example 134 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-isobutyrylpiperidin-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2908]
[2909] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and isobutyryl chloride.
[2910] Melting point: 266-272 ° C. (decomposition).
[2911]
[2912] Example 135 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2,2-dimethylpropanoyl) piperi Din-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2913]
[2914] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and pivaloyl chloride.
[2915] Melting point: 250-255 ° C. (decomposition).
[2916]
[2917] Example 136 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (3,3-dimethylbutanoyl) piperidine -3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2918]
[2919] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and tert-butylacetyl chloride.
[2920] Melting point: 260-265 ° C. (decomposition).
[2921]
[2922] Example 137 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2,2,2-trifluoroacetyl) Piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2923]
[2924] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and trifluoroacetic anhydride.
[2925] Melting point: 262-267 ° C. (decomposition).
[2926]
[2927] Example 138 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (cyclopropylcarbonyl) piperidine-3- Il] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2928]
[2929] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and cyclopropanecarbonyl chloride.
[2930] Melting point: 280-286 ° C. (decomposition).
[2931]
[2932] Example 139 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (cyclobutylcarbonyl) piperidine-3- Il] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2933]
[2934] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and cyclobutanecarbonyl chloride.
[2935] Melting point: 271-275 ° C. (decomposition).
[2936]
[2937] Example 140 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (cyclopentylcarbonyl) piperidine-3- Il] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2938]
[2939] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and cyclopentanecarbonyl chloride.
[2940] Melting point: 254-260 ° C. (decomposition).
[2941]
[2942] Example 141 Acetic acid 2-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-1-yl) -2-oxoethyl ester
[2943]
[2944] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and acetoxyacetyl chloride.
[2945]
[2946] Example 142 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-glycloylpiperidin-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2947]
[2948] The compound (301.8 mg) obtained in Example 141 was dissolved in tetrahydrofuran (10 ml), 1 N sodium hydroxide solution (0.53 ml) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride, and the organic layer was washed with water and brine in that order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1 to 10: 1) to distill the solvent under reduced pressure. This purified product was dissolved in ethanol (3 ml) and methylene chloride (2 ml), and 1 N ethanol hydrochloride solution (0.40 ml) was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (195 mg).
[2949] Melting point: 216-230 ° C. (decomposition).
[2950]
[2951] Example 143 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidine-3 -Yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2952]
[2953] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118.
[2954] Melting point: 214-228 ° C. (decomposition).
[2955]
[2956] Example 144 N-[(3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidine- 3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2957]
[2958] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 122 and methoxyacetyl chloride.
[2959] Melting point: 190-208 ° C. (decomposition).
[2960]
[2961] Example 145 N-((3R ^* , 4S ^* )-1- (3-{[tert-butyl (diphenyl) silyl] oxy} -2,2-dimethylpropanoyl) -4-{[( 5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Carboxamide
[2962]
[2963] To a chloroform (10 ml) solution of the compound (261 mg) obtained in Reference Example 158, thionyl chloride (3.0 ml) and a catalytic amount of dimethylformamide were added, and the mixture was stirred at 60 ° C overnight. The title compound (214 mg) was obtained in the same manner as in Example 100 from the yellow oil obtained by concentration of the reaction solution under reduced pressure and the compound (200 mg) obtained in Example 118.
[2964] Melting point: 153 DEG C (decomposition).
[2965]
[2966] Example 146 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (3-hydroxy-2,2-dimethylprop Panoyl) piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2967]
[2968] To a tetrahydrofuran (30 ml) solution of the compound (241 mg) obtained in Example 145, tetrabutylammonium fluoride (1 mol tetrahydrofuran solution, 0.594 ml) was added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 9: 1) to obtain the title compound (116 mg).
[2969] Melting point: 220 ° C. (decomposition).
[2970]
[2971] Example 147 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (3-methoxy-2,2-dimethylprop Panoyl) piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2972]
[2973] The title compound was obtained in the same manner as in Example 145 from the compound obtained in Example 118 and the compound obtained in Reference Example 160.
[2974] Melting point: 240 ° C. (decomposition).
[2975]
[2976] Example 148 Acetic acid 2-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-1-yl) -1,1-dimethyl-2-oxoethyl ester
[2977]
[2978] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and 2-acetoxyisobutyryl chloride.
[2979] Melting point: 190 ° C. (decomposition).
[2980]
[2981] Example 149 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-hydroxy-2-methylpropanoyl Piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[2982]
[2983] To the methanol (50 ml) solution of the compound (190 mg) obtained in Example 148 was added sodium methoxide (76.8 mg) and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 9: 1) to obtain the title compound (130 mg).
[2984] Melting point: 190 ° C. (decomposition).
[2985]
[2986] Example 150 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(3-hydroxycyclobutyl) carbonyl] Piperidin-3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2987]
[2988] Compound (306 mg) obtained in Example 118 in a mixed solution of compound (117 mg) in tetrahydrofuran (20 ml), methylene chloride (3.0 ml) and N, N-dimethylformamide (2.0 ml) obtained in Reference Example 152 (306 mg) ), N-methylmorpholine (200 μl), 1-hydroxybenzotriazole monohydrate (87 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (197 mg) were added, and room temperature Stirred for 3 days. The reaction solution was diluted with methylene chloride and saturated aqueous sodium hydrogen carbonate solution was added to form two layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give a free base (207 mg) of the title compound. This free base was treated with a 1N ethanol hydrochloride solution to afford the title compound.
[2989] Melting point: 200 ° C. (decomposition).
[2990]
[2991] Example 151 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(methoxycyclobutyl) carbonyl] piperi Din-3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2992]
[2993] The title compound was obtained in the same manner as Example 150 from the compound obtained in Example 118 and the compound obtained in Reference Example 154.
[2994] Melting point: 191 ° C. (decomposition).
[2995]
[2996] Example 152 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- [3-methoxy-2- (methoxymethyl ) Propanoyl] piperidin-3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[2997]
[2998] The title compound was obtained by condensing the carboxylic acid obtained by hydrolysis of the compound obtained in Reference Example 155 with the compound obtained in Example 118 in the same manner as in Example 150.
[2999] Melting point: 178-184 ° C. (decomposition).
[3000]
[3001] Example 153 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (tetrahydro-2H-pyran-4-ylcar Bonyl) piperidin-3-yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3002]
[3003] The title compound was obtained in the same manner as in Example 150 from the compound obtained in Example 118 and the compound obtained in Reference Example 156.
[3004] Melting point: 225-248 ° C. (decomposition).
[3005]
[3006] Example 154 N-((3R ^* , 4S ^* )-1-benzoyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3007]
[3008] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and benzoyl chloride.
[3009] Melting point: 215-225 ° C. (decomposition).
[3010]
[3011] Example 155 (3R ^* , 4S ^* )-3-({[5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl} amino) -4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidine-1 -Carboxylic acid tert-butyl ester
[3012]
[3013] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 207 and the compound obtained in Reference Example 42.
[3014]
[3015] Example 156 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -N-((3R ^* , 4S ^* )-4-{[(5- Chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride
[3016]
[3017] The compound obtained in Example 155 was treated in the same manner as in Example 95 to obtain the title compound.
[3018]
[3019] Example 157 5- (2-{[tert-butyl (diphenyl) silyl] oxy} -1,1-dimethylethyl) -N-[(3R ^* , 4S ^* )-4-{[(5- Chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl] -4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridine-2-carboxamide
[3020]
[3021] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 156 and methoxyacetyl chloride.
[3022]
[3023] Example 158 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidine-3 -Yl] -5- (2-hydroxy-1,1-dimethylethyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3024]
[3025] The title compound was obtained in the same manner as Example 146 from the compound obtained in Example 157.
[3026] Melting point: 221-232 ° C. (decomposition).
[3027]
[3028] Example 159 (3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -3-{[(5-isopropyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidine-1-carboxylic acid tert-butyl ester
[3029]
[3030] The title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 209 and the compound obtained in Reference Example 148.
[3031]
[3032] Example 160 N-((3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-isopropyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride
[3033]
[3034] The compound obtained in Example 159 was treated in the same manner as in Example 95 to obtain the title compound.
[3035]
[3036] Example 161 N-[(3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidine- 3-yl] -5-isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3037]
[3038] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 160 and methoxyacetyl chloride.
[3039] Melting point: 214-228 ° C. (decomposition).
[3040]
[3041] Example 162 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(dimethylamino) carbonyl] piperidine- 3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3042]
[3043] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and N, N-diketylcarbamoyl chloride.
[3044] Melting point: 267-270 ° C. (decomposition).
[3045]
[3046] Example 163 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(ethylamino) carbonyl] piperidine- 3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3047]
[3048] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and the isocyanic acid ethyl ester.
[3049] Melting point: 221-235 ° C. (decomposition).
[3050]
[3051] Example 164 N-((3R ^* , 4S ^* )-1-[(tert-butylamino) carbonyl] -4-{[(5-chloroindol-2-yl) carbonyl] amino} piperi Din-3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3052]
[3053] The title compound was obtained in the same manner as in Example 100 from the compound obtained in Example 118 and tert-butyl isocyanate.
[3054] Melting point: 236-238 ° C. (decomposition).
[3055]
[3056] Example 165 2-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-3-yl) acetic acid methyl ester dihydrochloride
[3057]
[3058] The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 118 and bromoacetic acid methyl ester.
[3059] Melting point: 253-255 ° C. (decomposition).
[3060]
[3061] Example 166 2-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-3-yl) acetic acid hydrochloride
[3062]
[3063] The compound obtained in Example 165 was treated in the same manner as in Example 101 to obtain the title compound.
[3064] Melting point: 234-240 ° C. (decomposition).
[3065]
[3066] Example 167 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyethyl) piperidine-3 -Yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride
[3067]
[3068] The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 118 and 2-bromoethylmethylether (NMR was determined by free base).
[3069] Melting point: 238-242 ° C. (decomposition).
[3070]
[3071] Example 168 N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-fluoroethyl) piperidine-3 -Yl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide dihydrochloride
[3072]
[3073] The title compound was obtained in the same manner as in Example 102 from the compound obtained in Example 118 and 2-fluoroethyl bromide (NMR measured by free base).
[3074] Melting point: 228-233 ° C. (decomposition).
[3075]
[3076] Example 169 N-((3R, 4S) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3077]
[3078] To the dioxane solution (15 ml) of the compound (630 mg) obtained in Reference Example 214 were added 4 dioxane hydrochloride solution (7.0 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the free base (330 mg) of the title compound was obtained in the same manner as in Example 91 using the obtained yellow solid (590 mg) and the compound obtained in Reference Example 10 (379 mg). This free base was treated with ethanol hydrochloride solution to afford the title compound (NMR measured by free base).
[3079] Melting point: 202-222 ° C. (decomposition).
[3080]
[3081] [α] ²⁵ _D = -56.0 ° (c = 0.50, methanol).
[3082] Example 170 N-((3R, 4R) -1-acetyl-4-{[(5-chloroindol-2-yl) carbonyl] amino} piperidin-3-yl) -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3083]
[3084] In the same manner as in Example 169, the title compound was obtained from the compound obtained in Reference Example 219 and the compound obtained in Reference Example 10.
[3085] Melting point: 221-238 ° C.
[3086]
[3087] [a] ²⁵ _D = -105.4 ° (c = 0.58, methanol).
[3088] Example 171 N-[(3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3089]
[3090] In the same manner as in Example 169, the title compound was obtained from the compound obtained in Reference Example 221.
[3091] Melting point: 207-220 ° C. (decomposition).
[3092]
[3093] [α] ²⁵ _D = -53.4 ° (c = 0.52, methanol).
[3094] Example 172 N-[(3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3095]
[3096] In the same manner as in Example 169, the title compound was obtained from the compound obtained in Reference Example 223.
[3097] Melting point: 213-230 ° C.
[3098]
[3099] [a] ²⁵ _D = -100.3 ° (c = 0.51, methanol).
[3100] Example 173 N-((3R, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3101]
[3102] The title compound was obtained in the same manner as in Example 169 from the low polar compound obtained in Reference Example 176 and the compound obtained in Reference Example 10.
[3103]
[3104] Example 174 N-((3R, 4S) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3105]
[3106] The title compound was obtained in the same manner as in Example 169 from the high polar compound obtained in Reference Example 176 and the compound obtained in Reference Example 10.
[3107]
[3108] Example 175 (3R, 4S) -5-{[tert-butyl (diphenyl) silyl] oxy} -3-{[(5-chloroindol-2-yl) carbonyl] amino} -4- { [(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} gyl acetate ethyl ester
[3109]
[3110] The title compound was obtained in the same manner as Example 169 from the compound obtained in Reference Example 225.
[3111]
[3112] Example 176 (3R, 4S) -3-{[(5-chloroindol-2-yl) carbonyl] amino} -5-hydroxy-4-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} yl acetic acid ethyl ester
[3113]
[3114] Hydrogen fluoride pyridine (0.4 ml) was added dropwise to a mixed solution of the compound (0.54 g), pyridine (4.0 ml) and tetrahydrofuran (10 ml) obtained in Example 175 under ice-cooling, and then the reaction solution was gradually cooled to room temperature. It stirred for 18 hours, returning. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain the title compound (0.31 g).
[3115]
[3116] Example 177 N-((3S, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -6-oxotetrahydro-2H-pyran-3-yl) -5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3117]
[3118] To the compound obtained in Example 176 (0.31 g) was added 4 dioxane hydrochloric acid solution (20 ml) and heated to reflux for 4 hours. The reaction solution was concentrated, and the obtained residue was recrystallized from diethyl ether to obtain the title compound (0.23 g).
[3119] Melting point: 221-238 ° C. (decomposition).
[3120] ¹ H-NMR and MS: consistent with Example 174, which is an enantiomer.
[3121] Example 178 N-((3R ^* , 4R ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran- 3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3122]
[3123] The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 227 and 5-chloroindole-2-carboxylic acid. This free base was treated with ethanol hydrochloride solution to afford the title compound.
[3124] Melting point: 241-244 ° C.
[3125]
[3126] Example 179 N-((3R ^* , 4R ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran 3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3127]
[3128] The free base of the title compound was obtained in the same manner as in Example 91 from the compound obtained in Reference Example 227 and 5-fluoroindole-2-carboxylic acid. This free base was treated with ethanol hydrochloride solution to afford the title compound.
[3129] Melting point: 243-245 ° C.
[3130]
[3131] Example 180 N-((3R ^* , 4R ^* )-3-{[(5-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran- 4-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3132]
[3133] From the compound obtained in Reference Example 229 and the compound obtained in Reference Example 10, the free base of the title compound was obtained in the same manner as in Example 91. This free base was treated with ethanol hydrochloride solution to afford the title compound.
[3134] Melting point: 242-247 ° C.
[3135]
[3136] Example 181 N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran- 3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3137]
[3138] From the compound obtained in Reference Example 231 and 5-chloroindole-2-carboxylic acid, the free base of the title compound was obtained in the same manner as in Example 91. This free base was treated with ethanol hydrochloride solution to afford the title compound.
[3139] Melting point: 244-249 ° C.
[3140]
[3141] Example 182 N-((3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran 3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3142]
[3143] From the compound obtained in Reference Example 231 and 5-fluoroindole-2-carboxylic acid, the free base of the title compound was obtained in the same manner as in Example 91. This free base was treated with ethanol hydrochloride solution to afford the title compound.
[3144] Melting point: 236-241 ° C.
[3145]
[3146] Example 183 N-((3R ^* , 4R ^* )-3-{[(5-fluoroindol-2-yl) carbonyl] amino} -1,1-dioxohexahydro-1-thiopyran -4-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3147]
[3148] From the compound obtained in Reference Example 233 and the compound obtained in Reference Example 10, the free base of the title compound was obtained in the same manner as in Example 91. This free base was treated with ethanol hydrochloride solution to afford the title compound.
[3149] Melting point: 244-249 ° C.
[3150]
[3151] Example 184 N-((3S, 4R) -4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-methyl-6-oxopiperidin-3-yl)- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (low polar compound) and N-((3R, 4R) -4-{[( 5-chloroindol-2-yl) carbonyl] amino} -1-methyl-6-oxopiperidin-3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridine-2-carboxamide (high polar compound)
[3152]
[3153] From the compound obtained in Reference Example 236 and the compound obtained in Reference Example 10, the title compound was obtained in the same manner as in Example 169.
[3154] Low Polar Compounds :
[3155] Melting point: 189-203 ° C. (decomposition).
[3156]
[3157] High Polar Compounds :
[3158] Melting point: 183-195 ° C. (decomposition).
[3159]
[3160] Example 185 5-Chloro-N-((1R ^* , 2S ^* )-2-{[4- (pyridin-4-yl) benzoyl] amino} cyclohexyl) indole-2-carboxamide hydrochloride
[3161]
[3162] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 237.
[3163]
[3164] [Example 186] 4- (4-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} phenyl) Pyridine N-oxide
[3165]
[3166] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 240.
[3167]
[3168] Example 187 5-chloro-N-((1R ^* , 2S ^* )-2-{[4- (pyridin-2-yl) benzoyl] amino} cyclohexyl) indole-2-carboxamide hydrochloride
[3169]
[3170] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and 4- (2-pyridyl) benzoic acid (Japanese Patent Laid-Open No. 2000-119253).
[3171]
[3172] Example 188 2- (4-{[((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} cyclohexyl) amino] carbonyl} phenyl) Pyridine N-oxide
[3173]
[3174] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 241.
[3175]
[3176] Example 189 5-Chloro-N-[(1R ^* , 2R ^* )-2-({[5- (4-pyridin-2-yl) thiazol-2-yl] carbonyl} amino) cyclohexyl Indole-2-carboxamide hydrochloride
[3177]
[3178] In the same manner as in Example 2, the title compound was obtained from a compound obtained in Reference Example 69 and 5- (4-pyridyl) thiazole-2-carboxylic acid lithium salt (Japanese Patent Laid-Open No. 2000-143623).
[3179]
[3180] Example 190 5-Chloro-N-[(1R ^* , 2S ^* )-2-({[1- (pyridin-4-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] Indole-2-carboxamide hydrochloride
[3181]
[3182] 1- (4-pyridyl) piperidine-4-carboxylic acid (Tetrahedron, 1998, Vol. 44, p. 7095) (206 mg) was suspended in methylene chloride (50 ml) and thionyl chloride (under ice-cooling) 144 μl) was added and stirred for 30 minutes. After triethylamine (969 µl) was added to the reaction solution, the compound (328 mg) obtained in Reference Example 71 was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the solution was concentrated under reduced pressure, and the precipitated precipitate was collected by filtration to obtain the title compound (310 mg).
[3183]
