Quinolinecarboxamides as Antiviral Agents

专利摘要:
The present invention provides a compound of formula (I) which is useful as an antiviral agent, in particular as an antiviral agent against the herpes family of viruses. <Formula I>
公开号:KR20010101421A
申请号:KR1020017008629
申请日:1999-12-22
公开日:2001-11-14
发明作者:스티븐 로날드 터너；조셉 월터 스트로바하；수빗 타이스리봉스；발레리 에이. 베일란코트；마크 이. 쉬누트；존 앨런 터커
申请人:로렌스 티. 마이젠헬더；파마시아 앤드 업존 캄파니；
IPC主号:

专利说明:

Quinolinecarboxamides as Antiviral Agents
[2] Herpesviruses make up a large family of double-stranded DNA viruses. These are the etiology of the most common viral diseases in humans. Eight of herpes viruses, namely herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) ) And human herpesviruses 6, 7 and 8 (HHV-6, HHV-7 and HHV-8) have been shown to infect humans.
[3] HSV-1 and HSV-2 cause herpes lesions on the lips and genitals, respectively. They also sometimes cause eye infections and encephalitis. HCMV causes birth defects in infants and various diseases such as retinitis, pneumonia and gastrointestinal diseases in immunocompromised patients. VZV is the virus that causes chickenpox and shingles. EBV causes infectious mononucleosis. It can also cause lymphoma in immunocompromised patients and is associated with Burkitt's lymphoma, nasopharyngeal cancer and Hodgkins disease. HHV-6 is the causative virus of erythema and may be associated with multiple sclerosis and chronic fatigue syndrome. The disease association of HHV-7 is not clear, but may be involved in some cases of erythema. HHV-8 is associated with Kaposi's sarcoma, celiac basal lymphoma and multiple myeloma.
[4] The compounds of the present invention are distinguished from all other hydroxyquinoline drugs in that the 4-substituents of the benzylamides of the present invention provide significantly improved antiviral activity. Certain compounds of formula (I) also contain a unique substituent R ⁴ which provides improved antiviral activity.
[5] Information literature
[6] U.S. Pat.Nos. 5,891,878 and WO 97/04775 disclose compounds reported to be useful in the treatment of disease states that can inhibit and regulate the production of phosphodiesterase IV or tumor necrosis factor. It is believed that the class of compounds disclosed in these applications overlaps with the compounds of formula (I) disclosed herein. However, none of the compounds having 4-substituted benzamide groups of the compounds herein are prepared in these PCT applications.
[7] U.S. Patent 3,960,868 discloses derivatives of 6, 7 or 8 cycloalkyl-4-oxoquinoline-3-carboxylic acids reported to have analgesic, anti-inflammatory, antimicrobial and histamine free inhibitory activity. The structure of these compounds differs from that of the compounds of formula (I) in that they require cycloalkyl substituents at positions 6, 7 or 8 of the quinoline ring.
[8] U.S. Patent 4,959,363 discloses quinolinecarboxamide compounds reported to have antiviral activity. The structure of these compounds differs from the structure of the compounds of formula (I) disclosed herein in that they do not comprise 4-substituted benzamides at position 3 and require hydrogen or fluoro substituents at position 6.
[9] U.S. Patent 5,175,151 discloses quinolone compounds reported to have antihypertensive and antiviral activity. The structure of these compounds differs from the structure of the compounds of formula (I) disclosed herein in that they do not comprise a 4-substituted benzamide at position 3 and require an oxygen bond substituent at position 2.
[10] British patent application 1,191,443 discloses quinoline compounds reported to have antiviral activity. The structures of these compounds do not include 4-substituted benzamides at position 3, and require herein a fused furan heterocyclic ring at position 5,6- 6,7- or 7,8- of the quinolone. It is different from the structure of the disclosed compound of formula (I).
[11] WO 97/14682 discloses quinoline derivatives that have been reported to be useful in the treatment of certain hormone dependent diseases. The structures of these compounds do not include 4-substituted benzamides at position 3, require halogenoaralkyl at position 1, and acylaminoaryl groups at position 7, and are of the formula (I) Is different from the structure.
[12] US Pat. No. 4,786,644 discloses 1-aryl-3-quinolinecarboxamide, which is reported to be useful for the treatment of pain and inflammation. The structure of these compounds differs from that of the compounds of formula I in that they do not comprise a 4-substituted benzamide at position 3 and require an optionally substituted phenyl substituent at position 1.
[13] U.S. Patent 4,835,163 discloses N-alkoxyalkyl derivatives of quinolonecarboxamides that have been reported to have anticonvulsant and psychotension activity. The structure of these compounds differs from that of the compounds of formula (I) disclosed herein in that they do not contain a 4-substituted benzamide substituent at position 3.
[14] U.S. Patent 5,096,901; British Application No. 2 236 751; And in T.J. Ward et al., Med. Chem. Res. (1993), 4, 267-272, discloses quinolone-3- (azabicyclo) carboxamides that have 5-HT3 activity and are reported to be useful for the treatment of neuropsychiatric disorders. The structure of these compounds differs from that of the compounds of formula (I) disclosed herein in that they require azabicyclo containing substituents at position 3.
[15] Japanese Patent 02124871 discloses a quinolone compound reported to have 5-lipoxygenase activity. The structure of these compounds differs from that of the compounds of formula (I) disclosed herein in that they do not contain a 4-substituted benzamide substituent at position 3.
[16] European Patent 0 332 930 A2 discloses quinolone compounds reported to have antimicrobial antiviral activity. The structure of these compounds differs from the structure of the compounds of formula (I) disclosed herein in that they do not comprise a 4-substituted benzamide at position 3 and require hydrogen, halo or nitro substituents at position 6.
[17] Chem. Abstracts (1969), 71, 101735q, disclose quinolone compounds reported to have anti-inflammatory activity. The structure of these compounds differs from that of the compounds of formula (I) disclosed herein in that they do not contain a 4-substituted benzamide substituent at position 3.
[18] U.S. Patents 5,051,418 and 4,908,366 disclose 8-cyano-quinolone compounds reported to have antimicrobial activity. The structures of these compounds differ from the structures of the compounds of formula (I) disclosed herein in that they do not comprise a 4-substituted benzamide at position 3 and require a cyano substituent at position 8.
[19] EP 0 370 686 discloses a process for the preparation of quinolone carboxylic acid intermediates. The structure of the disclosed compounds differs from the structure of the compounds of formula (I) disclosed herein in that they do not comprise a 4-substituted benzamide at position 3 and require a fluoro substituent at position 6.
[20] U.S. Patent 4,621,088 discloses quinolone amino acid derivatives that have been reported to have antiallergic, central nervous system and cardiovascular activity. The structure of these compounds differs from that of the compounds of formula (I) disclosed herein in that they do not comprise 4-substituted benzamides at position 3.
[21] U.S. Patent 5,328,887 discloses an arrangement of compounds comprising many quinolone compounds that have been reported to be useful as fluorescent donor materials for use in heat transfer processes. The single particular 4-quinolone compound prepared and tested in this application does not contain a 4-substituted benzamide at position 3, has a phenyl substituent at position 2, has hydrogen at position 6, and position 1 is unsubstituted Is different from the compounds of formula (I) disclosed herein.
[22] U.S. Patent 4,855,291 discloses quinolone compounds reported to have antihypertensive activity. The structure of these compounds differs from that of the compounds of formula (I) disclosed herein in that they do not comprise 4-substituted benzamides at position 3.
[23] U.S. Patent 3,524,858 discloses quinolone compounds reported to have antimicrobial activity. The structure of these compounds differs from the structure of the compounds of formula (I) disclosed herein in that they do not comprise a 4-substituted benzamide at position 3 and require a methylenedioxy substituent at position 6,7.
[24] WO 98/23608 discloses quinolone compounds reported to have integrin antagonism. The structure of these compounds differs from that of the compounds of formula (I) disclosed herein in that they do not comprise 4-substituted benzamides at position 3.
[25] US Pat. No. 5,026,856 discloses isoindole compounds reported to have antimicrobial activity. The structure of these compounds differs from the structure of the compounds of formula (I) disclosed herein in that they do not comprise a 4-substituted benzamide at position 3 and require a halo, hydroxy or lower alkoxy substituent at position 6.
[26] U.S. Patent 5,563,141 discloses an array of compounds reported to inhibit cell adhesion. The class of compounds disclosed may include 3 aminocarbonyl-4-quinolones, but these compounds do not include 4-substituted benzamides at position 3. All final compounds specially prepared in this patent include the 4-pyridyl (piperazin-1-yl) ring system.
[27] WO 9932450 discloses compounds of the formulas useful for the treatment of herpesvirus infection.
[28]
[29] Liebigs Ann. Chem. 1987, 871-879, describes the synthesis of the following structures through the combination of aryl acid chlorides and β-hydrazidoalkenyl amides.