[3184] Example 191 N ^1- (4-Chlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3185]
[3186] The compound (288 mg) obtained in the reference example 242 was dissolved in tetrahydrofuran (8.0 ml), lithium hydroxide (46 mg) and water (1.0 ml) were added sequentially, and it stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to give a crude product (292 mg) of 2- (4-chloroanilino) -2-oxoacetate as a colorless solid. This crude product and the compound obtained in Reference Example 253 were dissolved in N, N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate (164 mg) and 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (251 mg) was added and the mixture was stirred at room temperature for 64.5 hours. The solvent was distilled off under reduced pressure, and the residue was separated by adding saturated aqueous sodium hydrogen carbonate solution and methylene chloride, and then the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3). The obtained pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.52 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the precipitate formed was filtered and collected to obtain the title compound (245 mg).
[3187]
[3188] Example 192 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3189]
[3190] The compound (240 mg) obtained in the reference example 243 was dissolved in tetrahydrofuran (8.0 ml), lithium hydroxide (41 mg) and water (1.0 ml) were added sequentially, and it stirred at room temperature for 2.5 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid lithium salt (249 mg).
[3191] Meanwhile, 10% palladium carbon (200 mg) was added to a methanol (10 ml) solution of the compound (293 mg) obtained in Reference Example 252, and stirred for 18 hours at room temperature under a hydrogen atmosphere. After palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure to give N-{(1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5 A crude product of 2,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide (259 mg) was obtained.
[3192] This crude product (259 mg) and the lithium salt (249 mg) were added to N, N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate (166 mg) and 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (235 mg) was added and the mixture was stirred at room temperature for 63.5 hours. The solvent was distilled off under reduced pressure, an aqueous saturated sodium bicarbonate solution and methylene chloride were added to the residue for separation, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7). The obtained pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.855 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (209 mg).
[3193]
[3194] Example 193 N ^1- (3-chlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3195]
[3196] Compound (222 mg) and 3-chloroaniline (63 μl) obtained in Reference Example 270 were dissolved in N, N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (68 mg), 1 -(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (144 mg) was added and the mixture was stirred at room temperature for 40 hours. The solvent was distilled off under reduced pressure, and the residue was separated by adding saturated aqueous sodium hydrogen carbonate solution and methylene chloride, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1). The obtained pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.50 ml) was added, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (174 mg).
[3197]
[3198] Example 194 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (4-fluorophenyl) ethanediamide hydrochloride
[3199]
[3200] In the same manner as in Example 191, the compound obtained in Reference Example 254 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3201]
[3202] Example 195 N ^1- (4-bromophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3203]
[3204] The compound (152 mg) obtained in the reference example 255 was dissolved in tetrahydrofuran (5.0 ml), 1N sodium hydroxide aqueous solution (1.20 ml) and methanol (5.0 ml) were added sequentially, and it stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and methylene chloride (10 ml) and 1N hydrochloric acid (2.0 ml) were added to the residue and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of 2- (4-bromoanilino) -2-oxoacetic acid as a colorless solid. This crude product and the compound obtained in Reference Example 253 (280 mg) were dissolved in N, N-dimethylformamide (30 ml), and 1-hydroxybenzotriazole monohydrate (90 mg) and 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (226 mg) was added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was separated by adding saturated aqueous sodium hydrogen carbonate solution and methylene chloride, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3). The obtained pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloric acid solution (191 µl) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the precipitate formed was filtered and collected to obtain the title compound (103 mg).
[3205]
[3206] Example 196 N ^1- (4-Chloro- ² -methylphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3207]
[3208] In the same manner as in Example 191, the compound obtained in Reference Example 256 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3209]
[3210] Example 197 N ^1- (4-chloro-3-methylphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3211]
[3212] In the same manner as in Example 191, the compound obtained in Reference Example 257 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3213]
[3214] Example 198 N ^1- (4-Chloro- ² -fluorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3215]
[3216] In the same manner as in Example 191, the compound obtained in Reference Example 258 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3217]
[3218] Example 199 N ^1- (2,4-dichlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3219]
[3220] The compound (300 mg) obtained in Reference Example 270 was dissolved in N, N-dimethylformamide (5 ml), and 2,4-dichloroaniline (165 mg) and 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride (260 mg) and 1-hydroxybenzotriazole monohydrate (91 mg) were added and stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and an aqueous saturated sodium bicarbonate solution and methylene chloride were added to the residue and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to obtain the free base of the title compound. This was dissolved in methylene chloride, 1N ethanol hydrochloride solution (108 µl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, diethyl ether was added dropwise while irradiating with ultrasonic waves, and the resulting precipitate was collected by filtration. This was washed with diethyl ether to give the title compound (60 mg).
[3221]
[3222] Example 200 N ^1- (3,4-dichlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[3223]
[3224] 3,4-Dichloroaniline (1.62 g) was dissolved in methylene chloride (20 ml), triethylamine (1.67 ml) and chlorooxoacetic acid methyl ester (1.01 ml) were added sequentially under ice cooling, followed by stirring at room temperature for 21 hours. . Water and methylene chloride were added to the reaction mixture for separation, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol (50 ml), water (25 ml) and lithium hydroxide monohydrate (629 mg) were added sequentially, and it stirred at room temperature for 12.5 hours. Lithium hydroxide monohydrate (629 mg) was further added and stirred at room temperature for 5.5 hours. The reaction solution was concentrated to dryness under reduced pressure. Water and diethyl ether were added to the residue for separation, and hydrochloric acid was added to the aqueous layer to make it acidic. The resulting solid was collected by filtration to give a crude product of 2- (3,4-dichloroanilino) -2-oxoacetic acid (1.62 g) as a colorless solid. This crude product (191 mg) and the compound obtained in Reference Example 253 (250 mg) were dissolved in N, N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (110 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (157 mg) was added and the mixture was stirred at room temperature for 67 hours. The solvent was distilled off under reduced pressure, an aqueous saturated sodium bicarbonate solution and ethyl acetate were added to the residue for separation, and the aqueous layer was extracted three times with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5) to give the title compound (154 mg).
[3225]
[3226] Example 201 N ^1- (2,4-difluorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[3227]
[3228] In the same manner as in Example 191, the compound obtained in Reference Example 259 was hydrolyzed and then condensed with the compound obtained in Reference Example 253 to obtain the title compound.
[3229]
[3230] Example 202 N ^1- (3,4-difluorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[3231]
[3232] In the same manner as in Example 191, the compound obtained in Reference Example 260 was hydrolyzed and then condensed with the compound obtained in Reference Example 253 to obtain the title compound.
[3233]
[3234] Example 203 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (pyridin-4-yl) ethanediamide hydrochloride
[3235]
[3236] In the same manner as in Example 191, the compound obtained in Reference Example 261 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3237]
[3238] Example 204 N ^1- (5-Bromopyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3239]
[3240] In the same manner as in Example 195, the compound obtained in Reference Example 262 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3241]
[3242] Example 205 N ^1- (6-Chloropyridin-3-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3243]
[3244] The compound (200 mg) obtained in Reference Example 263 as a crude product was dissolved in methanol (10 ml), heated to 50 ° C, and added with 1 N aqueous sodium hydroxide solution (3 ml) and stirred for 5 minutes. A 1N aqueous hydrochloric acid solution was added thereto to adjust the pH to weak acidity, and the solvent was distilled off under reduced pressure to obtain a residue containing 2-[(2-chloropyridin-5-yl) amino] -2-oxoacetic acid. N, N-dimethylformamide (5 ml) was added to this residue and the compound (250 mg) obtained in Reference Example 253, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (328 mg) was added. ) And 1-hydroxybenzotriazole monohydrate (46 mg) were added and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate aqueous solution and methylene chloride were added to the residue and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 47: 3) to obtain the free base of the title compound as a pale yellow solid. This was dissolved in methylene chloride, 1N ethanol hydrochloric acid solution (862) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue to irradiate with ultrasonic waves, and ethyl acetate and diethyl ether were added dropwise to precipitate the resulting precipitate, which was collected and washed with acetic acid ethyl ester to obtain the title compound (229 mg).
[3245]
[3246] Example 206 N ^1- (6-Chloropyridazin-3-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3247]
[3248] In the same manner as in Example 191, the compound obtained in Reference Example 264 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3249]
[3250] Example 207 N ^1- (5-chlorothiazol-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3251]
[3252] In the same manner as in Example 191, the compound obtained in Reference Example 265 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3253]
[3254] Example 208 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3255]
[3256] The compound obtained in Reference Example 266 (210 mg) and the compound obtained in Reference Example 272 (350 mg) were dissolved in N, N-dimethylformamide (15 ml) and 1-hydroxybenzotriazole monohydrate (205 mg) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (290 mg) were added and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, an aqueous saturated sodium bicarbonate solution and methylene chloride were added to the residue and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1). The obtained pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.46 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (248 mg).
[3257]
[3258] Example 209 N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) acetyl] amino) -5-[(dimethylamino) carbonyl] cyclohexyl} -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3259]
[3260] The compound (2.3 g) obtained in the reference example 267 was dissolved in ethanol (10 ml), 1 N sodium hydroxide aqueous solution (20 ml) was added, and it stirred at room temperature for 2 hours. 1N aqueous hydrochloric acid solution (20 ml) was added to the reaction solution, diluted with water, and stirred for 30 minutes. The precipitated insolubles were collected by filtration to give 2- (4-chloroanilino) acetic acid (1.05 g) as a colorless solid. This solid and the compound (0.25 g) obtained in Reference Example 253 were dissolved in N, N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (0.11 g) and 1- (3-dimethylamino Propyl) -3-ethylcarbodiimide hydrochloride (0.23 g) was added and stirred at room temperature for 4 days. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3). The obtained pale yellow solid was dissolved in ethanol, 1N ethanol hydrochloric acid solution was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (0.15 g).
[3261]
[3262] Example 210 N-{(1R, 2S, 5S) -2-{[2- (4-chloro-2-fluoroanilino) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclo Hexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3263]
[3264] In the same manner as in Example 209, the compound obtained in Reference Example 268 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3265]
[3266] Example 211 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3267]
[3268] In the same manner as in Example 2, the compound obtained in Reference Example 432 and the compound obtained in Reference Example 34 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3269]
[3270] Example 212 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 5- (4,5-dihydro-oxazol-2-yl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[3271]
[3272] The compound (250 mg) obtained in Example 211 was suspended in methylene chloride, and saturated aqueous sodium hydrogen carbonate solution was added thereto and stirred well. The organic layer was separated, dried over anhydrous magnesium sulfate, triethylamine (0.5 ml) and bromoethyl isocyanate (43 µl) were added, followed by stirring at room temperature for 20 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 22: 3) to obtain the title compound (227 mg).
[3273]
[3274] Example 213 N-{(1R, 2S, 5S) -2-{[(5-chloro-4-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3275]
[3276] Compound (140 mg) obtained in Reference Example 144 was dissolved in N, N-dimethylformamide (10 ml), and Compound (100 mg) and 1- (3-dimethylaminopropyl) -3-ethyl obtained in Reference Example 274. Carbodiimide hydrochloride (140 mg) and 1-hydroxybenzotriazole monohydrate (110 mg) were added and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned between water and acetic acid ethyl ester, and the aqueous layer was extracted with acetic acid ethyl ester. The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to give (1R, 2S, 5S) -2-{[(5-chloro-4-fluoroindole- 2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl ester (260 mg) was obtained.
[3277] The above powder was dissolved in methylene chloride (5 ml), and tetrahydrochloric acid dioxane solution (1.2 ml) was added. The reaction solution was stirred at room temperature for 3.5 hours, and then the solvent was distilled off under reduced pressure. Methylene chloride (10 ml) was added to the residue and concentrated. The operation was repeated three times. The residue was dried under reduced pressure to prepare the crude N-{(1S, 2R, 4S) -2-amino-4-[(dimethylamino ) Carbonyl] cyclohexyl} -5-chloro-4-fluoroindole-2-carboxamide was obtained. This was dissolved in N, N-dimethylformamide (50 ml), and the compound (150 mg) obtained in Reference Example 10, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (140 mg), 1 -Hydroxybenzotriazole monohydrate (110 mg) was added and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned into a water-acetic acid ethyl ester-tetrahydrofuran mixture, and the aqueous layer was extracted with acetic acid ethyl ester. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to give the free base (270 mg) of the title compound. This was dissolved in methylene chloride (10 ml), 1N ethanol hydrochloride solution (0.72 ml) was added and stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration to obtain the title compound (200 mg).
[3278]
[3279] Example 214 N-{(1R, 2S, 5S) -2-{[(5-chloro-3-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3280]
[3281] The compound (250 mg) obtained in Reference Example 279 was dissolved in methylene chloride (60 ml), and tetrahydrochloric acid dioxane solution (1.3 ml) was added. After stirring the reaction liquid at room temperature for 5.5 hours, 4 dioxane hydrochloric acid solution (0.65 ml) was further added, and it stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the operation of adding methylene chloride (10 ml) to the residue and concentrating again was repeated three times. The residue obtained by drying the residue under reduced pressure was dissolved in N, N-dimethylformamide (50 ml), and the compound obtained in Reference Example 10 (160 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarb Bodyimide hydrochloride (150 mg) and 1-hydroxybenzotriazole monohydrate (120 mg) were added and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned into a water-acetic acid ethyl ester mixture, and the aqueous layer was extracted with acetic acid ethyl ester. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified twice by silica gel column chromatography (methanol: methylene chloride = 2: 23 → 1: 9) to give the free base (260 mg) of the title compound. This was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.69 ml) was added, the mixture was stirred at room temperature for 30 minutes, and the solvent was distilled off. The residue was dissolved in methanol, and crystallized by adding diethyl ether and hexane, which was collected by filtration to give the title compound (230 mg).
[3282]
[3283] Example 215 N-{(1R, 2S, 5S) -2-{[(3-bromo-5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3284]
[3285] In the same manner as in Example 214, the compound obtained in Reference Example 282 was treated with dibasic acid hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[3286]
[3287] Example 216 N-{(1R, 2S, 5S) -2-{[(3-chloro-5-fluoroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3288]
[3289] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 284.
[3290]
[3291] Example 217 N-{(1R, 2S, 5S) -2-{[(5-chloro-3-formylindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl ] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3292]
[3293] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 286.
[3294]
[3295] Example 218 5-chloro-N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ³ , N ³ -dimethylindole-2,3-dicarboxamide hydrochloride
[3296]
[3297] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 289.
[3298]
[3299] Example 219 N-{(1R, 2S, 5S) -2-[(6-chloro-2-naphthoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3300]
[3301] The compound (270 mg) obtained in Reference Example 294 was dissolved in methylene chloride (10 ml), 1N ethanol hydrochloride (10 ml) was added, and the mixture was stirred for 90 minutes. The residue obtained by distilling off the solvent under reduced pressure was dissolved in N, N-dimethylformamide (7 ml) and the compound (110 mg) obtained in Reference Example 10, 1- (3-dimethylaminopropyl) -3-ethylcarbodii Mid hydrochloride (100 mg) and 1-hydroxybenzotriazole monohydrate (70 mg) were added and stirred at room temperature for 23 hours. The reaction solution was concentrated under reduced pressure, water was added, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified twice by silica gel column chromatography (methylene chloride: methanol = 20: 1 → 10: 1), and the obtained free base was dissolved in methanol to obtain 1N ethanol hydrochloride solution (0.30 ml). Was added. The solvent was distilled off under reduced pressure and the residue was washed with acetic acid ethyl ester to give the title compound (130 mg).
[3302]
[3303] Example 220 7-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide hydrochloride
[3304]
[3305] The compound obtained in Reference Example 299 was treated with the ethanol hydrochloride solution in the same manner as in Example 219, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[3306]
[3307] Example 221 N-{(1R, 2S, 5S) -2-{[(5-chlorobenzimidazol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3308]
[3309] The compound obtained in Reference Example 300 was treated with the ethanol hydrochloride solution in the same manner as in Example 219, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[3310]
[3311] Example 222 N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -7-fluoroisoquinoline-3-carboxamide hydrochloride
[3312]
[3313] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 304.
[3314]
[3315] Example 223 N-{(1R, 2S, 5S) -2-{[(7-chloro-2H-chromen-3-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3316]
[3317] The compound (220 mg) obtained in Reference Example 252 was dissolved in methanol (10 ml), 10% palladium carbon (180 mg) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (30 ml), the compound obtained in Reference Example 306 (108 mg), 1-hydroxybenzotriazole monohydrate (78 mg), 1- (3-dimethylaminopropyl ) -3-Ethylcarbodiimide hydrochloride (196 mg) was added, and it stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain a pale yellow foamy material. This foamy substance was dissolved in methylene chloride (2 ml) and 1N ethanol hydrochloride solution (363 μl) was added. The solution was concentrated under reduced pressure, and diethyl ether was added to the residue, and the precipitated precipitate was collected by filtration to obtain the title compound (175 mg).
[3318]
[3319] Example 224 N-{(1R, 2S, 5S) -2-{[(E) -3- (4-chlorophenyl) -2-propenoyl] amino} -5-[(dimethylamino) car Bonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3320]
[3321] The compound obtained in Reference Example 307 was treated with the ethanol hydrochloride solution in the same manner as in Example 219, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[3322]
[3323] Example 225 6-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5.4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-oxo-1,4-dihydroquinoline-2-carboxamide hydrochloride
[3324]
[3325] In the same manner as in Example 5, the title compound was obtained from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 309.
[3326]
[3327] Example 226 2-[({(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } Amino) carbonyl] -4,6-dihydro-5H-pyrrolo [3,4-d] thiazole-5-carboxylic acid tert-butyl ester
[3328]
[3329] 1) The compound (1.46 g) obtained in Reference Example 310 was dissolved in methylene chloride (10 ml), an ethanol hydrochloride solution (10 ml) was added at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, the solvent was distilled off, ethanol was added, the mixture was concentrated, diisopropyl ether was added to the residue, solidified, filtered, and collected by N-{(1S, 2R, 4S) -2-amino-4-[(dimethylamino) car Bonyl] cyclohexyl} -5-chloroindole-2-carboxamide hydrochloride was obtained.
[3330] 2) This was dissolved in N, N-dimethylformamide (5 ml) at room temperature, the compound obtained in Reference Example 406 (1.31 g), 1-hydroxybenzotriazole monohydrate (640 mg) and 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.36 g) was added and stirred at room temperature for 3 days. The reaction solution was concentrated, followed by addition of methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to give the title compound (1.22 g).
[3331]
[3332] Example 227 5-chloro-N-{(1S, 2R, 4S) -2-[[(5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) Carbonyl] amino] -4-[(dimethylamino) carbonyl] cyclohexyl} indole-2-carboxamide hydrochloride
[3333]
[3334] The compound (1.22 g) obtained in Example 226 was dissolved in methylene chloride (5 ml), an ethanol hydrochloride solution (10 ml) was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the mixture, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 9) to give the free base (636 mg) of the title compound as a colorless glassy solid. This free base (200 mg) was dissolved in 1 N ethanol hydrochloric acid solution (1 ml), concentrated, and then added to acetic acid ethyl ester to solidify.
[3335]
[3336] Example 228 5-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pi Rolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) indole-2-carboxamide hydrochloride
[3337]
[3338] In the same manner as in Example 18, the title compound was obtained from the compound obtained in Example 227 and formalin.
[3339]
[3340] Example 229 2-{[((1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-{[(5-fluoroindol-2-yl) carbonyl] amino} cyclo Hexyl) amino] carbonyl} -4,6-dihydro-5H-pyrrolo [3,4-d] thiazole-5-carboxylic acid tert-butyl ester
[3341]
[3342] In the same manner as in Example 226, the title compound was obtained from the compound obtained in Reference Example 311 and the compound obtained in Reference Example 406.
[3343]
[3344] Example 230 N-{(1S, 2R, 4S) -2-[[(5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino ] -4-[(dimethylamino) carbonyl] cyclohexyl} -5-fluoroindole-2-carboxamide hydrochloride
[3345]
[3346] The title compound was obtained from the compound obtained in Example 229 in the same manner as in Example 227.
[3347]
[3348] Example 231 N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pyrrolo [3, 4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) -5-fluoroindole-2-carboxamide hydrochloride
[3349]
[3350] In the same manner as in Example 18, the title compound was obtained from the compound obtained in Example 230 and formalin.
[3351]
[3352] Example 232 N-{(1R, 2S, 5S) -2-[(6-chloro-2-naphthoyl) amino] -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl- 5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxamide hydrochloride
[3353]
[3354] In the same manner as in Example 226, the title compound was obtained from the compound obtained in Reference Example 294 and the compound obtained in Reference Example 293.
[3355]
[3356] Example 233 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pi Rolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide hydrochloride and 7-chloro-N-((1S, 2R, 4S) -4- [(Dimethylamino) carbonyl] -2-{[(5-methyl-5H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carbon Copy mid
[3357]
[3358]
[3359] To the dioxane (3.0 ml) -methylene chloride (3.0 ml) mixed suspension of the compound (330 mg) obtained in Reference Example 299 was added 4 dioxane hydrochloride solution (3.0 ml) and stirred for 30 minutes at room temperature. The white powder obtained by distilling off the solvent under reduced pressure was dissolved in N, N-dimethylformamide (5.0 ml), the compound (172 mg) obtained in Reference Example 293, 1-hydroxybenzotriazole monohydrate (130 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (192 mg) was added and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1). To the obtained high polar ethanol (4.0 ml) solution, 1 N ethanol hydrochloride solution (0.35 ml) was added, and the solvent was distilled off under reduced pressure. Ethanol and diethyl ether were added to the residue, and the precipitate formed was filtered and collected. 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide hydrochloride (184 mg) was obtained.
[3360]
[3361] In addition, 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl as a low polar byproduct in silica gel column chromatography purification -5H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) cinnoline-3-carboxamide (98 mg) was obtained.
[3362]
[3363] Example 234 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6-dihydro-4H-pi Rolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride
[3364]
[3365] The compound (500 mg) obtained in Reference Example 146 was dissolved in ethanol hydrochloride solution (5 ml) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (7 ml), the compound obtained in Reference Example 293 (299 mg), 1-hydroxybenzotriazole monohydrate (71 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (403 mg) was added and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, an aqueous saturated sodium bicarbonate solution and methylene chloride were added to the residue and the mixture was separated, and then extracted with methylene chloride from the aqueous layer. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 93: 7) to give the free base (260 mg) of the title compound as a pale yellow solid. This was dissolved in methylene chloride, 1 N ethanol hydrochloric acid solution (961 µl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, and diethyl ether was added dropwise. The resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (260 mg).
[3366]
[3367] Example 235 2-[({(1 (1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } Amino) carbonyl] -6,6-dimethyl-6,7-dihydrothiazolo [4,5-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester
[3368]
[3369] Under argon atmosphere, the compound (95.4 mg) obtained in Reference Example 316 was dissolved in diethyl ether (1 ml), and tert-butyllithium (1.60 pentane solution, 244 µL) was added dropwise at -78 ° C. After stirring at −78 ° C. for 1 hour, carbon dioxide gas was blown for 10 minutes. The temperature was raised to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (5 ml), and the compound (178 mg) obtained in Reference Example 432 and 1-hydroxybenzotriazole monohydrate ( 48.0 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (136 mg) were added sequentially and stirred overnight at room temperature. The reaction solution was concentrated, followed by addition of methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19) to give the title compound (140 mg).
[3370]
[3371] Example 236 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 6,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine-2-carboxamide hydrochloride
[3372]
[3373] The title compound was obtained from the compound obtained in Example 235 in the same manner as in Example 227.
[3374]
[3375] Example 237 2-[({(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } Amino) carbonyl] -5,7-dihydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester
[3376]
[3377] The compound (1.27 g) obtained in the reference example 50 was dissolved in tetrahydrofuran (48 ml), lithium hydroxide (117 mg) and water (6.0 ml) were added, and it stirred at room temperature for 4.5 hours. The reaction solution was dried under reduced pressure to obtain a crude lithium carboxylate (1.24 g), followed by condensation with the compound obtained in Reference Example 432 in the same manner as in Example 226, 2), to obtain the title compound.
[3378]
[3379] Example 238 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl}- 6-methyl-6,7-dihydro-5H-pyrrolo [3,4-d] pyrimidine-2-carboxamide hydrochloride
[3380]
[3381] The compound (367 mg) obtained in Example 237 was dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. The title compound was obtained in the same manner as in Example 18 from the crude product and formalin obtained by drying the reaction solution under reduced pressure.
[3382]
[3383] Example 239 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(6-methyl-6,7-dihydrothiazolo [4 , 5-d] pyrimidin-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride
[3384]
[3385] In the same manner as in Example 49, the compound obtained in Reference Example 146 was treated with an ethanol hydrochloride solution, and then condensed with the compound obtained in Reference Example 322 to obtain the title compound.
[3386]
[3387] Example 240 7-Chloro-N-((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[(5-methyl-4,5,6,7 Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) isoquinoline-3-carboxamide hydrochloride
[3388]
[3389] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 325 and the compound obtained in Reference Example 10.
[3390]
[3391] Example 241 N-{(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl) carbonyl] amino} -5- [2- (dimethylamino) -2 -Oxoethyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3392]
[3393] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 336 and the compound obtained in Reference Example 10.
[3394]
[3395] Example 242 N-{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(methylsulfonyl) methyl] cyclohexyl}- 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3396]
[3397] The compound obtained in Reference Example 340 was treated with the ethanol hydrochloride solution in the same manner as in Example 219, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.
[3398]
[3399] Example 243 N-{(1R, 2S, 5S) -2-{[(2-chloro-6H-thieno [2,3-b] pyrrol-5-yl) carbonyl] amino} -5- [(Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[3400]
[3401] In the same manner as in Example 223, the compound obtained in Reference Example 252 was reduced by contact, and then condensed with the compound obtained in Reference Example 345 to obtain the title compound.
[3402]
[3403] Example 244 N-{(1R, 2S, 5S) -2-{[3- (4-chlorophenyl) -2-propinoyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl } -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3404]
[3405] In the same manner as in Example 223, the compound obtained in Reference Example 252 was reduced by contact, and then condensed with the compound obtained in Reference Example 347 to obtain the title compound.
[3406]
[3407] Example 245 6-Chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -4-oxo-1,4-dihydroquinazolin-2-carboxamide hydrochloride
[3408]
[3409] In the same manner as in Example 223, the compound obtained in Reference Example 252 was reduced by contact, and then condensed with the compound obtained in Reference Example 349 to obtain the title compound.
[3410]
[3411] Example 246 N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2-oxoethanethioyl] amino} -5-[(dimethylamino) carbonyl] Cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[3412]
[3413] Compound (184 mg) obtained in Reference Example 253 and compound (150 mg) obtained in Reference Example 351 were dissolved in methanol (1 ml) -methylene chloride (4 ml), and the solvent was distilled off by heating and stirring at 150 ° C. Heating was continued for a minute. After cooling, the product was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to give the title compound (59 mg).
[3414]
[3415] Example 247 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethioyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[3416]
[3417] Compound (184 mg) obtained in Reference Example 253 and compound (150 mg) obtained in Reference Example 353 were dissolved in methanol (0.3 ml) -methylene chloride (0.3 ml), and the solvent was distilled off by heating and stirring at 150 ° C. Heating was continued for a minute. After cooling, the product was purified by silica gel column chromatography (methylene chloride: methanol = 24: 1) to give the title compound (52 mg).
[3418]
[3419] Example 248 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-thioxoacetyl} amino) -5-[(dimethyl Amino) carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[3420]
[3421] Compound (72 mg) and 2-amino-5-chloropyridine (100 mg) obtained in Reference Example 355 were dissolved in methanol (0.2 ml) -methylene chloride (0.2 ml), and the solvent was distilled off by heating and stirring at 150 ° C. Then heated for 8 minutes. After cooling, the product was purified by preparative silica gel thin layer chromatography (methylene chloride: methanol = 23: 2) to give the title compound (4 mg).
[3422]
[3423] Example 249 N ^1- (5-chloro-2-thienyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3424]
[3425] In the same manner as in Example 191, the compound obtained in Reference Example 356 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3426]
[3427] Example 250 N-{(1R, 2S, 5S) -2-{[(4-chloroanilino) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3428]
[3429] To the methylene chloride (20 ml) solution of the compound (183 mg) obtained in Reference Example 253, isocyanic acid 4-chlorophenyl ester (76.8 mg) was added and stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methyl chloride: methanol = 20: 1 → 10: 1) to distill the solvent. The residue was dissolved in ethanol (2 ml) and methylene chloride (2 ml), 1N ethanol hydrochloride solution (0.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (160 mg).
[3430]
[3431] Example 251 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (5-fluoropyridin-2-yl) ethanediamide hydrochloride
[3432]
[3433] In the same manner as in Example 191, the compound obtained in Reference Example 357 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3434]
[3435] Example 252 N ^1- (4-Chlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5,6 -Dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3436]
[3437] In the same manner as in Example 191, the title compound was obtained from the compound obtained in Reference Example 242 and the compound obtained in Reference Example 272.
[3438]
[3439] Example 253 N ^1- [4-Chloro-2- (trifluoromethyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- { [(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3440]
[3441] Thionyl chloride (1 ml) was added to a chloroform solution (10 ml) of the compound (269 mg) obtained in Reference Example 359, and the mixture was stirred at 75 ° C for 30 minutes. The solvent was distilled off under reduced pressure and dried. To this was added methylene chloride solution (7 ml) and pyridine (3 ml) of the compound (286 mg) obtained in Reference Example 253 under ice cooling, followed by stirring for 2 hours while the temperature was raised to room temperature. After saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction solution for liquid separation, the obtained organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was treated with silica gel column chromatography (methylene chloride: methanol = 20: 1) and LH-20 column chromatography (molecular sieve, methanol) to obtain the free base (90 mg) of the title compound. ) Was obtained as a pale yellow amorphous solid. Methylene chloride (5 ml), ethanol (5 ml), and 1 N ethanol hydrochloric acid solution (1 ml) were added thereto, followed by distillation and drying under reduced pressure to obtain the title compound.
[3442]
[3443] Example 254 N ^1- {4-Chloro-2-[(dimethylamino) carbonyl] phenyl} -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2 -{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3444]
[3445] In the same manner as in Example 191, the compound obtained in Reference Example 362 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3446]
[3447] Example 255 N ^1- [4-Chloro-2- (hydroxymethyl) phenyl] -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[ (5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3448]
[3449] In the same manner as in Example 199, the compound obtained in Reference Example 270 was condensed with 4-chloro-2-hydroxymethylaniline, and then treated with hydrochloric acid to obtain the title compound.
[3450]
[3451] Example 256 N ^1- (4-Chloro-2-methoxyphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3452]
[3453] In the same manner as in Example 191, the compound obtained in Reference Example 364 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3454]
[3455] Example 257 N-{(1R, 2S, 5S) -2-{[2- (4-chloroanilino) -2- (hydroxyimino) acetyl] amino} -5-[(dimethylamino) car Bonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3456]
[3457] In the same manner as in Example 214, the compound obtained in Reference Example 366 was deprotected by hydrochloric acid treatment, and then condensed with the compound obtained in Reference Example 10 and treated with hydrochloric acid to obtain the title compound.
[3458]
[3459] Example 258 N ^1- (4-chlorophenyl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride
[3460]
[3461] In the same manner as in Example 214, the compound obtained in Reference Example 367 was deprotected by hydrochloric acid treatment, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
[3462]
[3463] Example 259 N ^1- (5-chloropyridin-2-yl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride
[3464]
[3465] In the same manner as in Example 214, the compound obtained in Reference Example 368 was deprotected by hydrochloric acid treatment, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
[3466]
[3467] Example 260 N ^1- (5-bromopyridin-2-yl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride
[3468]
[3469] In the same manner as in Example 214, the compound obtained in Reference Example 369 was deprotected by hydrochloric acid treatment, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
[3470]
[3471] Example 261 N ^1- (4-chlorophenyl) -N ³ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) malonamide hydrochloride
[3472]
[3473] In the same manner as in Example 5, the compound obtained in Reference Example 371 and the compound obtained in Reference Example 253 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3474]
[3475] Example 262 N ^1- (3-chlorophenyl) -N ³ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) malonamide hydrochloride
[3476]
[3477] In the same manner as in Example 5, the compound obtained in Reference Example 373 and the compound obtained in Reference Example 253 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3478]
[3479] Example 263 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[( 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3480]
[3481] 10% palladium carbon (0.3 g) was added to an ethanol (20 ml) solution of the compound (0.33 g) obtained in Reference Example 404, and stirred for 24 hours under a hydrogen atmosphere. Insolubles were filtered off through a pad of celite and the filtrate was concentrated under reduced pressure. The obtained residue (0.37 g) was dissolved in N, N-dimethylformamide (20 ml), and the compound (0.3 g), 1-hydroxybenzotriazole monohydrate (0.2 g) and 1 obtained in Reference Example 266 at room temperature were obtained. -(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.37 g) was added sequentially and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with a mixed solvent of chloroform-methanol (9: 1) and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 95: 5) to concentrate the desired fraction. Ethanol hydrochloric acid solution was added to the obtained residue to make a hydrochloride, and then recrystallized from a mixed solvent of methanol and diethyl ether to obtain the title compound (0.28 g).
[3482]
[3483] Example 264 N ^1- (4-chlorophenyl) -N ² -((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3484]
[3485] In the same manner as in Example 263, the compound obtained in Reference Example 404 was converted to an amine, and then condensed with the compound obtained in Reference Example 374 and treated with hydrochloric acid to obtain the title compound.
[3486]
[3487] Example 265 N ^1- (5-bromopyridin-2-yl) -N ² -((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[ (5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3488]
[3489] In the same manner as in Example 263, the compound obtained in Reference Example 404 was converted to an amine, and then condensed with the compound obtained in Reference Example 375 and treated with hydrochloric acid to obtain the title compound.
[3490]
[3491] Example 266 N ^1- (4-chloro-3-fluorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3492]
[3493] In the same manner as in Example 263, the compound obtained in Reference Example 252 was converted to an amine, and then condensed with the compound obtained in Reference Example 378 and treated with hydrochloric acid to obtain the title compound.
[3494]
[3495] Example 267 N-{(1R, 2S, 5S) -2-{[3- (4-chlorophenyl) -3-oxopropanoyl] amino} -5-[(dimethylamino) carbonyl] cyclo Hexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide
[3496]
[3497] In the same manner as in Example 214, the compound obtained in Reference Example 383 was deprotected by hydrochloric acid treatment, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.
[3498]
[3499] Example 268 N ^1- (5-chloropyridin-2-yl) -N ² -((1R, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -5H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[3500]
[3501] In the same manner as in Example 214, the compound obtained in Reference Example 386 was deprotected by hydrochloric acid treatment and condensed with the compound obtained in Reference Example 293 to obtain the title compound.
[3502]
[3503] Example 269 N ¹ -[(5-chloropyridin-2-yl) amino] -N ^2- (1R, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3504]