[30]
[31] EP 343560 discloses an antimicrobial agent having the structure
[32]
[33] Japanese Patent 02040379 discloses a compound useful as an antibacterial agent having the following structure.
[34]
[35] US Pat. No. 5,412,104 discloses the following structures useful as antiviral agents for DNA containing viruses such as herpes family virus.
[36]
[37] Summary of the Invention
[38] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.
[39]
[40] Wherein X is a) 0 or b) S;
[41] W is a) R ² , b) NR ⁷ R ⁸ , C) OR ⁹ or d) SO _i R ⁹ ;
[42] R ¹ is a) Cl, b) F, c) Br, d) CN or e) N0 ₂ ;
[43] R ² is a) (CH ₂ CH ₂ 0) _m R ¹⁰ ,
[44] b) het bound via a carbon atom,
[45] C) OC _2- which may be partially unsaturated and substituted by NR ⁷ R ⁸ , R ¹¹ , CN, SO _i R ⁹ , or further by het, OR ^1O , OC (═O) aryl or NR ⁷ R ⁸ C _1-7 alkyl optionally substituted by one or more substituents selected from the group consisting of ₄ alkyl, or
[46] d) optionally unsaturated by C _1-7 alkyl which may be partially unsaturated and optionally substituted by R ¹¹ , NR ⁷ R ⁸ , SO _i R ⁹ , or optionally R ¹¹ , NR ⁷ R ⁸ or SO _i R ⁹ C _3-8 cycloalkyl;
[47] R ³ is a) H, b) halo or c) C _1-4 alkyl optionally substituted by one to three halo;
[48] R ⁴ is a) H, b) aryl, c) het, d) S0 ₂ NHR ¹² , e) CONHR ¹² , f) NR ⁷ R ⁸ , g) NHCOR ¹² , h) NHS0 ₂ R ¹² , i) optionally- OC _2-7 alkyl substituted by OH, j) SC _2-7 alkyl optionally substituted by OH, or
[49] k) C _1-8 which may be partially unsaturated and optionally substituted by one or more substituents selected from the group consisting of N ₃ , OR ¹⁰ , NR ⁷ R ⁸ , halo, SO _i R ⁹ , OR ¹³ or R ¹¹ Alkyl;
[50] R ⁵ is a) H, b) halo, c) C≡CR ¹⁴ , d) NR ⁷ R ⁸ , e) S0 ₂ NHR ¹² , f) het or g) C _1-7 alkyl optionally substituted by OH; ;
[51] R ⁶ is a) H, b) halo, c) SC _1-7 alkyl,
[52] e) C _1-7 alkoxy optionally substituted by one or more halo or OH, or
[53] f) OC _1-7 alkyl which may be partially unsaturated and further substituted with halo, NR ¹⁰ R ¹⁰ , (CH ₂ ) _n OR ¹³ , R ¹¹ , or SO _i R ⁹ , NR ⁷ R ⁸ , or het C _1-7 alkyl optionally substituted by;
[54] R ⁷ and R ⁸ are independently a) H, b) aryl,
[55] c) C _1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from the group consisting of NR ¹⁰ R ¹⁰ , CONR ¹⁰ R ¹⁰ , R ¹¹ , SO _i R ⁹ , halo; or
[56] d) R ⁷ and R ⁸ together with the nitrogen bonded to them form a het;
[57] R ⁹ is a) aryl, b) het, c) C _3-8 cycloalkyl, or
[58] d) may be partially unsaturated, optionally one or more OR ¹⁰ , Oaryl, het, aryl, NR ¹⁰ R ¹⁰ , CN, SH, SO _i C _1-6 alkyl, SO _i aryl, halo or CONR ¹⁰ R ¹⁰ C _1-7 alkyl which may be substituted by;
[59] R ¹⁰ is a) H or b) C _1-7 alkyl optionally substituted by OH;
[60] R ¹¹ is a) OR ¹⁰ , b) Ohet, c) Oaryl, d) CO ₂ R ¹⁰ , e) het, f) aryl or g) CN;
[61] R ¹² is a) H, b) het, c) aryl, d) C _3-8 cycloalkyl or e) C _1-7 alkyl optionally substituted by NR ⁷ R ⁸ or R ¹¹ ;
[62] R ¹³ is a) (P = O) (OH) ₂ , b) (P = O) (C _1-7 alkoxy) ₂ , c) CO (CH ₂ ) _n CON (CH ₃ ) (CH ₂ ) _n SO ₃ ^- M ⁺ , d) amino acids, e) C (= 0) aryl, f) C (= 0) C _1-6 alkyl optionally substituted by NR ¹⁰ R ¹⁰ or g) CO (CH ₂ ) _n CO ₂ H;
[63] R ¹⁴ is a) het, b) (CH ₂ ) _n OR ¹³ or
[64] c) C _1-7 alkyl substituted by one or more substituents selected from R ¹¹ , or OC _1-7 alkyl further substituted with SO _i R ⁹ , NR ⁷ R ⁸ , or het;
[65] Aryl is a phenyl radical or ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic;
[66] het contains 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and is optionally 4- (4), 5- (5), 6 fused to a benzene ring or any bicyclic heterocycle group (6) or 7- (7) membered saturated or unsaturated heterocyclic rings;
[67] Wherein any aryl is halo, OH, CF _3, C _1-6 alkoxy, and additional one to three ^{SR 10, NR 10 R 10,} OR 10 or C _1- which may be substituted by a C0 ₂ R ¹⁰ Optionally substituted by one or more substituents selected from the group consisting of ₆ alkyl;
[68] Wherein any het may be substituted by halo, OH, CF ₃ , C _1-6 alkoxy, oxo, auxin, and further one to three SR ¹⁰ , NR ¹⁰ R ¹⁰ , OR ¹⁰ or C0 ₂ R ¹⁰ . Optionally substituted by one or more substituents selected from the group consisting of C _1-6 alkyl;
[69] i is 0, 1 or 2;
[70] m is 1, 2 or 3;
[71] n is 1, 2, 3, 4, 5 or 6;
[72] M is sodium, potassium or lithium;
[73] Provided that X is O,
[74] R ² is C _1-7 alkyl optionally substituted by R ¹⁵ ;
[75] R ³ is H, methyl or halo;
[76] R ⁴ is H, CONH (C _1-7 alkyl), NR ¹⁶ R ^17, or optionally OR ^10, CN, COOH, or is a C _1-7 alkyl substituted by NR ¹⁶ R ^17;
[77] R ⁵ is H, halo, SO ₂ NHR ¹⁰ , NR ¹⁶ R ¹⁷ , or C _1-7 alkyl optionally substituted by OR ¹⁰ ;
[78] R ⁶ is H, halo, C _1-7 alkoxy, or an optionally halo, OR ^10, CO ₂ R ¹⁰ or is a C _1-7 alkyl substituted by NR ¹⁶ R ^17;
[79] R ¹⁵ is NR ¹⁶ R ¹⁷ , OR ¹⁰ , CN or C0 ₂ R ¹⁰ ;
[80] R ¹⁶ and R ¹⁷ are independently H or C _1-7 alkyl; Or when NR ¹⁶ R ¹⁷ together with the nitrogen to which they are attached form a 5- or 6-membered ring such as pyrrolidine, piperidine, morpholine or piperazine, R ¹ is not Cl, Br, F or CN.
[81] In another aspect the invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
[82] A method of treating or preventing a herpesvirus infection comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of treatment of a herpesvirus infection,
[83] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the medical treatment or prevention of a herpesvirus infection,
[84] The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of herpesvirus infection in a mammal,
[85] Provided are methods of inhibiting viral DNA polymerase comprising contacting (in vitro or in vivo) an inhibitory effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[86] The present invention also provides novel intermediates and methods disclosed herein useful for the preparation of compounds of formula (I).
[1] The present invention provides 4-oxo-1,4-dihydro-3-quinolinecarboxamide derivatives. These compounds are useful as antiviral agents, especially as antiviral agents against the virus of herpes family.
[87] The following definitions were used unless otherwise stated. Halo indicates fluoro, chloro, bromo or iodo. Alkyl, alkoxy and the like represent both straight and branched chain groups, but each radical such as "propyl" represents only a straight chain radical and branched chain isomers such as "isopropyl" are specifically mentioned. When alkyl may be partially unsaturated, the alkyl chain may contain one or more (eg 1, 2, 3 or 4) double or triple bonds in the chain.
[88] Aryl refers to phenyl radicals, or ortho-fused bicyclic carbocyclic radicals in which at least one ring is aromatic. Aryl is a group consisting of halo, OH, CF ₃ , C _1-6 alkoxy, further C _1-6 alkyl which may be substituted by 1 to 3 SR ¹⁰ , NR ¹⁰ R ¹⁰ , OR ¹⁰ or CO ₂ R ¹⁰ Optionally substituted with one or more substituents selected from.