[3505] The title compound was obtained by reducing the compound obtained in Reference Example 387 in the same manner as in Reference Example 253, condensing with the compound obtained in Reference Example 266 and treating with hydrochloric acid in the same manner as in Example 208.
[3506]
[3507] Example 270 N ^1- (4-chlorophenyl) -N ² -((1R, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[3508]
[3509] The compound obtained in Reference Example 387 was reduced in the same manner as in Reference Example 253, and the compound obtained in Reference Example 242 was condensed with hydrolyzed lithium salt and treated with hydrochloric acid in the same manner as in Example 191. The compound was obtained.
[3510]
[3511] Example 271 N ¹ -{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -N ^2- (pyridin-4-yl) ethanediamide hydrochloride
[3512]
[3513] 2-[(pyridin-4-yl) amino] -2- obtained by deprotecting the compound obtained in Reference Example 310 by hydrochloric acid treatment and hydrolyzing the compound obtained in Reference Example 261 in the same manner as in Example 191. After condensation with lithium oxoacetic acid salt, the title compound was obtained by treatment with hydrochloric acid.
[3514]
[3515] Example 272 N ¹ -{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -N ^2- (pyridin-3-yl) ethanediamide hydrochloride
[3516]
[3517] Reference is made to 2-[(pyridin-3-yl) amino] -2-oxoacetic acid methyl ester obtained by condensation of 3-aminopyridine and 2-chloro-2-oxoacetic acid methyl ester in the same manner as in the method described in Reference Example 242. The title compound was obtained in the same manner as the method described in Example 271 using the compound obtained in Example 310 as a raw material.
[3518]
[3519] Example 273 N ¹ -{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -N ^2- (piperidin-4-yl) ethanediamide hydrochloride
[3520]
[3521] To the ethanol (5.0 ml) solution of the compound (400 mg) obtained in Reference Example 389 was added 4 dioxane hydrochloric acid solution (8.0 ml) at room temperature and stirred for 5 hours at the same temperature. The solvent was distilled off under reduced pressure, washed with methylene chloride, and the insolubles were filtered off to obtain the title compound (320 mg).
[3522]
[3523] Example 274 N ¹ -{(1R, 2S, 5S) -2-{[(5-chloroindol-2-yl) carbonyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -N ^2- (1-methylpiperidin-4-yl) ethanediamide hydrochloride
[3524]
[3525] In the same manner as described in Reference Example 9, the compound obtained in Example 273 was methylated and then treated with hydrochloric acid to obtain the title compound.
[3526]
[3527] Example 275 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ¹ -methylethanediamide hydrochloride
[3528]
[3529] In the same manner as in Example 191, the compound obtained in Reference Example 390 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3530]
[3531] Example 276 N ^1- (5-chloropyrimidin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3532]
[3533] In the same manner as in Example 191, the compound obtained in Reference Example 391 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and then treated with hydrochloric acid to obtain the title compound.
[3534]
[3535] Example 277 N ^1- (4-chlorophenyl) -N ² -((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[(5-methyl- 5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3536]
[3537] The compound obtained in Reference Example 392 was reduced in the same manner as in Reference Example 253, and in the same manner as in Example 195, the compound obtained in Reference Example 242 was condensed with the carboxylic acid obtained by hydrolysis and treated with hydrochloric acid. The compound was obtained.
[3538]
[3539] Example 278 N ^1- (5-bromopyridin-2-yl) -N ² -((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[ (5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3540]
[3541] In the same manner as in Example 277, the title compound was obtained from the compound obtained in Reference Example 392 and the compound obtained in Reference Example 262.
[3542]
[3543] Example 279 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-{[ethyl (methyl) amino] carbonyl} -2-{[( 5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazol-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3544]
[3545] In the same manner as in Example 277, the title compound was obtained from the compound obtained in Reference Example 392 and the compound obtained in Reference Example 243.
[3546]
[3547] Example 280 N ^1- (4-chloro-3-methoxyphenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3548]
[3549] In the same manner as in Example 2, the compound obtained in Reference Example 395 and the compound obtained in Reference Example 10 were condensed, and treated with hydrochloric acid to obtain the title compound.
[3550]
[3551] Example 281 N ^1- (4-chlorophenyl) -N ² -((1R ^* , 2R ^* )-2-{[5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] amino} cyclopentyl) ethanediamide hydrochloride
[3552]
[3553] In the same manner as in Example 195, the compound obtained in Reference Example 242 was hydrolyzed, and then condensed with the compound obtained in Reference Example 62 and treated with hydrochloric acid to obtain the title compound.
[3554]
[3555] Example 282 N ^1- (5-chloropyridin-2-yl) -N ² -((1R ^* , 2R ^* ) -2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclopentyl) ethanediamide hydrochloride
[3556]
[3557] In the same manner as in Example 208, the compound obtained in Reference Example 62 and the compound obtained in Reference Example 266 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3558]
[3559] Example 283 N ¹ -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) -N ^2- (4-ethynylphenyl) ethanediamide
[3560]
[3561] In the same manner as in Example 263, the compound obtained in Reference Example 252 and the compound obtained in Reference Example 397 were condensed to obtain the title compound.
[3562]
[3563] Example 284 N ^1- (5-chloropyrazin- ² -yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3564]
[3565] In the same manner as in Reference Example 97, the compound obtained in Reference Example 253 and the compound obtained in Reference Example 399 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3566]
[3567] Example 285 N ^1- (4-chloro-3-nitrophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3568]
[3569] In the same manner as described in Reference Example 97, the compound obtained in Reference Example 253 and the compound obtained in Reference Example 400 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3570]
[3571] Example 286 N ^1- (4-chloro-2-nitrophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3572]
[3573] In the same manner as in Example 208, the compound obtained in Reference Example 253 and the compound obtained in Reference Example 401 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3574]
[3575] Example 287 N ^1- (3-amino-4-chlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3576]
[3577] The compound (236 mg) obtained in Example 285 was dissolved in ethanol (25 ml), and a catalytic amount of Raney nickel was added, followed by stirring at room temperature under a hydrogen atmosphere for 17 hours. After that, a catalytic amount of Raney nickel was added and the mixture was further stirred for 7 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 23: 2) to obtain a pale yellow solid (101 mg). This was dissolved in methylene chloride and 1N ethanol hydrochloride solution (360 µl) was added. The solvent was distilled off under reduced pressure, and a small amount of methanol was added to the residue, and diethyl ether was added dropwise while irradiating with ultrasonic waves. The resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound (95 mg).
[3578]
[3579] Example 288 N ^1- (2-amino-4-chlorophenyl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3580]
[3581] In the same manner as described in Example 287, the title compound was obtained from the compound obtained in Example 286.
[3582]
[3583] Example 289 N ^1- (6-chloro-4-methylpyridin-3-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[ (5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3584]
[3585] In the same manner as in Example 199, the compound obtained in Reference Example 270 and the compound obtained in Reference Example 402 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3586]
[3587] Example 290 N-{(1R, 2S, 5S) -2-({[(E) -2- (4-chlorophenyl) diazenyl] carbonyl} amino) -5-[(dimethylamino) car Bonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3588]
[3589] 10% palladium carbon (200 mg) was added to a tetrahydrofuran (10 ml) solution of the compound (700 mg) obtained in Reference Example 252, stirred at room temperature under a hydrogen atmosphere at 1 atmosphere, filtered, and the filtrate was concentrated. The compound (470 mg) obtained in the reference example 405 was added to the N, N- dimethylformamide (5.0 ml) solution of the obtained amine, and it stirred at 95 degreeC for 18 hours. The reaction solution was concentrated, separated with saturated aqueous sodium hydrogen carbonate solution (50 ml), water (50 ml) and methylene chloride (30 ml), and the aqueous layer was extracted with methylene chloride (2 x 20 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (methylene chloride: methanol = 12: 1), and treated with 1N hydrochloric acid to obtain the title compound (100 mg).
[3590]
[3591] Example 291 N-{(1R, 2S, 5S) -2-({[2- (4-chlorophenyl) hydrazino] carbonyl} amino) -5-[(dimethylamino) carbonyl] cyclohexyl } -5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3592]
[3593] In the reaction described in Example 290, the title compound was obtained by changing the reaction conditions to 40 ° C for 3 days with stirring.
[3594]
[3595] Example 292 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(4,5 , 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3596]
[3597] In the same manner as in Example 17, the compound obtained in Reference Example 34 and the compound obtained in Reference Example 420 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3598]
[3599] Example 293 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(1-hydroxycyclopropyl) carbonyl] Piperidin-3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3600]
[3601] The title compound was obtained by condensing the compound obtained in Example 118 with 1-hydroxy-1-cyclopropanecarboxylic acid in the same manner as in Example 150 and then treating with hydrochloric acid.
[3602]
[3603] Example 294 N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl) carbonyl] amino} -1-[(1-methoxycyclopropyl) carbonyl] Piperidin-3-yl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3604]
[3605] In the same manner as in Example 150, the compound obtained in Example 118 and the compound obtained in Reference Example 409 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3606]
[3607] Example 295 7-chloro-N-((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) -3-isoquinolinecarboxamide hydrochloride
[3608]
[3609] In the same manner as in Example 219, the compound obtained in Reference Example 410 was deprotected by treating with tetrahydrochloric acid dioxane solution, and then condensed with the compound obtained in Reference Example 10 to give hydrochloric acid to obtain the title compound.
[3610]
[3611] Example 296 N ^1- (4-chloro-3-fluorophenyl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride
[3612]
[3613] In the same manner as in Example 219, the compound obtained in Reference Example 411 was deprotected by treating with tetrahydrochloric acid dioxane solution, and then condensed with the compound obtained in Reference Example 10 to give hydrochloric acid to obtain the title compound.
[3614]
[3615] Example 297 N ^1- (5-chloro-2-thienyl) -N ² -((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) ethanediamide hydrochloride
[3616]
[3617] In the same manner as in Example 219, the compound obtained in Reference Example 412 was deprotected by treating with tetrahydrochloric acid dioxane solution, and then condensed with the compound obtained in Reference Example 10 to give hydrochloric acid to obtain the title compound.
[3618]
[3619] Example 298 N-{(1R, 2S, 5S) -2-{[2- (4-chlorophenoxy) acetyl] amino} -5-[(dimethylamino) carbonyl] cyclohexyl} -5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3620]
[3621] In the same manner as in Example 223, the compound obtained in Reference Example 252 was reduced, condensed with p-chlorophenoxy acetic acid, and treated with hydrochloric acid to obtain the title compound.
[3622]
[3623] Example 299 7-chloro-N-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-5H-pyrrolo [3,4-d ] Thiazol-2-yl) carbonyl] amino} cyclohexyl) -3-isoquinolinecarboxamide hydrochloride
[3624]
[3625] The lithium salt of the carboxylic acid obtained by hydrolysis of the compound obtained in Reference Example 413 and the compound obtained by the acid treatment of the compound obtained in Reference Example 146 were condensed, followed by hydrochloric acid treatment to obtain the title compound.
[3626]
[3627] Example 300 N-{(1R, 2S, 5S) -2-{[(6-chloro-4-oxo-4H-chromen-2-yl) carbonyl] amino} -5-[(dimethylamino ) Carbonyl] cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3628]
[3629] In the same manner as in Example 219, the compound obtained in Reference Example 417 was treated with dibasic acid hydrochloric acid solution, and the compound obtained in Reference Example 10 was condensed. Then, hydrochloric acid treatment was performed to obtain the title compound.
[3630]
[3631] Example 301 7-Chloro-N-((3R, 4S) -1- (2-methoxyacetyl) -3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] amino} piperidin-4-yl) -3-cinnolinecarboxamide hydrochloride
[3632]
[3633] In the same manner as in Example 219, the compound obtained in Reference Example 418 was treated with dibasic acid hydrochloric acid solution, and the compound obtained in Reference Example 10 was condensed. Then, hydrochloric acid treatment was performed to obtain the title compound.
[3634]
[3635] Example 302 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3636]
[3637] The compound obtained in Reference Example 421 was deprotected using hydrochloric acid, methylated in the same manner as in Example 18, and then hydrochloric acid to obtain the title compound.
[3638]
[3639] Example 303 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-iso Propyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide hydrochloride
[3640]
[3641] In the same manner as in Example 2, the compound obtained in Reference Example 148 and the compound obtained in Reference Example 420 were condensed, and then treated with hydrochloric acid to obtain the title compound.
[3642]
[3643] Example 304 N-((1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-{[2- (4-fluoroanilino) -2-oxoethanethioyl] amino } Cyclohexyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3644]
[3645] In the same manner as in Example 219, the compound obtained in Reference Example 424 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 10 to hydrochloric acid to obtain the title compound.
[3646]
[3647] Example 305 N-[(1R, 2S, 5S) -5-[(dimethylamino) carbonyl] -2-({2-[(5-fluoropyridin-2-yl) amino] -2- Oxoethanethioyl} amino) cyclohexyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3648]
[3649] In the same manner as in Example 219, the compound obtained in Reference Example 427 was treated with hydrochloric acid to deprotect it, and then condensed with the compound obtained in Reference Example 10 to hydrochloric acid to obtain the title compound.
[3650]
[3651] Example 306 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethioyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-5H-pyrrolo [3,4-d] thiazole-2-carboxamide
[3652]
[3653] In the same manner as in Example 219, the compound obtained in Reference Example 428 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 293 to obtain the title compound.
[3654]
[3655] Example 307 N-{(1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoethanethioyl} amino) -5-[( Dimethylamino) carbonyl] cyclohexyl} -5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxamide hydrochloride
[3656]
[3657] In the same manner as in Example 219, the compound obtained in Reference Example 428 was treated with hydrochloric acid to deprotect it, and then condensed with the compound obtained in Reference Example 293 under argon to give hydrochloric acid to obtain the title compound.
[3658]
[3659] Example 308 N ^1- (5-chloropyridin-2-yl) -N ² -[(1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-({[6- ( Dimethylamino) -4,5,6,7-tetrahydrobenzothiazol-2-yl] carbonyl} amino) cyclohexyl] ethanediamide
[3660]
[3661] The compound obtained in Reference Example 431 was treated with hydrochloric acid to be deprotected, methylated in the same manner as in Example 18, and treated with hydrochloric acid to obtain the title compound.
[3662]
[3663] Example 309 N-{(1R, 2S, 5S) -2-[({[(4-chlorophenyl) sulfonyl] amino} carbonyl) amino] -5-[(dimethylamino) carbonyl] cyclo Hexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxamide hydrochloride
[3664]
[3665] To the methylene chloride (10 ml) solution of the compound (328.0 mg) obtained in Reference Example 253, isocyanic acid 4-chlorophenylsulfonyl ester (148 µl) was added and stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer column chromatography (methylene chloride: methanol = 9: 1). The obtained product was dissolved in ethanol (2 ml) and methylene chloride (2 ml), 1N ethanol hydrochloride solution (0.25 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (104.3 mg).
[3666]
[3667] Example 310 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide
[3668]
[3669] In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 435 and the compound obtained in Reference Example 10.
[3670]
[3671] Example 311 N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonate monohydrate
[3672]
[3673] The compound (6.2 g) obtained in Example 310 was dissolved in methylene chloride (120 ml), and 1 mol / L p-toluenesulfonic acid-ethanol solution (11.28 ml) was added to distill the solvent. 15% water-containing ethanol (95 ml) was added to the residue, which was then dissolved by stirring at 60 占 폚. Then, it cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure at room temperature for 2 hours to obtain the title compound (7.4 g).
[3674]
[3675] Elemental Analysis: C ₂₄ H ₃₀ ClN ₇ O ₄ SC ₇ H ₈ O ₃ SH ₂ O
[3676] Theoretical value: C; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69
[3677] Found: C; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79
[3678] mp (decomposition): 245-248 degreeC.
[3679] Test Example 1 Measurement of Human FXa Inhibitory Activity (IC ₅₀ Value)
[3680] 10 μl of sample 5% DMSO solution appropriately graded in each well of a 96 well (pore) microplate, 40 μl of Tris buffer (100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH 7.4), 0.0625 U / After adding 10 µl of ml human FXa (dissolved and diluted in Enzyme Research Labolatories, Inc., Tris buffer), 40 µl of 750 µM aqueous solution of S-2222 (Chromogenix) was added and absorbance at 405 nm at room temperature. Was measured for 10 minutes to obtain an increase in absorbance (ΔOD / min). Tris buffer solution was used in place of the specimen.
[3681] The 50% inhibition concentration (IC ₅₀ value) was obtained by showing the inhibition rate (%) at each final concentration of the sample determined by the following equation on the vertical axis of the log probability plot and the final concentration of the sample on the horizontal axis.
[3682] % Inhibition = (ΔOD / min of 1 sample ΔOD / min of control) × 100
[3683] (Result) Table 1 shows that the compound of the present invention has a strong FXa inhibitory effect.
[3684]
[3685] Test Example 2 Measurement of Anti-FXa Activity in Rat Plasma After Oral Administration
[3686] (A) Administration and Blood Collection
[3687] A drug solution (1 mg / ml) dissolved or suspended in 0.5 mg methylcellulose (MC) in 10 mg of the sample was orally administered to the rat (10 ml / kg). 0.5 ml of blood was collected from the jugular vein using a syringe injected with 50 μl of 3.13% (w / v) trisodium citrate dihydrate solution after 0.5, 1, 2, and 4 hours of drug administration (volume of blood: 0.45 ml). . Rats of the control group were bled in the same manner as above after administering 0.5% MC solution. Each blood sample was centrifuged at 4 占 폚 and 1500 x g for 10 minutes to separate plasma, and then stored at -40 占 폚 until used for measuring anti-FXa activity in plasma.
[3688] (B) Determination of FXa inhibitory activity in plasma
[3689] Anti-FXa activity in plasma was measured using S-2222 as the substrate. 5456 μl of Tris buffer (100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH 7.4), 44 μl of human FXa (2.5 U / ml) and 550 μl of water were mixed. The obtained human FXa solution was used for the following test. Immediately after adding 5 µl of the rat plasma obtained in the above operation (A) to each well of the 96-well microplate, and then adding 55 µl of the human FXa solution and 40 µl of the 750 µM S-2222 solution in this order, The absorbance at 405 nm was measured at room temperature using an absorbance spectrometer SPECTRAmax 340 or 190 (Molecular Devices Co., USA) to determine the reaction rate (ΔOD / min).
[3690] Anti-FXa activity, ie inhibition rate (%) was calculated by the following formula.
[3691] % Inhibition = [1- (average of ΔOD / min of sample ÷ OD / min of control)] × 100
[3692] (Results) The compounds described in Examples 63, 191, 192, 194 and 204 showed FXa inhibitory activity in the plasma of 62% to 96% at 10 mg / kg oral administration.
[3693] Since the cyclic diamine derivatives of the present invention exhibit potent activating coagulation factor X inhibitors, medicines, activating coagulation factor X inhibitors, blood coagulation inhibitors, thrombosis or embolism prevention and / or treatment agents, thrombotic diseases Prophylactic and / or therapeutic drugs, further cerebral infarction, cerebral embolism, myocardial infarction, angina pneumonia, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve / joint replacement It is useful as a prophylactic and / or therapeutic agent for post thrombosis and reclosure, systemic inflammatory response syndrome (SIRS), multi-organ failure (MODS), thrombus formation in extracorporeal circulation or blood clotting during blood collection.