[89] Het contains 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and is 4- (4), 5- (5), 6- (optionally fused with a benzene ring or a bicyclic heterocycle group 6) or 7- (7) membered saturated or unsaturated heterocyclic ring. Het is halo, OH, CF ₃ , C _1-6 alkoxy, oxo, auxin, and C _1-, which may be further substituted by 1 to 3 SR ¹⁰ , NR ¹⁰ R ¹⁰ , OR ¹⁰ or C0 ₂ R ¹⁰ . Optionally substituted by one or more substituents selected from the group consisting of ₆ alkyl.
[90] “Amino acids” include natural amino acids of type D or L (eg, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val) as well as non-natural amino acids (e.g., phosphoserine, phosphoronine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hypuric acid, octahydroindole-2-carboxylic acid, Statins, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citrulline, -methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine And tert-butylglycine). The amino acids may be advantageously linked to the residues of the compound of formula (I) via the carboxy terminus, the amino terminus or via any other advantageous point of attachment, for example sulfur of cysteine. In particular amino acids may be advantageously linked to the residues of the compound of formula (I) via the carboxy terminus.
[91] Mammals refer to humans and animals.
[92] Those skilled in the art will appreciate that compounds of the present invention having chiral centers may exist as optically active and racemates and may be isolated. Some compounds may exhibit polymorphisms. The present invention includes any racemate, optically-active, polymorphic, tautomeric or stereoisomer, or mixtures thereof of the compounds of the present invention having the useful properties described herein (eg, recrystallization techniques By using the standard assays described herein or methods of preparing the optically active agent), by the resolution of the racemate by the synthesis, synthesis from the optically-active starting material, by chiral synthesis or by chromatographic separation using a chiral stationary phase It should be understood that methods for measuring antiviral activity using other similar assays known in the art are known in the art.
[93] The carbon atom content of various hydrocarbon containing moieties is indicated by a prefix indicating the minimum and maximum number of carbon atoms in the moiety, ie the prefix C _ij denotes residues of the integer "i" to the integer "j" carbon atoms. Thus, for example, C _1-7 alkyl represents alkyl of 1 to 7 carbon atoms.
[94] The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature. Abbreviations known to those skilled in the art can be used (for example phenyl is "Ph", methyl is "Me", ethyl is "Et", time is "h" and room temperature is "rt").
[95] The specific and preferred values described below for radicals, substituents, and ranges are for illustrative purposes only; It does not exclude other specific values for radicals and substituents or other values within defined ranges.
[96] Specifically alkyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, and the like; C _3-8 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; Alkoxy may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, 1-methylhexyloxy or heptyloxy ; het can be azetidinyl, 3,3-dihydroxy-1-azetinyl, pyrrolidino, piperidino, morpholino, thiomorpholino or heteroaryl; Heteroaryl is furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl (or its N-oxides) , Thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
[97] Particular R ¹ value is Cl.
[98] Particular R ¹ value is F.
[99] Particular R ¹ values are CN or NO ₂ .
[100] Particular R ² values are (CH ₂ CH ₂ O) _m H or (CH ₂ CH ₂ O) _m C _1-4 alkyl where m is 2 or 3.
[101] Particular R ² values are C _3-8 optionally substituted by R ¹¹ , NR ⁷ R ⁸ , SO _i R ⁹ , or optionally C _1-7 alkyl substituted by R ¹¹ , NR ⁷ R ⁸ or SO _i R ⁹ Cycloalkyl, wherein R ⁷ , R ⁸ , R ⁹ , R ¹¹ and i are as defined above.
[102] Particular R ² value is cyclopropyl.
[103] Particular R ² values are het bound via carbon atoms and as defined above.
[104] Particular R ² values are tetrahydro-2H-pyranyl, piperidinyl, 1-methyl-piperidinyl or 1,1-dioxo-tetrahydro-2H-thiopyran.
[105] Certain R ² values are partially unsaturated and optionally substituted by NR ² R ⁸ , R ¹¹ , SO _i R ⁹ , or OC _2-4 alkyl further substituted by het, OR ¹⁰ or OC (═O) aryl. C _2-7 alkyl, wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are the same as defined above.
[106] Particular R ² values are (Z or E) —CH═CHR ^1O or —CC≡CR ^1O where R ^1O is H or C _1-7 alkyl optionally substituted by OH.
[107] Particular R ² values are C _1-7 alkyl substituted by NR ⁷ R ⁸ , R ¹¹ , SO _i R ⁹ , or further OC _2-4 alkyl substituted by het, OR ¹⁰ or OC (═O) aryl. Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined above.
[108] Particular R ² values are further C _1-7 alkyl substituted by het, OH, OC _1-4 alkyl or OC _2-4 alkyl substituted by OC (═O) aryl.
[109] Particular R ² values are C _1-7 alkyl substituted with SO _i R ⁹ , wherein R ⁹ and i are as defined above.
[110] Particular R ² values are C _1-7 alkyl substituted by SO _i R ⁹ , wherein R ⁹ is C _1-4 alkyl optionally substituted by OH, or R ⁹ is phenyl optionally substituted by Cl, i Is 0, 1 or 2).
[111] Particular R ² value is methyl.
[112] Particular W value is NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined above.
[113] The specific W value is NR ⁷ R ⁸ where R ⁷ and R ⁸ together with the nitrogen to which they are bound form the same het as defined above.
[114] Particular W values are morpholine, piperidine, pyrrolidine, piperazine or 4-methyl-piperazine.
[115] Particular W value is NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently H or C _1-4 alkyl optionally substituted by OH.
[116] Particular W value is morpholine.
[117] Particular W values may be OR ⁹ or SO _i R ⁹ where R ⁹ is partially unsaturated and optionally substituted by OR ¹⁰ , Oaryl, het, aryl, NR ¹⁰ R ¹⁰ , CN, CONR ¹⁰ R ¹⁰ or halo. C _1-6 alkyl, wherein R ¹⁰ is H or C _1-4 alkyl.
[118] Particular R ³ value is H.
[119] Particular R ³ value is CF ₃ or halo.
[120] Particular R ⁴ values are aryl or het.
[121] Particular R ⁴ value is S0 ₂ NHR ¹² , CONHR ¹² , NHCOR ¹² or NHS0 ₂ R ¹² , wherein R ¹² is as defined above.
[122] Certain R ⁴ values are partially unsaturated and optionally C _2-8 alkyl substituted with OR ¹⁰ , NR ⁷ R ⁸ , halo, SO _i R ⁹ , OR ¹³ or R ¹¹ , wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹³ are the same as defined above).
[123] Particular R ⁴ values are (Z or E) —CH═CHC _1-4 alkyl, optionally substituted by OH.
[124] Particular R ⁴ values are -C≡CC _1-4 alkyl optionally substituted by OH or OR ¹³ , wherein R ¹³ is (P═O) (OH) ₂ , (P═O) (C _1-7 alkoxy) ₂ or CO (CH ₂ ) ₆ CON (CH ₃ ) (CH ₂ ) _n SO ₃ ^- M ⁺ .
[125] Particular R ⁴ values are C _1-8 alkyl substituted by OR ¹³ where R ¹³ is (P═O) (OH) ₂ , ( _P═O ) (C _1-7 alkoxy) ₂ or CO (CH ₂ ) _n CON (CH ₃ ) (CH ₂ ) ₆ SO ₃ ^- M ⁺ ).
[126] Particular R ⁴ value is C _1-8 alkyl substituted with SO _i R ⁹ , wherein R ⁹ is the same as defined above.
[127] Particular R ⁴ value is NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined above.
[128] Particular R ⁴ values are C _1-8 alkyl substituted by NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined above.
[129] Particular R ⁴ values are C _1-8 alkyl substituted by NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ together with the nitrogen to which they are attached form the same het as defined above.
[130] Particular R ⁴ values are determined by one or more substituents selected from C _1-8 alkyl substituted by NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently OH, the same aryl or CN as defined above Optionally substituted C _1-6 alkyl).
[131] Particular R ⁴ values are C _1-8 alkyl substituted by N ₃ .
[132] Particular R ⁴ values are C _1-8 alkyl substituted by the same het as defined above.
[133] Particular R ⁴ value is 4-morpholine methyl.
[134] Particular R ⁴ values are C _1-7 alkyl substituted with the same R ¹¹ as defined above.
[135] Particular R ⁵ values are H, or C _1-7 alkyl, optionally substituted by OH.
[136] Particular R ⁶ values are OC _1-7 alkyl, optionally substituted by one or more OH.
[137] Particular R ⁶ value is halo.