权利要求:
Claims (59)
[1" claim-type="Currently amended] Formula 1

[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, and a substituent A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a divalent, saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent;
Q ³ is

(In the group, Q ⁵ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-.)));
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group which may have an alkyl group and a substituent, an aryl group, an aralkyl group, heteroa Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo Substituted on a 3-6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an alkyl group which may have a nil group, a substituent N, N-dialkylcarbamoylacyl group which may have, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N- which may have a substituent on the alkyl group Alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group, or R ³ and R ⁴ together represent an alkylene group of 1 to 5 carbon atoms, 2 to 5 carbon atoms Represents an alkenylene group, an alkylenedioxy group having 1 to 5 carbon atoms, or a carbonyldioxy group.);
Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, heteroaryl with or without a substituent An alkenyl group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
T ⁰ represents a carbonyl group or a thiocarbonyl group;
T ¹ represents a carbonyl group, a sulfonyl group, a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, Group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(where R 'is a hydrogen atom , represents a hydroxyl group, alkyl group or alkoxy group), group ^{-C (= O) -A 1 -N} (R ") -. ( group of, a ¹ represents an alkylene group having 1 to 5 carbon atoms which may have a substituent , R ″ represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C (= O) -NH-, a group -C (= S) -NH-, a group -C (= O) -NH-NH -, Group -C (= O) -A ² -C (= O)-(wherein A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms), and the group -C (= O) -A ³ -C (= O) -NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms), the group -C (= O) -C (= NOR ^a ) -N (R ^b )- R ^a represents a hydrogen atom, an alkyl group, or an alkanoyl group in the group -C (= S) -C (= NOR ^a ) -N (R ^b )-(group, R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or Alkoxy group.), Group -C (= O) -N = N-, group -C (= S) -N = N-, group -C (= NOR ^c ) -C (= O) -N (R ^d )-(in the group, R ^c is the hydrogen source Here, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group is represented, and R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C (= NN (R ^e ) (R ^f ))-C ( = O) -N (R ^g )-(In the groups, R ^e and R ^f each independently represent a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl (thiocarbonyl) group, and R ^g represents a hydrogen atom, a hydroxyl group, or an alkyl group. Or an alkoxy group) or a thiocarbonyl group.], A salt thereof, a solvate thereof or an N-oxide thereof.
[2" claim-type="Currently amended] The compound according to claim 1, wherein in the formula (1), the group Q ⁴ has a phenyl group with or without a substituent, a naphthyl group with or without a substituent, an anthryl group with or without a substituent, a phenanthryl group with or without a substituent , Styryl group with or without substituent, phenylethynyl group with or without substituent, pyridyl group with or without substituent, pyridazinyl group with or without substituent, pyrazinyl group with or without substituent , A furyl group with or without a substituent, a thienyl group with or without a substituent, a pyrrolyl group with or without a substituent, a thiazolyl group with or without a substituent, an oxazolyl group with or without a substituent, and a substituent A pyrimidinyl group with or without a substituent, a tetrazolyl group with or without a substituent, a thienylethenyl group with or without a substituent, a pyri with or without a substituent Diethenyl group, indenyl group with or without substituent, indanyl group with or without substituent, tetrahydronaphthyl group with or without substituent, benzofuryl group with or without substituent, with or without substituent Isobenzofuryl group, benzothienyl group with or without substituent, indolyl group with or without substituent, indolinyl group with or without substituent, isoindolinyl group with or without substituent, with or without substituent Isoindolinyl group with or without substituent, indazolyl group with or without substituent, quinolyl group with or without substituent, dihydroquinolyl group with or without substituent, 4-oxodihydroqui with or without substituent Noyl group (dihydroquinolin-4-one), tetrahydroquinolyl group with or without substituent, isoquinolyl group with or without substituent, with substituent Tetrahydroisoquinolyl groups with or without substituents, chromanyl groups with or without substituents, chromanyl groups with or without substituents, isochromenyl groups with or without substituents, 4H-4-oxobenzo with or without substituents Pyranyl group, 3,4-dihydro-4H-4-oxobenzopyranyl group with or without substituent, 4H-quinolidinyl group with or without substituent, quinazolinyl group with or without substituent, substituent A dihydroquinazolinyl group with or without a substituent, a tetrahydroquinazolinyl group with or without a substituent, a quinoxalinyl group with or without a substituent, a tetrahydroquinoxalinyl group with or without a substituent, with or without a substituent Cynolinyl group, tetrahydrocinnolinyl group with or without substituent, indolinyl group with or without substituent, tetrahydride with or without substituent Indolizinyl groups, benzothiazolyl groups with or without substituents, tetrahydrobenzothiazolyl groups with or without substituents, benzoxazolyl groups with or without substituents, benzisothiazolyl with or without substituents Groups, benzisoxazolyl groups with or without substituents, benzimidazolyl groups with or without substituents, naphthyridinyl groups with or without substituents, tetrahydronaphthyridinyl groups with or without substituents, and substituents Thienopyridyl groups with or without substituents, tetrahydrothienopyridyl groups with or without substituents, thiazolopyridyl groups with or without substituents, tetrahydrothiazolopyridyl groups with or without substituents, with or without substituents Does not have a thiazolopyridazinyl group, a substituent with or without a tetrahydrothiazolopyridazinyl group, a substituent Pyrrolopyridyl groups with or without substituents, dihydropyrrolopyridyl groups with or without substituents, tetrahydropyrrolopyridyl groups with or without substituents, pyrrolopyrimidinyl groups with or without substituents, substituents Dihydropyrrolopyrimidinyl groups with or without substituents, pyridoquinazolinyl groups with or without substituents, dihydropyridoquinazolinyl groups with or without substituents, pyridopyrimidinyl groups with or without substituents, substituents A tetrahydropyridopyrimidinyl group with or without a substituent, a pyranothiazolyl group with or without a substituent, a dihydropyranothiazolyl group with or without a substituent, a furopyridyl group with or without a substituent, and a substituent A tetrahydrofuropyridyl group with or without a oxazolopyridyl group with or without a substituent, with or without a substituent Is a tetrahydrooxazolopyridyl group, an oxazolopyridazinyl group with or without a substituent, a tetrahydrooxazolopyridazinyl group with or without a substituent, a pyrrolothiazolyl group with or without a substituent, and a substituent Dihydropyrrolothiazolyl group with or without a substituent, pyrrolooxazolyl group with or without a substituent, dihydropyrrolooxazolyl group with or without a substituent, thienopyrrolyl group with or without a substituent Thiazolopyrimidinyl group with or without, 4-oxo-tetrahydrocinnolinyl group with or without substituent, 1,2,4-benzothiadiazinyl group with or without substituent, with or without substituent 1,1-dioxy-2H-1,2,4-benzothiadiazinyl group, 1,2,4-benzoxadiazinyl group with or without substituent, cyclopentapyranyl group with or without substituent , Substituent Thienofuranyl groups with or without substituents, furopyranyl groups with or without substituents, pyridoxazinyl groups with or without substituents, pyrazoleoxazolyl groups with or without substituents, imidazo with or without substituents Thiazolyl groups, imidazopyridyl groups with or without substituents, tetrahydroimidazopyridyl groups with or without substituents, pyrazinopyridazinyl groups with or without substituents, benzisoquis with or without substituents With or without a teal group, a furosynolyl group with or without a substituent, a pyrazolothiazolopyridazinyl group with or without a substituent, a tetrahydropyrazolothiazolopyridazinyl group with or without a substituent, or a substituent Hexahydrothiazolopyridazinopyridazinyl group having no, imidazotriazinyl group having or without a substituent, or having a substituent Oxazolopyridyl group with or without substituent, benzoazinyl group with or without substituent, benzoazinyl group with or without substituent, tetrahydrobenzoazinyl group with or without substituent, benzodia with or without substituent Zefinyl groups, benzotriazinyl groups with or without substituents, thienoazinyl groups with or without substituents, tetrahydrothienoazinyl groups with or without substituents, thienodiazefinyl groups with or without substituents, Thienotriazinylyl group with or without substituents, thiazoloazinyl group with or without substituents, tetrahydrothiazoloazinyl group with or without substituents, 4,5,6, with or without substituents, 5,6-trimethylene-4,5,6,7-tetrahydro with or without 7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group and a substituent A compound selected from thiazolopyridazinyl groups, salts thereof, solvates thereof or N-oxides thereof.
[3" claim-type="Currently amended] The substituent on group Q ⁴ is a hydroxyl group, halogen atom, halogenoalkyl group, amino group, cyano group, aminoalkyl group, nitro group, hydroxyalkyl group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycar A carbonylalkyl group, acyl group, amidino group, hydroxyamidino group, linear, branched or cyclic C1-C6 alkyl group, linear, branched or cyclic C1-C6 alkoxy group, straight chain Amidino groups, linear, branched or cyclic C2-C6 alkenyl groups, linear or branched C2-C6 substituted with a branched, branched or cyclic C2-C7 alkoxycarbonyl group Alkyl, straight, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms, carbamoyl group and a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms are substituted on the nitrogen atom. 1 to 3 compounds selected from mono or dialkylcarbamoyl groups, mono or dialkylamino groups substituted with linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms and nitrogen containing heterocyclic groups of 5 to 6 members; , Salts thereof, solvates thereof or N-oxides.
[4" claim-type="Currently amended] The compound, salts thereof, solvates thereof or N-oxides thereof according to claim 1, wherein group Q ⁴ in formula (1) represents any of the following groups.

[In the group, R ⁵ and R ⁶ are each independently a hydrogen atom, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, Or a phenyl group which may be substituted with a cyano group, a hydroxyl group, a halogen atom, an alkyl group or an alkoxy group, and R ⁷ and R ⁸ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group or an alkenyl group , Alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, An amidino group or an alkoxycarbonylalkyl group.],

[In the group, R ⁹ and R ¹⁰ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group. , Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.],

[In the group, R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group Alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.

[In the group, X ¹ represents CH ₂ , CH, NH, NOH, N, O or S, and R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, and a halogen Atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcar A barmoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.],

[Wherein, X ² represents NH, N, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH, and R ¹⁷ and R ¹⁸ are each independently a hydrogen atom , Hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N- An alkyl carbamoyl group, an N, N-dialkyl carbamoyl group, an alkoxycarbonyl group, an amidino group, or an alkoxycarbonylalkyl group is shown. Except that X ³ and X ⁴ are a combination of C and CH and both are C or CH.],

[Wherein N represents one or two carbon atoms of the ring substituted by R ¹⁹ is substituted with a nitrogen atom, and R ¹⁹ , R ²⁰ and R ²¹ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, Cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N A dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.],

[Wherein, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, Z ³ represents CH ₂ , CH , S, SO ₂ or C═O, X ⁵ -Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, R ²² and R ²³ are each independently a hydrogen atom, a hydroxyl group, Nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamo A diary, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group, and R ²⁴ represents a hydrogen atom or an alkyl group.],

[Wherein, X ⁶ represents O or S, and R ²⁵ and R ²⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, Hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group ],

[In the group, R ²⁷ and R ²⁸ are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group , Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.],

[In the group, E ¹ and E ² each independently represent N or CH, and R ²⁹ and R ³⁰ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, and an alkoxy group. Nyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino Group or an alkoxycarbonylalkyl group.],

[In group, Y <^1> represents CH or N, Y <^2> represents -N ( ^R33 )-(in group, ^R33 represents a hydrogen atom or a C1-C6 alkyl group.), O or S, R ³¹ and R ³² are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxy Alkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.], And

[Wherein, the numbers 1 to 8 represent positions, and each N represents any one of 1 to 4 carbon atoms and one of 5 to 8 carbon atoms is substituted with one nitrogen atom, R ³⁴ , R ³⁵ and R ³⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.
[5" claim-type="Currently amended] The compound, salts thereof, solvates thereof or N-oxides thereof according to claim 1, wherein group Q ⁴ in formula (1) represents any of the following groups.

[In the group, R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group, R ⁷ represents a hydrogen atom, and R ⁸ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.],

[In the group, R ⁹ represents a hydrogen atom, R ¹⁰ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.],

[In the group, both R ¹¹ and R ¹² represent a hydrogen atom, and R ¹³ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.],

[In the group, X ¹ represents NH, NOH, N, O or S, and R ¹⁴ represents a hydrogen atom, a halogen atom, an acyl group, an N-alkylcarbamoyl group, a N, N-dialkylcarbamoyl group or an alkyl group. R ¹⁵ represents a hydrogen atom or a halogen atom, and R ¹⁶ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.],

[Wherein, X ² represents NH, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH, R ¹⁷ represents a hydrogen atom, R ¹⁸ represents a hydrogen atom , A halogen atom, an alkyl group or an alkynyl group. Except that X ³ and X ⁴ are a combination of C and CH and both are C or CH.],

[In the group, N represents one or two carbon atoms of the ring substituted by R ¹⁹ is substituted with a nitrogen atom, R ¹⁹ and R ²⁰ both represent a hydrogen atom, R ²¹ represents a hydrogen atom, a cyano group, a halogen An atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group.],

[Wherein, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, Z ³ represents CH ₂ , CH , S, SO ₂ or C═O, X ⁵ -Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, R ²² represents a hydrogen atom, R ²³ is a hydrogen atom, A halogen atom, an alkyl group or an alkynyl group, and R ²⁴ represents a hydrogen atom.],

[In the group, X ⁶ represents O, R ²⁵ represents a hydrogen atom, R ²⁶ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.],

[In the group, R ²⁷ represents a hydrogen atom or a halogen atom, and R ²⁸ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.],

[In the group, E ¹ and E ² each independently represent N or CH, R ²⁹ represents a hydrogen atom or a halogen atom, and R ³⁰ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.],

[In group, Y <^1> represents CH or N, Y <^2> represents -N ( ^R33 )-(in group, ^R33 represents a hydrogen atom or a C1-C6 alkyl group.), O or S, R ³¹ represents a hydrogen atom or a halogen atom, R ³² represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.], And

[Wherein, the numbers 1 to 8 represent positions, and each N represents any one of 1 to 4 carbon atoms and one of 5 to 8 carbon atoms is substituted with one nitrogen atom, R ³⁴ represents a hydrogen atom or a halogen atom, R ³⁵ represents a hydrogen atom or a halogen atom, and R ³⁶ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.].
[6" claim-type="Currently amended] The compound Q ⁴ in any one of claims 1 to ³ is a 4-chlorostyryl group, a 4-fluorostyryl group, a 4-bromostyryl group, a 4-ethynylstyryl group, 4 -Chlorophenylethynyl group, 4-fluorophenylethynyl group, 4-bromophenylethynyl group, 4-ethynylphenylethynyl group, 6-chloro-2-naphthyl group, 6-fluoro-2- Naphthyl group, 6-bromo-2-naphthyl group, 6-ethynyl-2-naphthyl group, 7-chloro-2-naphthyl group, 7-fluoro-2-naphthyl group, 7-bromo-2-naph Tyl group, 7-ethynyl-2-naphthyl group, 5-chloroindol-2-yl group, 5-fluoroindol-2-yl group, 5-bromoindol-2-yl group, 5-ethynylindol-2-yl group , 5-methylindol-2-yl group, 5-chloro-4-fluoroindol-2-yl group, 5-chloro-3-fluoroindol-2-yl group, 3-bromo-5-chloroindol-2- Diary, 3-chloro-5-fluoroindol-2-yl group, 3-bromo-5-fluoroindol-2-yl group, 5-bromo-3-chloroindol-2-yl group, 5-bromo- 3-fluoroindol-2-yl group, 5-chloro-3-form Milindole-2-yl group, 5-fluoro-3-formylindol-2-yl group, 5-bromo-3-formylindol-2-yl group, 5-ethynyl-3-formylindole-2- Diary, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-bro Mo-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 6-chloroindole-2- Diary, 6-fluoroindol-2-yl group, 6-bromoindol-2-yl group, 6-ethynylindol-2-yl group, 6-methylindol-2-yl group, 5-chlorobenzothiophen-2- Diary, 5-fluorobenzothiophen-2-yl group, 5-bromobenzothiophen-2-yl group, 5-ethynylbenzothiophen-2-yl group, 5-methylbenzothiophen-2-yl group, 5 -Chloro-4-fluorobenzothiophen-2-yl group, 6-chlorobenzothiophen-2-yl group, 6-fluorobenzothiophen-2-yl group, 6-bromobenzothiophen-2-yl group, 6-ethynylbenzothiophen-2-yl group, 6-methylbenzothiophen-2-yl group, 5-chlorobenzofuran-2-yl group, 5-fluoro Benzofuran-2-yl group, 5-bromobenzofuran-2-yl group, 5-ethynylbenzofuran-2-yl group, 5-methylbenzofuran-2-yl group, 5-chloro-4-fluorobenzofuran- 2-yl group, 6-chlorobenzofuran-2-yl group, 6-fluorobenzofuran-2-yl group, 6-bromobenzofuran-2-yl group, 6-ethynylbenzofuran-2-yl group, 6-methyl Benzofuran-2-yl group, 5-chlorobenzimidazol-2-yl group, 5-fluorobenzimidazol-2-yl group, 5-bromobenzimidazol-2-yl group, 5-ethynylbenzimidazole- 2-yl group, 6-chloroquinolin-2-yl group, 6-fluoroquinolin-2-yl group, 6-bromoquinolin-2-yl group, 6-ethynylquinolin-2-yl group, 7-chloroquinoline-3- Diary, 7-fluoroquinolin-3-yl group, 7-bromoquinolin-3-yl group, 7-ethynylquinolin-3-yl group, 7-chloroisoquinolin-3-yl group, 7-fluoroisoquinoline-3 -Group, 7-bromoisoquinoline-3-yl group, 7-ethynylisoquinolin-3-yl group, 7-chlorocinnolin-3-yl group, 7-fluorocinnoline-3-yl group, 7-bromosin Nolin-3-day Group, 7-ethynylcinnoline-3-yl group, 7-chloro-2H-chromen-3-yl group, 7-fluoro-2H-chromen-3-yl group, 7-bromo-2H-chromen-3 -Yl group, 7-ethynyl-2H-chromen-3-yl group, 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-fluoro-4-oxo-1,4- Dihydroquinolin-2-yl group, 6-bromo-4-oxo-1,4-dihydroquinolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl group, 6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-bromo-4- Oxo-1,4-dihydroquinazolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl group, phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-ethynylphenyl group, 3-chlorophenyl group, 3-fluorophenyl group, 3-bromophenyl group, 3-ethynylphenyl group, 3-chloro-4-fluorophenyl group, 4-chloro-3 -Fluorophenyl group, 4-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group, 4-bro Mother-2-fluorophenyl group, 2-bromo-4-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dibromophenyl group, 4-chloro-3- Methylphenyl group, 4-fluoro-3-methylphenyl group, 4-bromo-3-methylphenyl group, 4-chloro-2-methylphenyl group, 4-fluoro-2-methylphenyl group, 4-bromo-2-methylphenyl Group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dibromophenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-chloro-2-pyridyl group , 4-fluoro-2-pyridyl group, 4-bromo-2-pyridyl group, 4-ethynyl-2-pyridyl group, 4-chloro-3-pyridyl group, 4-fluoro-3-pyridyl group, 4-bromo-3-pyridyl group, 4-ethynyl-3-pyridyl group, 5-chloro-2-pyridyl group, 5-fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5 -Ethynyl-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 5-chloro-4-fluoro-2-pyridyl group, 5-chloro-3-pyridyl group, 5-fluoro 3-pyridyl group, 5-bromo-3-pyridyl group, 5-e Neyl-3-pyridyl group, 6-chloro-3-pyridazinyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 6-ethynyl-3-pyrid Dazinyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl, 5-ethynyl-2-thiazolyl, 2-chloro Thieno [2,3-b] pyrrole-5-yl, 2-fluorothieno [2,3-b] pyrrole-5-yl, 2-bromothieno [2,3-b] pyrrole-5 A compound which is a -group or a 2-ethynyl-thieno [2,3-b] pyrrole-5-yl group, salts thereof, solvates thereof or N-oxides thereof.
[7" claim-type="Currently amended] The saturated or unsaturated 2 according to any one of claims 1 to 6, wherein the group Q ^{1 in} formula (1) has or does not have a substituent or a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group or a substituent. Compounds which are cyclic or tricyclic condensed heterocyclic groups, salts thereof, solvates thereof or N-oxides thereof.
[8" claim-type="Currently amended] The thienopyridyl group according to any one of claims 1 to 6, wherein the group Q ¹ may or may not have a substituent, a tetrahydrothienopyridyl group, which may or may not have a substituent, or a substituent. Thiazolopyridyl groups with or without substituents, tetrahydrothiazolopyridyl groups with or without substituents, thiazolopyridazinyl groups with or without substituents, tetrahydrothiazolopyridazinyl groups with or without substituents, substituents Pyranothiazolyl group with or without a substituent, Dihydropyranothiazolyl group with or without a substituent, Furopyridyl group with or without a substituent, Tetrahydrofuropyridyl group with or without a substituent, With or without a substituent An oxazolopyridyl group with or without a substituent, a tetrahydrooxazolopyridyl group with or without a substituent, a pyrrolopyridyl group with or without a substituent, and Dihydropyrrolopyridyl groups with or without ventilation, tetrahydropyrrolopyridyl groups with or without substituents, pyrrolopyrimidinyl groups with or without substituents, dihydropyrrolopyrimidis with or without substituents Nilsazolopyridazinyl group with or without a substituent, tetrahydrooxazolopyridazinyl group with or without a substituent, pyrrolothiazolyl group with or without a substituent, dihydro with or without a substituent Pyrrolothiazolyl groups, pyrrolooxazolyl groups with or without substituents, dihydropyrrolooxazolyl groups with or without substituents, benzothiazolyl groups with or without substituents, tetras with or without substituents Hydrobenzothiazolyl groups, thiazolopyrimidinyl groups with or without substituents, dihydrothiazolopyrimines with or without substituents Dinyl group, benzoazinyl group with or without substituent, tetrahydrobenzoazinyl group with or without substituent, thiazoloazinyl group with or without substituent, tetrahydrothiazoloa with or without substituent Zefinyl, thienoazinyl with or without substituents, tetrahydrothienoazinyl with or without substituents, 4,5,6,7-tetrahydro-5,6-tetramethylene with or without substituents Thiazolopyridazinyl groups or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups with or without substituents, salts thereof, solvates thereof or their N-jade Seed.
[9" claim-type="Currently amended] The substituent on the group Q ¹ is a hydroxyl group, a halogen atom, a halogenoalkyl group, an amino group, a cyano group, an amidino group, a hydroxyamidino group, a C ₁ -C ₆ alkyl group. , C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group, hydroxy C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, carboxyl group, C _2- C ₆ carboxyalkyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkoxycarbonyl group substituted amidino group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkoxycarbonyl group, amino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl group, di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl group, C _2- C ₆ alkoxycarbonylamino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkanoyl group, C ₁ -C ₆ alkanoylamino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ alkylsulfonylamino C ₁ -C ₆ alkyl group, carbamoyl group, C ₁ -C ₆ alkylcar A barmoyl group, an N, N-di (C ₁ -C ₆ alkyl) carbamoyl group, a C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, one or two or the same or two nitrogen species, 5-6 membered heterocyclic group containing oxygen or sulfur atom, 5-6 membered heterocyclic group-C ₁ -C ₄ alkyl group and 5-6 membered heterocyclic group-amino-C ₁ -C ₄ alkyl group 1 to 3 compounds, salts thereof, solvates or N-oxides thereof.
[10" claim-type="Currently amended] The compound T ¹ according to any one of claims 1 to 9, wherein in the general formula (1), the group T ¹ is a carbonyl group, a group -C (= 0) -C (= 0) -N (R ')-, and a group -C (= S) -C (= O) -N (R ')-, group -C (= O) -C (= S) -N (R')-or group -C (= S) -C (= S) -N (R ')-(wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a salt thereof, a solvate thereof or an N-oxide.
[11" claim-type="Currently amended] The compound T ¹ according to any one of claims 1 to 9, wherein in the formula (1), the group T ¹ is a group -C (= 0) -C (= 0) -N (R ')-, a group -C (= S). -C (= O) -N (R ')-, group -C (= O) -C (= S) -N (R')-or group -C (= S) -C (= S) -N (R ')-(wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a compound thereof, a salt thereof, a solvate thereof or an N-oxide.
[12" claim-type="Currently amended] The group Q ³ according to any one of claims 1 to 11, wherein