[138] Particular R ⁶ values are C≡CC _1-7 alkyl substituted by one or more OH, or C _2-7 alkoxy substituted by one or more OH.
[139] Particular R ⁶ values are H, or C _1-7 alkyl optionally substituted by halo, NR ¹⁰ R ¹⁰ , OH, CO ₂ R ¹⁰ or het, wherein R ¹⁰ and het are as defined above.
[140] Particular M values are sodium, potassium or lithium.
[141] The specific X value is S; W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are the same as defined above.
[142] The specific X value is O; R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined above and W is NR ⁷ R ⁸ , OR ⁹ , SO _i R ⁹ or R ² ; Where R ² is a) (CH ₂ CH ₂ 0) _n R ¹⁰ ,
[143] b) het bound via a carbon atom,
[144] C) C _1-7 alkyl partially unsaturated and optionally substituted by OH,
[145] d) C _3-8 cycloalkyl, or
[146] e) C optionally substituted by one or more substituents selected from Ohet, Oaryl, SO _i R ⁹ , or additionally OC _2-4 alkyl substituted by het, OR ¹⁰ or OC (═O) aryl. _1-7 alkyl; Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and n are the same as defined above.
[147] The specific X value is O or S; R ¹ is Cl; R ³ is H; R ⁵ is H; R ⁶ is H or F; R ⁴ is 4-morpholinylmethyl; R ² is
[148] a) SO _i R ^9, or added by OH, het, OC _1-4 alkyl or OC (= O) C _1-4 alkyl substituted by a C _1-4 alkoxy substituted by phenyl,
[149] b) (CH ₂ CH ₂ 0) ₂ C _1-4 alkyl,
[150] C) C _1-6 alkyl partially unsaturated and optionally substituted by OH,
[151] d) cyclopropyl, tetrahydro-2H-pyranyl, piperidinyl, morpholinyl, 1-methyl-piperidinyl or 1,1-dioxo-tetrahydro-2H-thiopyran;
[152] Wherein R ⁹ is phenyl optionally substituted by Cl, or R ⁹ is C _1-6 alkyl optionally substituted by OH.
[153] The specific X value is O or S; R ¹ is Cl; R ³ is H; R ⁵ is H; R ⁶ is H or F; R ⁴ is partially unsaturated and C _1-6 alkyl optionally substituted by OH or OR ¹³ ; Or R ⁴ is C _1-4 alkyl substituted by OR ¹³ ; W may be NR ¹⁰ R ¹⁰ , cyclopropyl, (CH ₂ CH ₂ 0) ₂ OR ¹⁰ , or partially unsaturated and optionally OH, morpholinyl, NR ¹⁰ R ¹⁰ , C (═O) OC _1-4 alkyl C _1-6 alkyl substituted by; Wherein R ¹⁰ is H or C _1-4 alkyl; R ¹³ is (P = O) (C _{1-7 alkoxy) 2, CO (CH 2)} n CON (CH 3) (CH 2) n SO 3 - M ⁺ or is (P = O) (OH) 2.
[154] The specific X value is O or S; R ¹ is Cl; R ³ is H; R ⁵ is H; R ⁶ is C≡CC _1-4 alkyl optionally substituted by OH; R ⁴ is H, or C _1-4 alkyl which is partially unsaturated and may optionally be substituted by OH; W is C _1-4 alkyl optionally substituted by OH.
[155] Alkyl is, when partially unsaturated, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl , 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl, 1-propynyl, 2 -Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexen-1-ynyl, 2-hexyl Or hexyl, 3-hexynyl, 4-hexynyl or 5-hexynyl.
[156] An example of the present invention is as follows.
[157] (1) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-isopropyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[158] (2) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[159] (3) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -8-methoxy-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[160] (4) N- (4-chlorobenzyl) -8- (2-hydroxyethoxy) -6- (3-hydroxypropyl) -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[161] (5) N- (4-chlorobenzyl) -8- [2-hydroxy-1- (hydroxymethyl) ethoxy] -6- (3-hydroxypropyl) -1-methyl-4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
[162] (6) N- (4-chlorobenzyl) -8-fluoro-6- (hydroxymethyl) -4-oxo-1- [3- (tetrahydro-2H-pyran-2-yloxy) propyl]- 1,4-dihydro-3-quinolinecarboxamide;
[163] (7) N- (4-chlorobenzyl) -6- [3-hydroxy-1-propenyl] -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
[164] (8) N- (4-chlorobenzyl) -8-fluoro-6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecar Boxamide;
[165] (9) N- (4-chlorobenzyl) -8-fluoro-6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[166] (10) N- (4-chlorobenzyl) -1- [2- (diethylamino) ethyl] -8-fluoro-6- (3-hydroxy-1-propynyl) -4-oxo-1, 4-dihydro-3-quinolinecarboxamide;
[167] (11) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-propyl-1,4-dihydro-3-quinolinecarboxamide;
[168] (12) N- (4-chlorobenzyl) -1- [2- (diethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[169] (13) N- (4-chlorobenzyl) -1- [2- (dimethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide hydrochloride;
[170] (14) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-piperidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
[171] (15) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [3- (1-piperidinyl) propyl] -1,4-di Hydro-3-quinolinecarboxamide;
[172] (16) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (1-methyl-2-pyrrolidinyl) ethyl] -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
[173] (17) N- (4-chlorobenzyl) -1- [2- (diisopropylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro 3-quinolinecarboxamide;
[174] (18) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-pyrrolidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
[175] (19) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
[176] (20) N- (4-chlorobenzyl) -1- [3- (dimethylamino) propyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
[177] (21) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-vinyl-1,4-dihydro-3-quinolinecarboxamide;
[178] (22) N- (4-chlorobenzyl) -6-[(E) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[179] (23) N- (4-chlorobenzyl) -6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[180] (24) N- (4-chlorobenzyl) -6- [ethyl (2-hydroxyethyl) amino] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[181] (25) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[182] (26) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[183] (27) N- (4-chlorobenzyl) -1-cyclopropyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[184] (28) tert-butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinoli Nil] acetate;
[185] (29) 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinolinyl] acetic acid ;
[186] (30) N- (4-chlorobenzyl) -1- (2-hydroxyethyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[187] (31) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[188] (32) di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl Phosphate;
[189] (33) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl dihydrogen phosphate;
[190] (34) di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl) Propyl phosphate;
[191] (35) sodium 2-[{8- [3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinoli Nil) propoxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate;
[192] (36) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinoli Nil) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
[193] (37) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinoli Nil) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
[194] (38) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-qui Nolinyl) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
[195] (39) 1- (tert-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[196] (40) sodium 2-[{8- [3- (1- (tert-butyl) -3-{[(4-chlorobenzyl) amino] -carbonyl} -4-oxo-1,4-dihydro- 6-quinolinyl) propoxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate;
[197] (41) sodium 2-[(8-{[3- (1- (tert-butyl) -3-{[(4-chlorobenzyl) amino] -carbonyl} -4-oxo-1,4-dihydro -6-quinolinyl) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
[198] (42) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy) -ethyl] -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
[199] (43) N- (4-cyanobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[200] (44) 6-{[bis (2-hydroxyethyl) amino] methyl} -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
[201] (45) N- (4-chlorobenzyl) -6-{[(2-hydroxyethyl) (methyl) amino] methyl} -1-methyl-4-oxo-1,4-dihydro-3-quinolinecar Boxamide;
[202] (46) N- (4-chlorobenzyl) -1-methyl-6- (1,4-oxazepan-4-ylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[203] (47) N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (1,4-thiazepan-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide;
[204] (48) N- (4-chlorobenzyl) -1-methyl-6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) -4-oxo-1,4-dihydro 3-quinolinecarboxamide;
[205] (49) N- (4-chlorobenzyl) -6- (2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl) -1-methyl-4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[206] (50) 6-((benzyl (2-hydroxyethyl) amino) methyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
[207] (51) 6- (azidomethyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[208] (52) N- (4-chlorobenzyl) -6-[(4,4-difluoro-1-piperidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[209] (53) N- (4-chlorobenzyl) -6-{[4-fluoro-3,6-dihydro-1 (2H) -pyridinyl] methyl} -1-methyl-4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
[210] (54) N- (4-chlorobenzyl) -1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinolinecarboxamide;
[211] (55) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[212] (56) N- (4-chlorobenzyl) -1- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
[213] (57) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[214] (58) N- (4-chlorobenzyl) -1- [2- (2-ethoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[215] (59) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (2-propynyl) -1,4-dihydro-3-quinolinecarboxamide;
[216] (60) N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[217] (61) N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[218] (62) N- (4-chlorobenzyl) -1- (4-hydroxy-2-butynyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[219] (63) N- (4-chlorobenzyl) -6-{[(2-hydroxy-2-phenylethyl) (methyl) amino] methyl} -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[220] (64) 1- {2- [bis (2-hydroxyethyl) amino] ethyl} -N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[221] (65) N- (4-chlorobenzyl) -1- [3- (methylsulfinyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[222] (66) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[223] (67) N- (4-chlorobenzyl) -1- [3- (methylsulfonyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[224] (68) N- (4-chlorobenzyl) -1- [2- (ethylsulfinyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[225] (69) N- (4-chlorobenzyl) -1- [2- (ethylsulfonyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[226] (70) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfinyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[227] (71) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfonyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[228] (72) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- [2- (phenylsulfanyl) ethyl] -1,4-dihydro-3-quinoline Carboxamides;