(In the group, Q ⁵ is an alkylene group having 3 to 6 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (In the group, m and n are each independently 0 or 1 represents A, and A represents the same as described above.), R ³ and R ⁴ each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, an amino group, and a hydroxyimide. No group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxy N-alkylcarbamoyl group which may have a substituent on an alkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylamino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an alkyl group, a substituent on an alkyl group N, N- you may have Dialkylcarbamoyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N- Alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted with 1 to 3 alkyl groups, Alkylsulfonyl group, alkylsulfonylalkyl group, 3-6 membered heterocyclic carbonyl group which may have a substituent, 3-6 membered heterocyclic carbonyloxyalkyl group which may have a substituent, carbamoylalkyl group, carbamoyloxyalkyl group , N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkyl group, N, N- which may have a substituent on an alkyl group Dialkylcarbamoylalkyl group, alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy , Acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkylaminoacyl group , Acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoylacyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, Aminocarbothioyl group, N-alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group.), A salt thereof, a solvate thereof or N thereof -Oxide.
[13" claim-type="Currently amended] The group Q ³ according to any one of claims 1 to 11, wherein

(In the group, Q ⁵ represents the group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (In the group, m and n each independently represent 0 or 1, and A is And R ³ and R ⁴ each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, an amino group, a hydroxyimino group, an alkoxyimino group, or an aminoalkyl group. , N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxy N, N-di which may have a substituent on the carbonyl group, the alkoxycarbonylalkyl group, the alkoxycarbonylamino group, the alkoxycarbonylaminoalkyl group, the carbamoyl group, and the alkyl group Alkylcarbamoyl group, N-alke Nylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl- N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3-6 membered heterocyclic carbonyl group which may have a substituent, 3-6 membered heterocyclic carbonyloxyalkyl group, carbamoylalkyl group, carbamoyloxyalkyl group, and N-alkylcarbamoyloxyalkyl group which may have a substituent , N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, alkylsul Phenylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsul Nyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkylaminoacyl group, acyloxyacyl group, hydroxide Roxyl group, alkoxy acyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoyl acyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonyl acyl group, aminocarbothioyl group, N -Alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group.), Salts thereof, solvates thereof or their N-oxides.
[14" claim-type="Currently amended] The group Q ³ according to any one of claims 1 to 11, wherein

(In the group, Q ⁵ represents an alkylene group having 3 to 6 carbon atoms, and R ³ and R ⁴ each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, an amino group, and a hydroxy group. Imino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxide N-alkylcarbamoyl group which may have a substituent on an oxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylamino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an alkyl group, a substituent on an alkyl group N, N-dialkylcarbamoyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N- which may have Alkylcarba Even if monoalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, 1-3 alkyl groups are substituted. A carbazoyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, a 3-6 membered heterocyclic carbonyl group which may have a substituent, a 3-6 membered heterocyclic carbonyloxyalkyl group, a carbamoylalkyl group, which may have a substituent, Carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkyl group, Even if it has a substituent on an alkyl group N, N-dialkylcarbamoylalkyl group, alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, Alkoxycarbonylacyl Group, Carboxia Real group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoyl Acyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (Thiocarbonyl) group.), A salt thereof, a solvate thereof, or an N-oxide thereof.
[15" claim-type="Currently amended] The group Q ³ according to any one of claims 1 to 11, wherein

(In the group, Q ⁵ represents an alkylene group having 4 carbon atoms, R ³ represents a hydrogen atom, and R ⁴ represents an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group.), Salts thereof, solvates thereof or their N-oxides.
[16" claim-type="Currently amended] The group Q ³ according to any one of claims 1 to 11, wherein

(In the group, Q ⁵ represents an alkylene group having 4 carbon atoms, R ³ represents a hydrogen atom, and R ⁴ represents an N, N-dimethylcarbamoyl group.) A compound thereof, a salt thereof, a solvate thereof or N thereof -Oxide.
[17" claim-type="Currently amended] According to claim 1, Formula 1
Formula 1

Wherein R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, and a substituent A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a divalent, saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent;
Q ³ is

(In the group, Q ⁵ represents the group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (In the group, m and n each independently represent an integer of 0, 1 to 3, A is an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-.));
R ³ and R ⁴ are substituted on a carbon atom, a nitrogen atom or a sulfur atom on the ring containing Q ⁵ , and each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, a cya Furano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acyl Aminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group N-alkylcarbamoyl group which may have a substituent on the alkyl group, N, N-dialkylcarbamoyl which may have a substituent on the alkyl group Group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group , N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkylsulfonylalkyl group, the 3-6 membered heterocyclic carbonyl group which may have a substituent, a carbamoylalkyl group, an alkyl group, N which may have a substituent on an alkyl group, N-dialkyl carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3-6 membered heterocyclic carbonyl which may have a substituent 3-6 membered heterocyclic carbonyloxyalkyl group which may have an alkyl group and a substituent, an aryl group, an aralkyl group, heteroa Group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsul Phenylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbon Niyl acyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfo Substituted on a 3-6 membered heterocyclic sulfonyl group, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an alkyl group which may have a nil group, a substituent N, N-dialkylcarbamoylacyl group which may have, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N- which may have a substituent on the alkyl group Alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group, or R ³ and R ⁴ together represent an alkylene group of 1 to 5 carbon atoms, 2 to 5 carbon atoms Represents an alkenylene group, an alkylenedioxy group having 1 to 5 carbon atoms, or a carbonyldioxy group.);
Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, heteroaryl with or without a substituent An alkenyl group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
T ⁰ represents a carbonyl group or a thiocarbonyl group;
T ¹ represents a carbonyl group, sulfonyl group or thiocarbonyl group), salts thereof, solvates thereof or N-oxides thereof.
[18" claim-type="Currently amended] 18. The method of claim 17, wherein Q ¹ is a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, Q ² is a single bond, salts thereof, solvates thereof or N-oxides thereof.
[19" claim-type="Currently amended] Claim 17 according to any one of claims 18, wherein, Q ¹ is which may have a substituent thieno pyridyl group, which may have a substituent tetrahydro-thieno pyridyl group, which may have a substituent thiazolo a pyridyl group, a substituent Tetrahydrothiazolopyridyl groups with or without substituents, thiazolopyridazinyl groups with or without substituents, tetrahydrothiazolopyridazinyl groups with or without substituents, pyranothiazolyl groups with or without substituents , Dihydropyranothiazolyl group with or without substituent, furopyridyl group with or without substituent, tetrahydrofuropyridyl group with or without substituent, oxazolopyridyl group with or without substituent, substituent Tetrahydrooxazolopyridyl groups with or without, pyrrolopyridyl groups with or without substituents, di or without substituents Dropyrrolopyridyl groups, tetrahydropyrrolopyridyl groups with or without substituents, pyrrolopyrimidinyl groups with or without substituents, dihydropyrrolopyrimidinyl groups with or without substituents, with or without substituents An oxazolopyridazinyl group, a tetrahydrooxazolopyridazinyl group with or without a substituent, a pyrrolothiazolyl group with or without a substituent, a dihydropyrrolothiazolyl group with or without a substituent, and a substituent A pyrrolooxazolyl group with or without a substituent, a dihydropyrrolooxazolyl group with or without a substituent, a benzothiazolyl group with or without a substituent, a tetrahydrobenzothiazolyl group with or without a substituent, a substituent With or without a thiazolopyrimidinyl group, with or without a dihydrothiazolopyrimidinyl group, with or without a substituent A benzoazinyl group with or without a substituent, a tetrahydrobenzoazinyl group with or without a substituent, a thiazoloazinyl group with or without a substituent, a tetrahydrothiazoloazinyl group with or without a substituent, with or without a substituent A thienoazinyl group, a tetrahydrothienoazinyl group with or without a substituent, a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group with or without a substituent, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group with or without substituents, salts thereof, solvates thereof or N-oxides thereof.
[20" claim-type="Currently amended] The substituent according to any one of claims 17 to 19, wherein the substituent on Q ¹ is a hydroxyl group, a halogen atom, a halogenoalkyl group, an amino group, a cyano group, an amidino group, a hydroxyamidino group, a C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group, hydroxy C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, carboxyl group, C ₂ -C ₆ carboxyalkyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkinocarbonyl group substituted amidino group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkoxycarbonyl group, amino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl group, di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkoxycarbonylamino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkanoyl group, C ₁ -C ₆ alkanoylamino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ alkyl sulfonylamino C ₁ -C ₆ alkyl group, a carbamoyl group, C ₁ -C ₆ alkyl carbonyl Parent group, N, N- di (C ₁ -C ₆ alkyl) carbamoyl, C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, one or the same or two nitrogen heterologous, 5-6 membered heterocyclic group containing oxygen or sulfur atom, 5-6 membered heterocyclic group-C ₁ -C ₄ alkyl group and 5-6 membered heterocyclic group-amino-C ₁ -C ₄ alkyl group 1 to 3 compounds, salts thereof, solvates or N-oxides thereof.
[21" claim-type="Currently amended] The compound of any one of claims 17-20, wherein Q ³ is

(In the group, Q ⁵ represents the group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (In the group, m and n each independently represent 0 or 1, and A is And R ³ and R ⁴ each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, an amino group, a hydroxyimino group, an alkoxyimino group, an aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group N-alkylcarbamoyl group which may have a substituent on alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, alkyl group, N, N-dialkyl which may have a substituent on alkyl group Carbamoyl group, N-alkenylcarbamo Group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxy Carbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1-3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, substituent 3-6 membered heterocyclic carbonyl group which may have a 3-6 membered heterocyclic carbonyloxyalkyl group, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group which may have a substituent, N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on an alkyl group, N, N-dialkylcarbamoylalkyl group which may have a substituent on an alkyl group, an alkylsulfonylamino group, Alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxy Carbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N, N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group , Alkoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoylacyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylamino Carbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group.), Salts thereof, solvates thereof or N-oxides.
[22" claim-type="Currently amended] The group Q ⁴ has a naphthyl group with or without a substituent, an anthryl group with or without a substituent, a phenanthryl group with or without a substituent, and a substituent. Styryl group with or without substituent, phenylethynyl group with or without substituent, thienylethenyl group with or without substituent, pyridylethenyl group with or without substituent, indenyl group with or without substituent, Indanyl groups with or without substituents, tetrahydronaphthyl groups with or without substituents, benzofuryl groups with or without substituents, isobenzofuryl groups with or without substituents, benzothienyl groups with or without substituents , Indolyl groups with or without substituents, indolinyl groups with or without substituents, isoindolinyl groups with or without substituents, iso with or without substituents Indolinyl groups, indazolyl groups with or without substituents, quinolyl groups with or without substituents, dihydroquinolyl groups with or without substituents, 4-oxo-dihydroquinolyl with or without substituents Groups (dihydroquinolin-4-ones), tetrahydroquinolyl groups with or without substituents, isoquinolyl groups with or without substituents, tetrahydroisoquinolyl groups with or without substituents, substituents Chromenyl groups with or without substituents, chromenyl groups with or without substituents, isochromenyl groups with or without substituents, 4H-4-oxobenzopyranyl groups with or without substituents, 3,4 with or without substituents -Dihydro-4H-4-oxobenzopyranyl group, 4H-quinolidinyl group with or without substituent, quinazolinyl group with or without substituent, dihydroquinazolinyl group with or without substituent, substitution Tetrahydroquinazolinyl groups with or without groups, quinoxalinyl groups with or without substituents, tetrahydroquinoxalinyl groups with or without substituents, cynolinyl groups with or without substituents, tetras with or without substituents Hydrocinnolinyl groups, indolinyl groups with or without substituents, tetrahydroindolinyl groups with or without substituents, benzothiazolyl groups with or without substituents, tetrahydrobenzothia with or without substituents Zolyl group, benzoxazolyl group with or without substituent, benzisothiazolyl group with or without substituent, benzisoxazolyl group with or without substituent, benzimidazolyl group with or without substituent, substituent A naphthyridinyl group with or without a tetrahydronaphthyridinyl group with or without a substituent A thienopyridyl group with or without a substituent, a tetrahydrothienopyridyl group with or without a substituent, a thiazolopyridyl group with or without a substituent, a tetrahydrothiazolopyridyl group with or without a substituent, or a substituent Thiazolopyridazinyl groups with or without substituents, tetrahydrothiazolopyridazinyl groups with or without substituents, pyrrolopyridyl groups with or without substituents, dihydropyrrolopyridyl groups with or without substituents, substituents Tetrahydropyrrolopyridyl groups with or without substituents, pyrrolopyrimidinyl groups with or without substituents, dihydropyrrolopyrimidinyl groups with or without substituents, pyridoquinazolinyl groups with or without substituents, substituents Dihydropyridoquinazolinyl group, with or without substituents, pyridopyrimidinyl group, with or without substituents Tetrahydropyridopyrimidinyl groups with or without substituents, pyranothiazolyl groups with or without substituents, dihydropyranothiazolyl groups with or without substituents, furypyridyl groups with or without substituents, and substituents With or without a tetrahydrofuropyridyl group, an oxazolopyridyl group with or without a substituent, a tetrahydrooxazolopyridyl group with or without a substituent, an oxazolopyridazinyl group with or without a substituent, a substituent Tetrahydrooxazolopyridazinyl groups, with or without substituents, pyrrolothiazolyl groups with or without substituents, dihydropyrrolothiazolyl groups with or without substituents, pyrrolooxazolyl groups with or without substituents, Dihydropyrrolooxazolyl group with or without substituent, thienopyrrolyl group with or without substituent, with substituent Thiazolopyrimidinyl group with or without substituent, 4-oxo-tetrahydrocinnolinyl group with or without substituent, 1,2,4-benzothiadiazinyl group with or without substituent, 1, with or without substituent 1-dioxy-2H-1,2,4-benzothiadiazinyl group, 1,2,4-benzoxadiazinyl group with or without substituent, cyclopentapyranyl group with or without substituent, substituent Thienofuranyl groups with or without substituents, furopyranyl groups with or without substituents, pyridoxazinyl groups with or without substituents, pyrazoleoxazolyl groups with or without substituents, imidazo with or without substituents Thiazolyl groups, imidazopyridyl groups with or without substituents, tetrahydroimidazopyridyl groups with or without substituents, pyrazinopyridazinyl groups with or without substituents, benzisoquis with or without substituents A aryl group, a furosynolyl group with or without a substituent, a pyrazolothiazolopyridazinyl group with or without a substituent, a tetrahydropyrazolothiazolopyridazinyl group with or without a substituent, with or without a substituent Hexahydrothiazolopyridazinopyridazinyl group, with or without imidazotriazinyl group, with or without substituent, oxazolopyridyl group, with or without substituent, benzoxepinyl group, with or without substituent A benzoazinyl group with or without a substituent, a tetrahydrobenzoazinyl group with or without a substituent, a benzodiazepynyl group with or without a substituent, a benzotriazinyl group with or without a substituent, a tier with or without a substituent Noazinyl group, tetrahydrothienoazinyl group with or without substituent, thienodi with or without substituent Zepinyl group, thienotriazinyl group with or without substituent, thiazoloazinyl group with or without substituent, tetrahydrothiazoloazinyl group with or without substituent, 4,5 with or without substituent , 6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group and 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group with or without substituents The compounds selected from, the salts thereof, their solvates or their N-oxides.
[23" claim-type="Currently amended] 22. The substituent according to any one of claims 17 to 21, wherein the substituent on Q ⁴ is a hydroxyl group, a halogen atom, a halogenoalkyl group, an amino group, a cyano group, an aminoalkyl group, a nitro group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyl group, or a carboxyalkyl group. , Alkoxycarbonylalkyl group, acyl group, amidino group, hydroxyamidino group, linear, branched or cyclic C1-C6 alkyl group, linear, branched or cyclic C1-C6 alkoxy Amidino groups in which groups, linear, branched or cyclic alkoxycarbonyl groups having 2 to 7 carbon atoms are substituted, straight, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, straight or branched carbon atoms 2 Alkynyl, straight, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms, carbamoyl group and nitrogen atom having linear, branched or cyclic carbon atoms of 1 to 6 carbon atoms 1 to 1 selected from mono- or dialkylcarbamoyl groups substituted with a group, mono- or dialkylamino groups substituted with linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- to 6-membered nitrogen-containing heterocyclic groups. Trivalent compounds, salts thereof, solvates or N-oxides thereof.
[24" claim-type="Currently amended] The compound of any one of claims 17-21, wherein Q ⁴ is