[229] (73) N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[230] (74) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) -amino] methyl} -1-methyl-4-oxo- 1,4-dihydro-3-quinolinecarboxamide;
[231] (75) N- (4-chlorobenzyl) -6-[(3-hydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[232] (76) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
[233] (77) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl]-(methyl) amino] methyl} -1-methyl 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[234] (78) N- (4-chlorobenzyl) -6-[(3,3-dihydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[235] (79) N- (4-chlorobenzyl) -1-[(methylsulfinyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[236] (80) N- (4-chlorobenzyl) -1-[(methylsulfonyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[237] (81) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfinyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
[238] (82) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfonyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
[239] (83) N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
[240] (84) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[241] (85) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-6-[(4-oxo-1-piperidinyl) methyl] -1 , 4-dihydro-3-quinolinecarboxamide;
[242] (86) N- (4-chlorobenzyl) -6-{[(cyanomethyl) (methyl) amino] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
[243] (87) N- (4-chlorobenzyl) -6-{[(3R) -3-hydroxypyrrolidinyl] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo -1,4-dihydro-3-quinolinecarboxamide;
[244] (88) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6-[(methylsulfanyl) methyl] -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[245] (89) N- (4-chlorobenzyl) -6-{[[(1R, 2S) -2-hydroxy-1-methyl-2-phenylethyl] (methyl) -amino] methyl} -1- [2 -(2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[246] (90) N- (4-chlorobenzyl) -6-{[(2-hydroxy-2-phenylethyl) (methyl) amino] methyl} -1- [2- (2-methoxyethoxy) ethyl] 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[247] (91) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) amino] -methyl} -1- [2- (2- Methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[248] (92) 1- {2- [2- (tert-butoxy) ethoxy] ethyl} -N- (4-chlorobenzyl) -6- (4-morpholinyl-methyl) -4-oxo-1, 4-dihydro-3-quinolinecarboxamide;
[249] (93) 1- {2- [2- (tert-butoxy) ethoxy] ethyl} -N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl ) Ethyl] (methyl) amino] methyl} -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[250] (94) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide;
[251] (95) N- (4-chlorobenzyl) -1-methyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbothioamide;
[252] (96) N- (4-chlorobenzyl) -8- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[253] (97) N- (4-chlorobenzyl) -8- (4-hydroxy-1-butynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[254] (98) N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (tetrahydro-2H-pyran-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide;
[255] (99) N- (4-chlorobenzyl) -6-{[3- (hydroxyimino) -1-azetidinyl] methyl} -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[256] (100) N- (4-chlorobenzyl) -1- {2- [2- (4-morpholinyl) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1, 4-dihydro-3-quinolinecarboxamide;
[257] (101) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[258] (102) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfinyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[259] (103) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfonyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[260] (104) N- (4-chlorobenzyl) -1-[(4-chlorophenoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
[261] (105) N- (4-chlorobenzyl) -1-[(2-methoxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[262] (106) 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] methoxy} Ethyl benzoate;
[263] (107) N- (4-chlorobenzyl) -1-[(2-hydroxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[264] (108) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinoline Carboxamides;
[265] (109) N- (4-chlorobenzyl) -1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[266] (110) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
[267] (111) N- (4-chlorobenzyl) -1- (1,1-dioxohexahydrothiopyran-4-yl) -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[268] (112) N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
[269] (113) N- (4-chlorobenzyl) -1- (4-methyl-1-piperazinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
[270] (114) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
[271] (115) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-pyrrolidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
[272] (116) N- (4-chlorobenzyl) -1-[(2R) -2- (methoxymethyl) pyrrolidinyl] -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[273] (117) N- (4-chlorobenzyl) -1- (dimethylamino) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[274] (118) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[275] (119) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[276] (120) N- (4-chlorobenzyl) -1- (dimethylamino) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
[277] (121) N- (4-chlorobenzyl) -1- (dimethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[278] (122) 1- (allyloxy) -N- (4-chlorobenzyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[279] (123) N- (4-chlorobenzyl) -1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
[280] (124) N- (4-bromobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[281] (125) N- (4-fluorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
[282] (125) N- (4-chlorobenzyl) -1-{[2- (4-morpholinyl) ethoxy] methyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
[283] (126) N- (4-chlorobenzyl) -1-{[2- (dimethylamino) ethoxy] methyl} -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
[284] (127) N- (4-chlorobenzyl) -1-{[2- (4-methyl-1-piperazinyl) ethoxy] methyl} -6- (4-morpholinylmethyl) -4-oxo- 1,4-dihydro-3-quinolinecarboxamide;
[285] (128) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-{[2- (1-piperidinyl) ethoxy] methyl} -1,4- Dihydro-3-quinolinecarboxamide;
[286] (129) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-{[2- (1-pyrrolidinyl) ethoxy] methyl} -1,4- A compound which is dihydro-3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof.
[287] Schemes A-AA below describe the preparation of the compounds of the present invention. All starting materials are prepared by the procedures described in these schemes or by similar procedures well known to those skilled in the art of organic chemistry. The final compounds of the present invention are all prepared by the procedures described in these schemes or by similar procedures well known to those skilled in the art of organic chemistry. The variable groups used in the schemes are all as defined below or in the claims.
[288] The ethyl ester of formula A-1, ie, ethyl 4-hydroxy-6-iodo-3-quinolinecarboxylate, is first heated to about 150 ° C. with diethyl ethoxymethylenemalonate and then to reflux diphenyl ether It manufactures by heating in water. Compound A-1 is aminated by 4-substituted benzylamine at about 160 ° C. to give amide A-2. Compound A-2 is palladium and copper mediated coupling of propargyl alcohol to give compound A-3. Pyridone nitrogen is alkylated with potassium carbonate and optionally substituted alkyl halides to afford compounds of formula A-4. Alternatively, partially hydrogenation of compound A-3 yields an alkenyl derivative, ie compound A-5 (E or Z). Similarly, the 4-quinolone structure of formula A-4 is partially hydrogenated to give alkenyl derivatives (E or Z) of formula A-6. Alkylation of Compound A-5 with optionally substituted alkyl halides and potassium carbonate also affords compounds of Formula A-6.
[289]
[290] Compounds of formula B-1, namely 2-fluoro-5-iodobenzoic acid, are prepared by carbonation of anions of 4-fluoroiodobenzene, prepared by deprotonation of 4-fluoroiodobenzene with LDA. After reacting carbonyldiimidazole with acid B-1, the resulting acyl imidazolide is treated with ethyl trimethylsilyl malonate and then decarboxylated to obtain β-ketoester B-2. The ketoesters are converted to quinolinone B-3 by treatment sequentially with triethyl orthoformate, amine and potassium tert-butoxide. The esters are treated with 4-chlorobenzylamine to effect amination to afford the compound of formula B-4. Propargyl alcohol is coupled using palladium and a copper catalyst to give a compound of formula B-5. The triple bond is hydrogenated using hydrogen gas and a platinum catalyst to obtain hydroxypropyl derivative B-6.
[291]
[292] Palladium catalyzed carbonylation of 6-iodo-4-hydroxyquinoline-3-carboxamide A-2 to give the corresponding ester C-1, followed by reduction with LAH yields alcohol C-2. Pyridone nitrogen is alkylated with alkyl bromide, iodide or tosylate (X is I, Br, Ts and R ² is as defined above) in the presence of an alkali metal carbonate to give a compound of formula C-3. Compound C-3 is treated with methanesulfonyl chloride and then substituted with amine HNR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined above, to give a compound of formula C-4.
[293]
[294] The compound of formula (D-1) is phosphitylated with di-tert-butyl diethyl phosphoramidite to obtain an intermediate phosphite, which is oxidized in place with m-chloroperbenzoic acid to di-tert- Obtain butyl phosphate. Phosphate is treated with trifluoroacetic acid to cleave the tert-butyl group to obtain phosphoric acid of formula D-3.
[295]
[296] The alcohol of formula (D-1) was converted to sulfeptanic triethylammonium salt, ie triethylammonium 2-[(7-carboxyheptanoyl) (methyl) amino] -1- using diisopropylcarbodiimide and 4-dimethylaminopyridine. Coupling with ethanesulfonate yields the corresponding ester. Triethylammonium salt is exchanged with sodium ions to give sodium salt E-1.