(In the group, R ⁵ and R ⁶ are each independently a hydrogen atom, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, Or a phenyl group which may be substituted with a cyano group, a hydroxyl group, a halogen atom, an alkyl group or an alkoxy group, and R ⁷ and R ⁸ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group or an alkenyl group , Alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, An amidino group or an alkoxycarbonylalkyl group.),

(In the groups, R ⁹ and R ¹⁰ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group. , Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.),

(In the group, R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group. Alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.

(In the group, X ¹ represents CH ₂ , CH, NH, NOH, N, O or S, and R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, and a halogen. Atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcar A barmoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.),

Wherein X ² represents NH, N, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH, and R ¹⁷ and R ¹⁸ each independently represent a hydrogen atom , Hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N- Alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, provided that both X ³ and X ⁴ are a combination of C and CH and C or CH , Except)

(N represents that one or two carbon atoms of the ring substituted by R ¹⁹ is substituted with a nitrogen atom, and R ¹⁹ , R ²⁰ and R ²¹ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, Cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N -Dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.),

(Wherein X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, Z ³ represents CH ₂ , CH , S, SO ₂ or C═O, X ⁵ -Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, R ²² and R ²³ are each independently a hydrogen atom, a hydroxyl group, Nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamo Diary, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, R ²⁴ represents a hydrogen atom or an alkyl group.),

(In the group, X ⁶ represents O or S, R ²⁵ and R ²⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, Hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group ), Or

(In the group, numbers 1 to 8 represent positions, and each N represents any one of 1 to 4 carbon atoms and one of 5 to 8 carbon atoms is substituted with one nitrogen atom, respectively. R ³⁴ , R ³⁵ and R ³⁶ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. Their solvates or their N-oxides.
[25" claim-type="Currently amended] The compound of any one of claims 17-21, wherein Q ⁴ is

(In the group, R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group, R ⁷ represents a hydrogen atom, and R ⁸ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.),

(In the group, R ⁹ represents a hydrogen atom, R ¹⁰ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.),

(In the group, R ¹¹ and R ¹² both represent a hydrogen atom, and R ¹³ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.),

(In the group, X ¹ represents NH, NOH, N, O or S, and R ¹⁴ represents a hydrogen atom, a halogen atom, an acyl group, an N-alkylcarbamoyl group, a N, N-dialkylcarbamoyl group or an alkyl group. R ¹⁵ represents a hydrogen atom or a halogen atom, and R ¹⁶ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.

Wherein X ² represents NH, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH, R ¹⁷ represents a hydrogen atom and R ¹⁸ represents a hydrogen atom , A halogen atom, an alkyl group or an alkynyl group, except when X ³ and X ⁴ are a combination of C and CH and both are C or CH.

(Wherein N represents one or two carbon atoms of the ring substituted by R ¹⁹ is substituted with a nitrogen atom, R ¹⁹ and R ²⁰ both represent hydrogen atoms, R ²¹ represents a hydrogen atom, a cyano group, a halogen) An atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenoalkyl group.),

(Wherein X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, Z ³ represents CH ₂ , CH , S, SO ₂ or C═O, X ⁵ -Z ² represents that X ⁵ and Z ² are bonded by a single bond or a double bond, R ²² represents a hydrogen atom, R ²³ is a hydrogen atom, A halogen atom, an alkyl group or an alkynyl group, and R ²⁴ represents a hydrogen atom.),

(In the group, X ⁶ represents O, R ²⁵ represents a hydrogen atom, R ²⁶ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.), Or

(In the group, numbers 1 to 8 represent positions, and each N represents any one of 1 to 4 carbon atoms and one of 5 to 8 carbon atoms is substituted with one nitrogen atom, respectively. R ³⁴ represents a hydrogen atom or a halogen atom, R ³⁵ represents a hydrogen atom or a halogen atom, and R ³⁶ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.), A salt thereof, a solvate thereof or their N-oxide.
[26" claim-type="Currently amended] 22. A compound according to any one of claims 17 to 21, wherein Q ⁴ is 4-chlorostyryl group, 4-fluorostyryl group, 4-bromostyryl group, 4-ethynylstyryl group, 4-chlorophenylethy. Nyl group, 4-fluorophenylethynyl group, 4-bromophenylethynyl group, 4-ethynylphenylethynyl group, 6-chloro-2-naphthyl group, 6-fluoro-2-naphthyl group, 6- Bromo-2-naphthyl group, 6-ethynyl-2-naphthyl group, 7-chloro-2-naphthyl group, 7-fluoro-2-naphthyl group, 7-bromo-2-naphthyl group, 7-e Tinyl-2-naphthyl group, 5-chloroindol-2-yl group, 5-fluoroindol-2-yl group, 5-bromoindol-2-yl group, 5-ethynylindol-2-yl group, 5-methylindole -2-yl group, 5-chloro-4-fluoroindol-2-yl group, 5-chloro-3-fluoroindol-2-yl group, 3-bromo-5-chloroindol-2-yl group, 3-chloro -5-fluoroindol-2-yl group, 3-bromo-5-fluoroindol-2-yl group, 5-bromo-3-chloroindol-2-yl group, 5-bromo-3-fluoroindole -2-yl group, 5-chloro-3-formylindol-2-yl group, 5-fluoro-3-formylindol-2-yl group, 5-bromo-3-formylindol-2-yl group, 5-ethynyl-3-formylindol-2-yl group, 5-chloro-3 -(N, N-dimethylcarbamoyl) indol-2-yl group, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-bromo-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl group, 6-chloroindol-2-yl group, 6-fluoroindole -2-yl group, 6-bromoindol-2-yl group, 6-ethynylindol-2-yl group, 6-methylindol-2-yl group, 5-chlorobenzothiophen-2-yl group, 5-fluorobenzo Thiophen-2-yl group, 5-bromobenzothiophen-2-yl group, 5-ethynylbenzothiophen-2-yl group, 5-methylbenzothiophen-2-yl group, 5-chloro-4-fluoro Benzothiophen-2-yl group, 6-chlorobenzothiophen-2-yl group, 6-fluorobenzothiophen-2-yl group, 6-bromobenzothiophen-2-yl group, 6-ethynylbenzothiophene -2-yl group, 6-methylbenzothiophen-2-yl group, 5-chlorobenzofuran-2-yl group, 5-fluorobenzofuran-2-yl , 5-bromobenzofuran-2-yl group, 5-ethynylbenzofuran-2-yl group, 5-methylbenzofuran-2-yl group, 5-chloro-4-fluorobenzofuran-2-yl group, 6- Chlorobenzofuran-2-yl group, 6-fluorobenzofuran-2-yl group, 6-bromobenzofuran-2-yl group, 6-ethynylbenzofuran-2-yl group, 6-methylbenzofuran-2-yl group , 5-chlorobenzimidazol-2-yl group, 5-fluorobenzimidazol-2-yl group, 5-bromobenzimidazol-2-yl group, 5-ethynylbenzimidazol-2-yl group, 6- Chloroquinolin-2-yl group, 6-fluoroquinolin-2-yl group, 6-bromoquinolin-2-yl group, 6-ethynylquinolin-2-yl group, 7-chloroquinolin-3-yl group, 7-fluoro Quinolin-3-yl group, 7-bromoquinolin-3-yl group, 7-ethynylquinolin-3-yl group, 7-chloroisoquinolin-3-yl group, 7-fluoroisoquinoline-3-yl group, 7-bro Moisoquinolin-3-yl group, 7-ethynylisoquinolin-3-yl group, 7-chlorocinnoline-3-yl group, 7-fluorocinnolin-3-yl group, 7-bromosinolin-3-yl group, 7-ethynylcin Nolin-3-yl group, 7-chloro-2H-chromen-3-yl group, 7-fluoro-2H-chromen-3-yl group, 7-bromo-2H-chromen-3-yl group, 7-e Tinyl-2H-chromen-3-yl group, 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinoline-2- Diary, 6-bromo-4-oxo-1,4-dihydroquinolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl group, 6-chloro-4- Oxo-1,4-dihydroquinazolin-2-yl group, 6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl group, 6-bromo-4-oxo-1,4- Dihydroquinazolin-2-yl group, 6-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl group, 2-chlorothieno [2,3-b] pyrrole-5-yl group, 2 -Fluorothieno [2,3-b] pyrrole-5-yl, 2-bromothieno [2,3-b] pyrrol-5-yl or 2-ethynylthieno [2,3-b] Pyrrole-5-yl groups, salts thereof, solvates thereof or their N-oxides.
[27" claim-type="Currently amended] 27. The compound according to any one of claims 17 to 26, wherein T ¹ is a carbonyl group, salts thereof, solvates thereof or N-oxides thereof.
[28" claim-type="Currently amended] According to claim 1, Formula 1
Formula 1

Wherein R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;
Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, saturated or unsaturated 2 with or without substituents Cyclic or tricyclic condensed hydrocarbon groups or saturated or unsaturated dicyclic or tricyclic condensed heterocyclic groups with or without substituents;
Q ² has a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group with or without a substituent, a divalent saturated or unsaturated 5-7 membered heterocyclic group with or without a substituent, and a substituent A divalent saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a divalent, saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent;
Q ³ is

(In the group, Q ⁵ is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (in the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO _2- , -NH-, -O-NH-, and -NH-NH -, -S-NH-, -SO-NH- or -SO ₂ -NH-.
R ³ and R ⁴ are substituted on the carbon atom on the ring containing Q ⁵ , and each independently hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group, cyanoalkyl group , Amino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group A substituent on an alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, alkyl group N-alkylcarbamoyl group which may have, N, N-dialkylcarbamoyl group which may have a substituent on an alkyl group, N-alkenylcarbamoyl Group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxy Carbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1-3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, substituent N-alkylcarbamoylalkyl group which may have a substituent on the 3-6 membered heterocyclic carbonyl group, carbamoylalkyl group, an alkyl group, and N, N-dialkylcarbamoylalkyl group which may have a substituent on an alkyl group , Carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N, N-dialkylcarbamoyloxyalkyl group, 3 to 6-membered heterocyclic carbonylalkyl group which may have a substituent, 3 which may have a substituent A 6-membered heterocyclic carbonyloxyalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, Alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, Oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxy Have a carbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, substituent N, N-di which may have a substituent on the 3-6 membered heterocyclic sulfonyl group, N-alkylaminoacyl group, N, N-dialkylaminoacyl group, and an alkyl group which become N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N, which may have a substituent on the chelkcarbamoylacyl group, alkyl group N-dialkylaminocarbothioyl group or an alkoxyalkyl (thiocarbonyl) group, or R ³ and R ⁴ together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, and 1 to 5 carbon atoms Represents an alkylenedioxy group or a carbonyldioxy group.
Q ⁴ is an aryl group with or without a substituent, an arylalkenyl group with or without a substituent, an arylalkynyl group with or without a substituent, a heteroaryl group with or without a substituent, heteroaryl with or without a substituent An alkenyl group, a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group with or without a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without a substituent;
T ⁰ represents a carbonyl group or a thiocarbonyl group;
T ¹ is a group -C (= O) -C (= O) -N (R ')-, a group -C (= S) -C (= O) -N (R')-, a group -C (= O) -C (= S) -N (R ')-, group -C (= S) -C (= S) -N (R')-(where R 'is a hydrogen atom, a hydroxyl group, an alkyl group or Alkoxy group.), Group -C (= O) -A ¹ -N (R ")-(In group, A <^1> shows a C1-C5 alkylene group which has a substituent, and R" represents hydrogen. Atom, hydroxyl group, alkyl group or alkoxy group), group -C (= O) -NH-, group -C (= S) -NH-, group -C (= O) -NH-NH-, group -C (= O) -A ² -C (= O)-(A ² represents a single bond or an alkylene group having 1 to 5 carbon atoms.), And the group -C (= O) -A ³ -C (= O) -NH- (wherein A ³ represents an alkylene group having 1 to 5 carbon atoms), group -C (= O) -C (= NOR ^a ) -N (R ^b )-, group -C ( = S) -C (= NOR ^a ) -N (R ^b )-(In the group, R ^a represents a hydrogen atom, an alkyl group or an alkanoyl group, and R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.) , Group -C (= O) -N = N-, group -C (= S) -N = N-, group -C (= NOR ^c ) -C (= O) -N (R ^d )-(group Wherein R ^c is a hydrogen atom, an alkyl group, an alkanoyl group , An aryl group or an aralkyl group, R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.), A group -C (= NN (R ^e ) (R ^f ))-C (= O) -N (R ^g )-(In the groups, R ^e and R ^f each independently represent a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl (thiocarbonyl) group, and R ^g represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group.) or Thiocarbonyl group.), Salts thereof, solvates thereof or their N-oxides.
[29" claim-type="Currently amended] 29. The method of claim 28, wherein Q ¹ is a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group with or without a substituent, or a saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without a substituent, Q ² is a single bond, salts thereof, solvates thereof or N-oxides thereof.
[30" claim-type="Currently amended] Claim 28 according to any one of claims 29, wherein, Q ¹ is which may have a substituent thieno pyridyl group, which may have a substituent tetrahydro-thieno pyridyl group, which may have a substituent thiazolo a pyridyl group, a substituent Tetrahydrothiazolopyridyl groups with or without substituents, thiazolopyridazinyl groups with or without substituents, tetrahydrothiazolopyridazinyl groups with or without substituents, pyranothiazolyl groups with or without substituents , Dihydropyranothiazolyl group with or without substituent, furopyridyl group with or without substituent, tetrahydrofuropyridyl group with or without substituent, oxazolopyridyl group with or without substituent, substituent Tetrahydrooxazolopyridyl groups with or without, pyrrolopyridyl groups with or without substituents, di or without substituents Dropyrrolopyridyl groups, tetrahydropyrrolopyridyl groups with or without substituents, pyrrolopyrimidinyl groups with or without substituents, dihydropyrrolopyrimidinyl groups with or without substituents, with or without substituents An oxazolopyridazinyl group, a tetrahydrooxazolopyridazinyl group with or without a substituent, a pyrrolothiazolyl group with or without a substituent, a dihydropyrrolothiazolyl group with or without a substituent, and a substituent A pyrrolooxazolyl group with or without a substituent, a dihydropyrrolooxazolyl group with or without a substituent, a benzothiazolyl group with or without a substituent, a tetrahydrobenzothiazolyl group with or without a substituent, a substituent With or without a thiazolopyrimidinyl group, with or without a dihydrothiazolopyrimidinyl group, with or without a substituent A benzoazinyl group with or without a substituent, a tetrahydrobenzoazinyl group with or without a substituent, a thiazoloazinyl group with or without a substituent, a tetrahydrothiazoloazinyl group with or without a substituent, with or without a substituent A thienoazinyl group, a tetrahydrothienoazinyl group with or without a substituent, a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group with or without a substituent, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group with or without substituents, salts thereof, solvates thereof or N-oxides thereof.
[31" claim-type="Currently amended] The substituent according to any one of claims 28 to 30, wherein the substituent on Q ¹ is a hydroxyl group, a halogen atom, a halogenoalkyl group, an amino group, a cyano group, an amidino group, a hydroxyamidino group, a C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group, hydroxy C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, carboxyl group, C ₂ -C ₆ carboxyalkyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkinocarbonyl group substituted amidino group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₂ -C ₆ alkoxycarbonyl group, amino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl group, di (C ₁ -C ₆ alkyl) amino C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkoxycarbonylamino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkanoyl group, C ₁ -C ₆ alkanoylamino C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ alkyl sulfonylamino C ₁ -C ₆ alkyl group, a carbamoyl group, C ₁ -C ₆ alkyl carbonyl Parent group, N, N- di (C ₁ -C ₆ alkyl) carbamoyl, C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, one or the same or two nitrogen heterologous, 5-6 membered heterocyclic group containing oxygen or sulfur atom, 5-6 membered heterocyclic group-C ₁ -C ₄ alkyl group and 5-6 membered heterocyclic group-amino-C ₁ -C ₄ alkyl group 1 to 3 compounds, salts thereof, solvates or N-oxides thereof.
[32" claim-type="Currently amended] 32. The compound of any of claims 28-31, wherein Q ³ is