[297]
[298] 4-iodoaniline F-0 is reductively alkylated with [(1-ethoxycyclopropyl) oxy] trimethylsilane and sodium cyanoborohydride to afford N-cyclopropyl aniline F-1. Treatment in pyridine with diethyl ethoxymethylenemalonate yields enamine F-2, which is cyclized with polyphosphoric acid to give quinoline F-3. The ester is converted to amide F-4 by treatment with p-chlorobenzylamine at elevated temperature. Iodide is coupled to palladium catalyzed by propargyl alcohol to give compound F-5. Reduction with platinum and hydrogen gas affords saturated propyl alcohol F-6.
[299]
[300] 4-nitrobenzyl bromide is treated with morpholine and potassium carbonate in acetone to give 4- (4-nitrobenzyl) morpholine G-1. Reduction of the nitro group with platinum and hydrogen gas affords aniline G-2 which is then treated with [(1-ethoxycyclopropyl) -oxy] trimethylsilane and sodium cyanoborohydride to give N-cyclopropyl aniline G-3 . Reaction with diethyl ethoxymethylenemalonate in pyridine affords enamine G-4, which is then cyclized with polyphosphoric acid to give quinoline G-5. The ester is converted to amide G-6 by treatment with p-chlorobenzylamine at elevated temperature.
[301]
[302] N- (4-chlorobenzyl) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide is alkylated with potassium carbonate and tert-butylbromoacetate to give compound H-1 . Palladium-catalyzed coupling of propargyl alcohol and iodide affords compound H-2. Reaction with platinum and hydrogen gas gives saturated propyl alcohol H-3. Treatment with trifluoroacetic acid gives the free acid H-4. Alternatively compound H-2 is treated with trifluoroacetic acid to give compound H-5.
[303]
[304] 1-fluoro-4-nitrobenzene I-1 is converted to 2- (4-nitroanilino-N-ethyl) -1-ethanol I-2 by heating with N-ethylethanolamine in ethanol. Compound I-2 is treated with acetyl chloride to convert to the corresponding acetate I-3. The nitro group is reduced with palladium on carbon and hydrogen gas to give the free amine. The resulting aniline is treated with diethyl ethoxymethylenemalonate to give compound I-4. The resulting enamine is heated in diphenyl ether to cyclize to yield quinoline I-5. Compound I-5 is treated with iodoalkyl and potassium carbonate in pyridone nitrogen to N-alkylate to yield compound I-6. The diester is amine-degraded with 4-chlorobenzylamine to give compound I-7.
[305]
[306] 2-fluoro-6-iodoaniline is condensed with diethyl ethoxymethylenemalonate and then heated in diphenyl ether to afford 4-hydroxyquinoline ethyl ester J-1. Amination of compound J-1 with 4-chlorobenzylamine affords the corresponding amide J-2. Compound J-2 is heated in the presence of an alkoxide to give compound J-3. The resulting quinoline is catalytically coupled with propargyl alcohol to obtain alkyne J-4. The pyridone nitrogen of J-4 is then N-alkylated with alkyl halide and potassium carbonate to afford 4-quinolones of formula J-5. Compound J-5 is hydrogenated to give hydroxypropyl derivative of formula J-6.
[307]
[308] Palladium catalyzed carbonylation of 6-iodo-8-fluoro-4-hydroxyquinoline-3-carboxamide J-2 to give the corresponding ester K-1, which is then reduced to LAH to alcohol K-2 Get Pyridone nitrogen is alkylated with alkyl halides and potassium carbonate to give compounds of formula K-3.
[309]
[310] 6-iodo-8-fluoro-4-hydroxyquinoline-3-carboxamide J-2 is palladium catalyzed coupling with propargyl alcohol to obtain alkyne L-1. The pyridone nitrogen of L-1 is then N-alkylated with alkyl halide and potassium carbonate to afford 4-quinolones of formula L-2. Compound L-2 is then semi-hydrogenated to give the hydroxyalkenyl derivative of formula L-3.
[311]
[312] Compound C-2 is treated with methanesulfonyl chloride and then reacted with morpholine to give compound M-1. Pyridone nitrogen is alkylated with alkyl bromide, iodide or tosylate (X is I, Br, Ts and R is alkyl) in the presence of an alkali metal carbonate, or alternatively under the Mitsunobu conditions Alkylation with alkyl alcohols yields compounds of formula M-2.
[313]
[314] Compound C-3 is treated with methanesulfonyl chloride to yield benzyl chloride N-1. Compound N-1 may be treated with the corresponding primary or secondary amines to afford compounds of formula C-4, or the chloride atoms may be substituted with other nucleophiles (eg, azides).
[315]
[316] Compound M-1 is treated with a thiol-containing alkyl halide in the presence of an inorganic base, or alternatively with a corresponding thiol-containing alkyl alcohol under Mitsunobu conditions, wherein R ⁹ is as defined above. Same as the above). The sulfide of formula O-1 is oxidized with m-chloroperoxybenzoic acid in the presence of p-toluenesulfonic acid to give the compound of formula O-2.
[317]
[318] Compound A-2 can be reacted with alkyl bromide, iodide or tosylate (X is Br, I, Ts and R is alkyl) in the presence of an alkali metal carbonate to afford a compound of formula P-1. The resulting 6-iodo-4-quinolone is catalyzed with PdCl ₂ (PPh ₃ ) ₂ and coupled with trialkyl alkenyl stanans (eg tributyl vinyl stanan) to give a compound of formula P-2.
[319]
[320] Alkyl chloride N-1 is treated with the sodium salt of alkyl thiol to give the sulfide of formula Q-1, wherein R ² and R ⁹ are as defined above.
[321]
[322] 3-thioamide substituted compounds are prepared by reacting compound A-2 (see Scheme A) with PCl ₅ to afford chloroimidate R-1. Chloroimidate R-1 is then treated with H ₂ S to give thioamide R-2, which is alkylated under Mitsunobu conditions to give compound R-3. Subsequently, analogs chemically similar to the carboxamide derivatives described in Schemes A through E, N, P or Q can be used to transform Compound R-3 to the desired analog.
[323]
[324] Quinolinecarboximidoyl chloride S-1 by treating N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide (Scheme A-2, R = Cl) with phosphorus pentachloride To form. Thereafter, treatment with hydrogen sulfide forms thioamide S-2. Alkylation under Mitsunobu conditions affords Compound S-3, where R is alkyl, and coupling with propargyl alcohol using a palladium catalyst to yield Compound S-4.
[325]
[326] Palladium-catalyzed carbomethylation of N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarbothioamide S-2 affords quinoline 6-methyl ester T-1. Reduction with alcohol followed by mesylation and substitution with morpholine yields 6-morpholinylmethyl quinoline T-3. Methylated under Mitsunobu conditions to yield N- (4-chlorobenzyl) -1-methyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbothioamide T- Gets 4
[327]
[328] 2-iodoaniline is treated with diethyl ethoxyethylenemalonate at 130 ° C. The resulting enamine is then dissolved in Ph ₂ O and heated to 250 ° C. to give ethyl quinolinecarboxylate U-1. Condensation with pure 4-chlorobenzylamine at 180 ° C. yielded 4-chlorobenzylamide U-2, which was methylated with iodomethane to give N- (4-chlorobenzyl) -8-iodo-1-methyl-4- Obtain oxo-1,4-dihydro-3-quinolinecarboxamide U-3. Palladium catalyst coupling with acetylene or alkenes yields a compound of formula U-4.
[329]
[330] 4-nitrobenzylbromide is treated with triphenylphosphine to form phosphonium salt V-1. Deprotonation to form a Wittich reagent and condensation with tetrahydropyran-4-one to give nitrobenzylidene V-2. After hydrogenation with saturated amine and condensation with diethyl ethoxymethylenemalonate, the resulting enamine is thermally cyclized to give quinolinecarboxylic ester V-3. The resulting ester is condensed with 4-chlorobenzylamine and methylated to give compound V-5.
[331]
[332] Aniline of formula G-2 is reductively alkylated with substituted cyclohexanone (W-1; Z = O, NMe, NBoc) to obtain N-alkylated aniline (W-2; Z = O, NMe, NBoc). Reaction with diethyl ethoxymethylenemalonate to give enamine (W-3; Z = O, NMe, NBoc), which is cyclized with polyphosphoric acid to give quinoline (W-4; Z = O, NMe, NH) Get The ester is treated with 4-chlorobenzylamine at elevated temperature to give the amide (W-5; Z = O, NMe, NH). Similarly, aniline of formula G-2 is reductively alkylated with tetrahydrothiopyran-4-one (W-1; Z = S) to obtain N-alkylated aniline (W-2; Z = S). Reaction with diethyl ethoxymethylenemalonate yields enamine (W-3; Z = S). oxidation with m-chloroperoxybenzoic acid to give sulfone (W-2; Z = SO ₂ ), which was reacted with diethyl ethoxymethylenemalonate to obtain enamine (W-3; Z = SO ₂ ), Cyclization with polyphosphoric acid affords quinoline (W-4; Z = SO ₂ ). The ester is converted to amide (W-5; Z = SO ₂ ) by treatment with 4-chlorobenzylamine at elevated temperature.