(In the group, Q ⁵ is an alkylene group having 3 to 6 carbon atoms or a group-(CH ₂ ) _m -CH ₂ -A-CH _2- (CH ₂ ) _n- (In the group, m and n are each independently 0 or 1 represents A, and A is the same as described above.), And R ³ and R ⁴ each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a halogenoalkyl group, an amino group, and a hydroxyimino group. , Alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may have a substituent, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group , A carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylamino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an alkyl group which may have a substituent on the alkyl group, and a substituent on the alkyl group N, N-dialkylcarba which may be Moyl group, N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamo Dibasic, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group optionally substituted by 1 to 3 alkyl groups, alkylsulfonyl group , Alkylsulfonylalkyl group, 3-6 membered heterocyclic carbonyl group which may have a substituent, 3-6 membered heterocyclic carbonyloxyalkyl group, carbamoylalkyl group, carbamoyloxyalkyl group, N- which may have a substituent N, N-dialkylcar which may have a substituent on an alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, an alkyl group, and an alkyl group Bamoylalkyl group, alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxy Kyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, carboxyl group, alkoxyalkyloxycarbonyl, halogenoacyl, N, N-dialkylaminoacyl, acyloxy Acyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N, N-dialkylcarbamoylacyl group, N, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbo Thioyl group, N-alkylaminocarbothioyl group, N, N-dialkylaminocarbothioyl group or alkoxyalkyl (thiocarbonyl) group.), A salt thereof, a solvate thereof or an N-oxide.
[33" claim-type="Currently amended] 32. The compound of any of claims 28-31, wherein Q ³ is

(In the group, Q ⁵ represents an alkylene group having 4 carbon atoms, R ³ represents a hydrogen atom, and R ⁴ represents an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group.), Salts thereof, solvates thereof or their N-oxides.
[34" claim-type="Currently amended] 32. The compound of any of claims 28-31, wherein Q ³ is

(In the group, Q ⁵ represents an alkylene group having 4 carbon atoms, R ³ represents a hydrogen atom, and R ⁴ represents an N, N-dimethylcarbamoyl group.) A compound thereof, a salt thereof, a solvate thereof or N thereof -Oxide.
[35" claim-type="Currently amended] 35. A compound according to any one of claims 28 to 34, wherein Q ⁴ has or without a substituent, a pyridyl group with or without a substituent, a pyridazinyl group with or without a substituent, a substituent Pyrazinyl group with or without substituent, furyl group with or without substituent, thienyl group with or without substituent, pyrrolyl group with or without substituent, thiazolyl group with or without substituent, oxazolyl with or without substituent Groups, pyrimidinyl groups with or without substituents and tetrazolyl groups with or without substituents, compounds thereof, salts thereof, solvates thereof or N-oxides thereof.
[36" claim-type="Currently amended] 36. The substituent of any one of claims 28 to 35, wherein the substituent on Q ⁴ is a hydroxyl group, a halogen atom, a halogenoalkyl group, an amino group, a cyano group, an aminoalkyl group, a nitro group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyl group, or a carboxyalkyl group. , Alkoxycarbonylalkyl group, acyl group, amidino group, hydroxyamidino group, linear, branched or cyclic C1-C6 alkyl group, linear, branched or cyclic C1-C6 alkoxy Amidino groups in which groups, linear, branched or cyclic alkoxycarbonyl groups having 2 to 7 carbon atoms are substituted, straight, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, straight or branched carbon atoms 2 Alkynyl, straight, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms, carbamoyl group and nitrogen atom having linear, branched or cyclic carbon atoms of 1 to 6 carbon atoms 1 to 1 selected from mono- or dialkylcarbamoyl groups substituted with a group, mono- or dialkylamino groups substituted with linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- to 6-membered nitrogen-containing heterocyclic groups. Trivalent compounds, salts thereof, solvates or N-oxides thereof.
[37" claim-type="Currently amended] 35. The compound of any one of claims 28-34, wherein Q ⁴ is

(In the group, R ²⁷ and R ²⁸ are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group , Carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.),

(In the groups, E ¹ and E ² each independently represent N or CH, and R ²⁹ and R ³⁰ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, and an alkoxy group). Nyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino Group or an alkoxycarbonylalkyl group), or

(In the group, Y ¹ represents CH or N, Y ² represents -N (R ³³ )-(in the group, R ³³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.), And represents O or S, R ³¹ and R ³² are each independently a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxy Alkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group.), Salts thereof, solvates thereof Or N-oxide.
[38" claim-type="Currently amended] 35. The compound of any one of claims 28-34, wherein Q ⁴ is

(In the group, R ²⁷ represents a hydrogen atom or a halogen atom, and R ²⁸ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.),

(In the group, E ¹ and E ² each independently represent N or CH, R ²⁹ represents a hydrogen atom or a halogen atom, and R ³⁰ represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.), Or

(In the group, Y ¹ represents CH or N, Y ² represents -N (R ³³ )-(in the group, R ³³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.), And represents O or S, R ³¹ represents a hydrogen atom or a halogen atom, and R ³² represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group.), A salt thereof, a solvate thereof or an N-oxide thereof.
[39" claim-type="Currently amended] The method according to any one of claims 28 to 34, wherein Q ⁴ is a phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-ethynylphenyl group, 3-chlorophenyl group, 3-fluoro Rophenyl group, 3-bromophenyl group, 3-ethynylphenyl group, 3-chloro-4-fluorophenyl group, 4-chloro-3-fluorophenyl group, 4-chloro-2-fluorophenyl group, 2-chloro-4 -Fluorophenyl group, 4-bromo-2-fluorophenyl group, 2-bromo-4-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dibromo Phenyl group, 4-chloro-3-methylphenyl group, 4-fluoro-3-methylphenyl group, 4-bromo-3-methylphenyl group, 4-chloro-2-methylphenyl group, 4-fluoro-2-methylphenyl group, 4-bromo-2-methylphenyl group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dibromophenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-chloro-2-pyridyl group, 4-fluoro-2-pyridyl group, 4-bromo-2-pyridyl group, 4-ethynyl-2-pyridyl , 4-chloro-3-pyridyl group, 4-fluoro-3-pyridyl group, 4-bromo-3-pyridyl group, 4-ethynyl-3-pyridyl group, 5-chloro-2-pyridyl group, 5 -Fluoro-2-pyridyl group, 5-bromo-2-pyridyl group, 5-ethynyl-2-pyridyl group, 4-chloro-5-fluoro-2-pyridyl group, 5-chloro-4-fluoro Ro-2-pyridyl group, 5-chloro-3-pyridyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyridyl group, 6-chloro- 3-pyridazinyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 6-ethynyl-3-pyridazinyl group, 5-chloro-2-thia A compound which is a jolyl group, 5-fluoro-2-thiazolyl group, 5-bromo-2-thiazolyl group or 5-ethynyl-2-thiazolyl group, salts thereof, solvates thereof or their N-oxides.
[40" claim-type="Currently amended] 40. The compound of any one of claims 28-39, wherein T ¹ is a group -C (= 0) -C (= 0) -N (R ')-, a group -C (= 0) -C (= 0). ) -N (R ')-, group -C (= O) -C (= S) -N (R')-or group -C (= S) -C (= S) -N (R ')- Phosphorus compounds, salts thereof, solvates or N-oxides thereof.
[41" claim-type="Currently amended] 41. A medicament containing the compound according to any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides.
[42" claim-type="Currently amended] 41. An activated hemagglutinating factor X inhibitor comprising the compound of any one of claims 1-40, a salt thereof, a solvate thereof, or an N-oxide thereof.
[43" claim-type="Currently amended] 41. A blood coagulation inhibitor containing the compound of any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides.
[44" claim-type="Currently amended] 41. A prophylactic and / or therapeutic agent for thrombus or embolism containing the compound of any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides.
[45" claim-type="Currently amended] 41. Compounds of any one of claims 1 to 40, their salts, their solvates or their N-oxides, cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, Disseminated intravascular coagulation syndrome, thrombus formation after prosthetic valve / joint replacement, thrombus formation and reclosure after blood circulation reconstruction, systemic inflammatory response syndrome (SIRS), multiorgan organ failure (MODS), thrombus formation in extracorporeal circulation or blood in blood collection Prophylactic and / or therapeutic agents of coagulation.
[46" claim-type="Currently amended] 41. A pharmaceutical composition comprising the compound of any one of claims 1-40, a salt thereof, a solvate thereof, or an N-oxide thereof and a pharmaceutically acceptable carrier.
[47" claim-type="Currently amended] 41. Use of a compound of any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides for the manufacture of a medicament.
[48" claim-type="Currently amended] 41. Use of a compound of any one of claims 1-40, a salt thereof, a solvate thereof, or an N-oxide thereof for the preparation of an activated hemagglutinating factor X inhibitor.
[49" claim-type="Currently amended] 41. Use of a compound of any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides for the preparation of a blood coagulation inhibitor.
[50" claim-type="Currently amended] 41. Use of a compound of any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides for the preparation of prophylactic and / or therapeutic agents for thrombus or embolism.
[51" claim-type="Currently amended] 41. A compound of any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides, cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, pancreas Vascular coagulation syndrome, thrombus formation after prosthetic valve / joint replacement, thrombus formation and reclosure after blood circulation reconstruction, systemic inflammatory response syndrome (SIRS), multiorgan organ failure (MODS), thrombus formation during extracorporeal circulation or blood coagulation in blood collection For the preparation of prophylactic and / or therapeutic agents.
[52" claim-type="Currently amended] An effective amount of the compound of any one of claims 1 to 40, a salt thereof, a solvate thereof or an N-oxide thereof is administered.
[53" claim-type="Currently amended] 41. A cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, burger characterized by administering an effective amount of the compound of any one of claims 1 to 40, salts thereof, solvates thereof or their N-oxides. Seed disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after prosthetic valve / joint replacement, thrombus formation and reclosure after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), extracorporeal circulation A method of treating blood clotting during thrombus formation or blood collection.
[54" claim-type="Currently amended] Formula 4
Formula 4

(In formula, R <^1> , R <^2> and T <^1> show a thing of Claim 1,
Q ³ is

(Wherein, Q ⁵ , R ³ and R ⁴ are those of claim 1), and Q ⁴ is an aryl group with or without a substituent, a heteroaryl group with or without a substituent, with or without a substituent. Or a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group, or a saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without substituents.), A salt thereof, a solvate thereof, or Their N-oxides.
[55" claim-type="Currently amended] Formula 9
Formula 9

(Wherein, Q ² , R ¹ and R ² are those of claim ¹ , Q ¹ represents a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without substituents,
Q ³ is

(In the group, Q ⁵ , R ³ and R ⁴ represent the compound of claim 1).), A salt thereof, a solvate thereof or an N-oxide thereof.
[56" claim-type="Currently amended] Formula 4
Formula 4

(In formula, R <^1> , R <^2> and T <^1> represent a thing of Claim 17,
Q ³ is

(Wherein, Q ⁵ , R ³ and R ⁴ are those of claim 17), Q ⁴ is an aryl group with or without a substituent, a heteroaryl group with or without a substituent, with or without a substituent Or a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group, or a saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without substituents.), A salt thereof, a solvate thereof, or Their N-oxides.
[57" claim-type="Currently amended] Formula 9
Formula 9

(Wherein Q ² , R ¹ and R ² are those of claim 17, Q ¹ represents a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without substituents,
Q ³ is

(Wherein, Q ⁵ , R ³ and R ⁴ represent the ones of claim 17).), A salt thereof, a solvate thereof or an N-oxide thereof.
[58" claim-type="Currently amended] Formula 4
Formula 4

(In formula, R <^1> , R <^2> and T <^1> represent a thing of Claim 28,
Q ³ is

(Wherein, Q ⁵ , R ³ and R ⁴ are those of claim 28), Q ⁴ is an aryl group with or without a substituent, a heteroaryl group with or without a substituent, with or without a substituent Or a saturated or unsaturated dicyclic or tricyclic condensed hydrocarbon group, or a saturated or unsaturated dicyclic or tricyclic condensed heterocyclic group with or without substituents.), A salt thereof, a solvate thereof, or Their N-oxides.
[59" claim-type="Currently amended] Formula 9
Formula 9

(Wherein Q ² , R ¹ and R ² are those of claim 28, Q ¹ represents a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group with or without substituents,
Q ³ is

(In the group, Q ⁵ , R ³ and R ⁴ represent the thing of claim 28.), a compound represented by the salt thereof, a solvate thereof or an N-oxide thereof.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US9469640B2|2016-10-18|Compounds and methods for kinase modulation, and indications therefor

---

JP6563017B2|2019-08-21|Glycosidase inhibitor

---

US10035800B2|2018-07-31|Substituted 1,4,10-triazadibenzo[cd,f]azulenes, substituted 1,4,5,10-tetraazadibenzo[cd,f]azulenes and substituted 1,4,5,7,10-pentaazadibenzo[cd,f]azulenes as bromodomain inhibitors

---

RU2632870C2|2017-10-11|Tricyclic heterocyclic compounds and jak inhibitors

---

RU2671571C1|2018-11-02|Bromdomain inhibitors

---

ES2576182T3|2016-07-06|Novel heterocyclic derivatives and their use in the treatment of neurological disorders

---

EP2961749B1|2019-10-09|Perfluorinated 5,6-dihydro-4h-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use

---

US10428077B2|2019-10-01|Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor4 | inhibitors for treating platelet aggregation

---

RU2696270C1|2019-08-01|Tetrahydroimidazopyridine derivatives as modulators of tnf activity

---

RU2708395C2|2019-12-06|Primary carboxamides as btk inhibitors

---

US8883828B2|2014-11-11|2-aminopyridine analogs as glucokinase activators

---

BR112019012993A2|2019-12-03|benzo-oxazole derivatives as immunomodulators

---

CA2515343C|2010-12-14|Antiparasitic terpene alkaloids

---

US6436966B1|2002-08-20|Adenosine A3 receptor antagonists

---

EP1948652B1|2011-08-24|Glucokinase activators

---

ES2738123T3|2020-01-20|Heterocyclic sulfur-containing derivative that has β-secretase inhibitory activity

---

JP6374889B2|2018-08-15|Perfluorinated cyclopropyl-fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use

---

DE60018037T2|2006-01-12|Substituted 2-aryl-3- | -imidazo [1,2-alpha] pyrimidine and its related medicament and method

---

AU2010315126B2|2015-06-25|Compounds and methods for kinase modulation, and indications therefor

---

US8143393B2|2012-03-27|Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

---

US7915411B2|2011-03-29|Anti-viral compounds

---

CA2631775C|2015-02-03|Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

---

CA2504385C|2012-12-18|Thiadiazine compounds and uses thereof

---

EP1979348B1|2012-01-18|Anti-viral compounds

---

RU2685234C1|2019-04-17|Condensed bicyclic heteroaromatic derivatives as modulators of tnf activity

同族专利:

---

公开号 | 公开日

---

KR100863113B1|2008-10-13|

---

PL367532A1|2005-02-21|

---

NO20035634L|2004-02-18|

---

BR0210541A|2004-06-22|

---

PL214669B1|2013-08-30|

---

WO2003000680A1|2003-01-03|

---

MXPA03011951A|2004-03-26|

---

EP1405852B9|2013-03-27|

---

LU92835I2|2015-11-23|

---

RU2004101279A|2005-06-10|

---

IL159438D0|2004-06-01|

---

EP1405852A1|2004-04-07|

---

JP4944759B2|2012-06-06|

---

US20050245565A1|2005-11-03|

---

BRPI0210541B1|2018-12-04|

---

NO20035634D0|2003-12-17|

---

DK1405852T3|2012-08-27|

---

PL220739B1|2015-12-31|

---

JPWO2003000680A1|2004-10-07|

---

AU2002346300C1|2014-03-06|

---

AU2002346300B2|2007-11-01|

---

ZA200400926B|2005-02-04|

---

EP1405852A4|2006-07-26|

---

IL159438A|2011-09-27|

---

NO332919B1|2013-02-04|

---

PL398653A1|2012-07-16|

---

CA2451605C|2010-08-10|

---

RU2319699C2|2008-03-20|

---

CN1826333B|2012-12-26|

---

JP2008143905A|2008-06-26|

---

ES2389027T3|2012-10-22|

---

NO2015022I2|2015-10-12|

---

EP1405852B1|2012-08-01|

---

CA2451605A1|2003-01-03|

---

CN1826333A|2006-08-30|

---

NO2015022I1|2015-10-19|

---

JP4128138B2|2008-07-30|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
2001-06-20|Priority to JP2001187105

---

2001-06-20|Priority to JPJP-P-2001-00187105

---

2001-08-09|Priority to JPJP-P-2001-00243046

---

2001-08-09|Priority to JP2001243046

---

2001-10-09|Priority to JPJP-P-2001-00311808

---

2001-10-09|Priority to JP2001311808

---

2001-12-28|Priority to JPJP-P-2001-00398708

---

2001-12-28|Priority to JP2001398708

---

2002-03-20|Priority to PCT/JP2002/002683

---

2002-03-20|Priority to WOPCT/JP02/02683

---

2002-06-20|Application filed by 다이이찌 세이야꾸 가부시기가이샤

---

2002-06-20|Priority to PCT/JP2002/006141

---

2004-04-06|Publication of KR20040029322A

---

2008-10-13|Application granted

---

2008-10-13|Publication of KR100863113B1

---

2013-05-01|First worldwide family litigation filed

优先权:

---

申请号 | 申请日 | 专利标题

---

JP2001187105|2001-06-20|

---

JPJP-P-2001-00187105|2001-06-20|

---

JPJP-P-2001-00243046|2001-08-09|

---

JP2001243046|2001-08-09|

---

JPJP-P-2001-00311808|2001-10-09|

---

JP2001311808|2001-10-09|

---

JPJP-P-2001-00398708|2001-12-28|

---

JP2001398708|2001-12-28|

---

PCT/JP2002/002683|WO2003000657A1|2001-06-20|2002-03-20|Diamine derivatives|

---

WOPCT/JP02/02683|2002-03-20|

---

PCT/JP2002/006141|WO2003000680A1|2001-06-20|2002-06-20|Diamine derivatives|