[333]
[334] Reductive amination of 3-bromo-4-fluorobenzaldehyde with morpholine and sodium triacetoxyborohydride yields aryl bromide X-1. Halogen-lithium exchange followed by acetylation with N-methoxy-N-methylacetamide yields methyl ketone X-2. The resulting ketone is converted to β-keto ester X-3 by reaction with diethyl carbonate under basic conditions. β-keto ester X-3 is refluxed in triethylorthoformate and acetic anhydride to give the intermediate enol ether and then reacted with the selected hydrazide. The resulting enamine X-4 is heated with sodium hydride in THF to cyclize to give the corresponding quinolone-3-ester X-5. The ester is pyrolyzed directly at 190 ° C. with 4-substituted benzylamine, wherein X is Cl, Br, F or CN and R ⁷ and R ⁸ are as defined above to give the amide of formula X-6.
[335]
[336] Butyl acetate silyl ketene acetal is reacted with 2-chloro-5-iodobenzoylchloride to obtain β-ketoester Y-1. Compound Y-1 is refluxed in triethylorthoformate and acetic anhydride to afford the intermediate enol ether and then reacted with the selected hydrazide. The resulting enamine Y-2, wherein R ⁷ and R ⁸ are as defined above, is heated with sodium hydride to cyclize to yield the corresponding quinolone-3-ester Y-3. The ester is pyrolyzed directly with 4-chlorobenzylamine to give the amide of formula Y-4. Compound Y-4 is catalytically coupled with propargyl alcohol to obtain a compound of formula Y-5. Alkyne is then catalytically hydrogenated to give hydroxypropyl derivatives of the formula Y-6.
[337]
[338] Alternatively, when the N1-substituent is amino, N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide A-2 is replaced by O- (methylsulfonyl) hydroxylamine Treatment yields 1-amino-quinolone Z-1. Compound Z-1 can be modified in a similar manner as described for intermediate Y-4 above.
[339]
[340] Ethyl 3- (2-fluorophenyl) -3-oxopropanoate AA-1 was refluxed in triethylorthoformate and acetic anhydride to obtain intermediate enol ethers, followed by reaction with selected N-alkoxyamines. The resulting enamine AA-2 was cyclized by heating with sodium hydride to give the corresponding quinolone-3-ester AA-3. The ester was directly pyrolyzed with 4-chlorobenzylamine to give an amide of formula AA-4.
[341]
[342] It may be appropriate to administer the compound as a salt if the compound is basic or acidic enough to form a stable non-toxic acid or base salt. Examples of pharmaceutically acceptable salts include acids that form physiologically acceptable anions such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, etogle Organic acid addition salts formed with rutarate and glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate and carbonate salts.
[343] Pharmaceutically acceptable salts can be obtained using standard methods known in the art, for example by reacting sufficient basic compounds such as amines with a suitable acid to obtain a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can also be prepared.
[344] The compounds of the present invention are advantageously administered in pharmaceutical compositions comprising the compound with a suitable excipient, which compositions are useful for the treatment of viral infections. Pharmaceutical compositions comprising compounds suitable for antiviral preparations are prepared by methods known in the art and include excipients known in the art. A generally accepted overview of these methods and components is described in Remington's Pharmaceutical Sciences, E.W. Martin, Mark Publ. Co., 15th Ed., 1975. The compounds and compositions of the present invention may be administered parenterally (eg, by intravenous, intraperitoneal or intramuscular injection), topically, orally, depending on whether the formulation is used to treat internal or external viral infections. Or rectally.
[345] For therapeutic oral administration, the active compounds can be mixed with one or more excipients and used in the form of tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentages of the compositions and formulations can of course vary, advantageously from about 2 to about 60 weight percent of the unit dosage form. The amount of active compound included in such therapeutically useful compositions is such that an effective dosage level will be obtained.
[346] Tablets, troches, pills, capsules and the like may also be used as binders such as gum tragacanth, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; And sweetening agents such as sucrose, fructose, lactose or aspartame, or flavoring agents such as peppermint, gingko oil or cherry flavoring agents. When the unit dosage form is a capsule, in addition to the above types of substances, it may include a liquid carrier such as cooking oil or polyethylene glycol. Various other materials may be present as coatings or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar, and the like. Syrups or elixirs may include active compounds, sucrose or fructose as sweeteners, methyl and propylparabens as preservatives, dyes and flavoring agents such as cherry or orange flavors. Of course, all materials used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the active compounds may be incorporated into sustained release preparations and devices.
[347] The compounds or compositions can also be administered by intravenous or intraperitoneal intravenous or injection. Solutions of the active compounds or salts thereof can be prepared in water, optionally mixed with non-toxic surfactants. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
[348] Pharmaceutical dosage forms suitable for injection or intravenous can include sterile aqueous solutions or dispersions or sterile powders, optionally comprising an active ingredient encapsulated in liposomes, prepared as a sterile injectable or intravenous solution or dispersion. In all cases the ultimate dosage form should be sterile liquid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be, for example, water, ethanol, polyols (e.g. glycerol, propylene glycol, liquid polyethylene glycols, etc.), edible oils. , Solvent or liquid dispersion media comprising non-toxic glyceryl esters and suitable mixtures thereof. Suitable liquidity can be maintained, for example, by the formation of liposomes, the maintenance of the required particle size in the case of dispersions, or the use of surfactants. Various antibacterial and antifungal agents can be used to prevent the action of microorganisms, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Absorption delaying agents such as aluminum monostearate and gelatin may be used to prolong the absorption of the injectable composition.
[349] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount with many of the other ingredients in an appropriate solvent and, if necessary, by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization techniques, whereby a powder of the active ingredient and any desired additional ingredients previously present in the sterile-filter solution are obtained.
[350] The compounds can be used in pure form, ie as a liquid, for topical administration. However, it is generally desirable to apply it to the skin in a composition or formulation with a dermatologically acceptable carrier, which can be either solid or liquid.
[351] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, wherein the compounds may be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Additives such as flavorings and additional antimicrobial agents may be added to optimize the properties for a given use. The resulting liquid composition may be applied to absorbent pads used for impregnate bandages and other bandages, or may be applied using a pump-type or aerosol sprayer. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified minerals may also be used with the liquid carrier to form dispersible pastes, gels, ointments, soaps and the like for direct application to the user's skin. Can be.
[352] Examples of useful skin compositions that can be used to deliver the compound of formula I to the skin are known in the art; See, for example, US Pat. No. 4,608,392 to Jacquet et al., US Pat. No. 4,992,478 to Geria, US Pat. No. 4,559,157 to Smith et al. And US Pat. No. 4,820,508 to Wortzman.
[353] Useful dosages of the compounds of formula (I) can be determined by comparing their in vitro and in vivo activity in an animal model. Methods of externalizing effective amounts in mice and other animals to humans are known in the art (see, eg, US Pat. No. 4,938,949).
[354] The compound is advantageously administered in unit dosage form comprising, for example, 5 to 1000 mg, advantageously 10 to 750 mg, most advantageously 50 to 500 mg of active ingredient per unit dosage form. The desired dose may advantageously be presented as a single dose or in divided doses administered at appropriate intervals, eg, twice, three times, four times or more per day. The subunit-dose itself may be, for example, many dosage forms loosely separated in space; For example, it can be further dispensed with a large amount of inhalation from the insufflator or many drops instilled.
[355] For internal infection the composition can be administered orally or parenterally at a dosage level calculated as free base of about 0.1 to 300 mg / kg (mammalian body weight), preferably 0.1 to 30 mg / kg, 1 per unit dose. It can be used in humans in unit dosage forms administered once to four times daily in an amount of from 1000 mg.
[356] For parenteral administration or when administered as eye drops for eye infection, the compound is provided in an aqueous solution at a concentration of about 0.1 to about 10%, more preferably about 0.1 to about 7%. The solution may contain other ingredients such as emulsifiers, antioxidants or buffers.
[357] Generally the concentration of compound (s) of formula (I) in a liquid composition, such as lotion, will be about 0.1 to 25% by weight, preferably about 0.5 to 10% by weight. The concentration in the semisolid or solid composition, such as gel or powder, will be about 0.1 to 5% by weight, preferably about 0.5 to 2.5% by weight.
[358] The exact dosing regimen of the compounds and compositions disclosed herein will vary depending on the needs of each individual to be treated, the type of treatment, and of course the judgment of the attending physician.
[359] Antiviral activity of the compounds of the invention can be determined using pharmacological models known in the art, or using Test A described below.
[360] Compounds of formula (I) and their pharmaceutically acceptable salts are useful as antiviral agents. Thus, these compounds are useful for treating viral infections in animals, including humans. These compounds generally have activity against herpesviruses and are particularly useful against varicella zoster virus, Epstein-Barr virus, herpes simplex virus and human herpesvirus type 8 (HHV-8) and cytomegalovirus (CMV). .
[361] While many of the compounds of the present invention show activity against CMV polymerases, these compounds may be active against cytomegalovirus with these or other mechanisms of action. Thus, the following description of the activity of these compounds on CMV polymerases does not mean to limit the invention to specific mechanisms of action.
[362] Exam A
[363] HCMV polymerase assays are described in several references, for example, ND Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992), incorporated herein by reference; [K. Takeuchi, Laboratory Practice, September issue (1992); It is performed using a scintillation proximity assay (SPA) as described in US Pat. No. 4,568,649 (1986). The reaction is carried out in 96-well plates. The assay is performed in 100 μl volume using 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl ₂ , 0.36 mg / ml BSA and 90 nM ³ H-dTTP. The assay proceeds with or without CHAPS (3-[(3-colamidopropyl) -dimethylammonio] -1-propane-sulfonate) at a final concentration of 2 mM. HCMV polymerase is diluted with enzyme dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 μg / ml BSA and 0.01% sodium azide. HCMV polymerase, expressed in recombinant baculovirus infected SF-9 cells and purified according to literature procedures, is added at 10% (or 10 μl) of the final reaction volume (ie 100 μl). Dilute the compound in 50% DMSO and add 10 μl to each well. Control wells contain the same concentration of DMSO. Unless otherwise indicated, the reaction is initiated by adding 6 nM biotinylated poly (dA) -oligo (dT) template / primer to the reaction mixture comprising the enzyme, substrate and compound of interest. Plates are incubated in a 25 ° C. or 37 ° C. H ₂ O bath and terminated by addition of 40 μl / reaction of 0.5 M EDTA (pH 8) per well. The reaction ends in a time-frame in which the substrate addition is linear, which depends on the enzyme and conditions used, ie 30 minutes for HCMV polymerase. 10 μl of streptavidin-SPA beads (20 mg / ml in PBS / 10% glycerol) are added after the reaction is complete. Plates are incubated at 37 ° C. for 10 minutes and then equilibrated to room temperature and counted on Packard Topcount. Linear regression is performed and IC ₅₀ is calculated using computer software.
[364] Strain analysis of the HCMV polymerase assay is performed as described above except for the following changes. Compounds are diluted in 100% DMSO and finally diluted with assay buffer. In this assay, the compound is diluted in 50% DMSO. 4.5 mM dithioteritol (DTT) is added to the polymerase buffer. In addition, different lots of CMV polymerase are used, and being more active appears to cause a faster polymerase reaction. The test results of representative compounds of formula (I) in this assay are shown in Table 1 below.
[365]
[366]
[367]
[368]
[369] <Description of Preferred Embodiments>
[370] Preparation method 1
[371] N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide
[372]
[373] A mixture of 11.85 g of 2-fluoro-4-iodoaniline and 10.81 g of diethylethoxymethylene malonate was heated to 130 ° C. in a flask equipped with a Dean-Stark trap to collect ethanol. The mixture was then cooled to 75 ° C. and diluted with hexanes. The resulting solids were collected and dried. The solid was then dissolved in 60 ml of diphenyl ether and heated to 250 ° C. for 3 hours in a flask equipped with a Dean-Stark trap to collect ethanol. The solution was cooled to room temperature and the resulting solid was collected and dried to give 11.73 g of ethyl 8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylate. This material (0.55 g) and 4- 3 ml of chlorobenzylamine were heated at 180 ° C. for 1 hour. The reaction was cooled down and poured into 75 mL of diethyl ether. The resulting solid was filtered and recrystallized from ethyl acetate / hexanes to give the title compound as off white solid (0.45 g).
[374] Physical properties are as follows.
[375]
[376] Preparation method 2
[377] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide
[378]
[379] N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (2.95 g) and sodium hydride (60% suspension, 520 mg) from Preparation 1 Suspended in DMF (60 mL) and methanol (288 μL) was added to this mixture. After heating to 135 ° C. for 1 hour, additional sodium hydride (200 mg) was added and the mixture was heated for an additional 1 hour. The reaction mixture was cooled to room temperature and then poured into saturated aqueous ammonium chloride solution (200 mL). The resulting precipitate was filtered off and washed with water (20 mL), tert-butyl methyl ether (20 mL) and heptane (20 mL). The crude product was purified by column chromatography (heptane / 2-propane, 9/1; 4/1) to give 1.68 g (56%) of the title compound as a white solid. Hydrate (1H ₂ O) was obtained by recrystallization (acetic acid, water).
[380] Physical properties are as follows.
[381]
[382] Preparation method 3
[383] N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8-methoxy-3-quinolinecarboxamide
[384]
[385] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469 mg), copper iodide (I) (57 mg) and bis from Preparation 2 (Triphenylphosphine) -palladium (II) chloride (35 mg) was suspended in diethylamine (15 mL). Propargyl alcohol (70 μl) was added and the mixture was stirred at rt for 16 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (3 × 10 mL) and brine (10 mL). The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol, 50/1; 33/1; 25/1; 20/1) to give 289 mg of the title compound ( 73%) was obtained as a white solid.
[386] Physical properties are as follows.
[387]
[388] Recipe 4
[389] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide
[390]
[391] 4-iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) were heated at 130 ° C. for 1 hour. The reaction was cooled to room temperature and 60 ml of diphenyl ether was added. The solution was heated at 250 ° C. for 1.5 h while removing ethanol with a Dean-Stark trap. The reaction was cooled to room temperature and the resulting solid was filtered, washed with hexanes and dried to give 11.20 g of ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g) and 4-chlorobenzylamine (4.0 mL) was heated at 180 ° C. for 1.5 h. The reaction was cooled and poured into 50 mL of diethyl ether. The resulting solid was filtered, triturated in ethyl acetate and filtered again to afford the desired product (0.50 g).
[392] Physical properties are as follows.
[393]
[394] Recipe 5
[395] N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide
[396]
[397] CuI (10.8 mg) to a mixture of N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide (0.494 g) from Preparation 4 in Et ₂ NH (12.9 mL) and (Ph ₃ P) ₂ PdCl ₂ (39.7 mg) was added. DMF (2 mL) was added to dissolve the reaction. To this solution propargyl alcohol (0.066 mL) was added and the reaction stirred at room temperature for 2 days. The reaction mixture was concentrated to remove Et ₂ NH. The resulting residue was partitioned between CH ₂ Cl ₂ (3X) and H ₂ O. The brown solid precipitated from the CH ₂ Cl ₂ layer was collected by filtration to give the pure product which was confirmed by NMR. The organic layers were combined, dried over Na ₂ SO ₄ and concentrated to give a brown residue. The residue was placed under high vacuum to remove residual DMF. The residue was chromatographed and adsorbed onto silica and developed with 3% MeOH in CH ₂ Cl ₂ and 2% MeOH in CH ₂ Cl _2. The homogeneous fractions were combined by TLC, concentrated and recrystallized from EtOAc / hexanes to give a pale yellow solid. Two materials gave 325.4 mg (79%) of the desired product as a tan solid.
[398] Physical properties are as follows.
[399]
[400] Preparation method 6
[401] Methyl 3-(((4-chlorobenzyl) amino) carbonyl) -8-fluoro-4-hydroxy-6-quinolinecarboxylate
[402]
[403] N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (1.0 g) from Preparation 1 in 12 mL DMSO, Et ₃ N (0.61 mL) , A solution of methanol (3.55 mL), Pd (OAc) ₂ (13.7 mg) and 1,3-bis (diphenylphosphino) propane (25.2 mg) was stirred at room temperature until the whole dissolved. CO (g) was slowly bubbled in the reaction for 3 hours and the mixture was heated at 70 ° C. overnight. Again, CO (g) was bubbled in the reaction mixture for 4 hours. The mixture was cooled to rt and diluted with water. The precipitated white solid was collected and the filtrate was partitioned against CH ₂ Cl ₂ . The aqueous layer was washed with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give an orange residue. The residue was placed under high vacuum to remove residual DMSO. The previously collected solid was combined with the residue, dissolved in methanol and adsorbed onto silica. The crude product was chromatographed with developing with 2% MeOH in CH ₂ Cl ₂ . The homogeneous fractions were combined by TLC, concentrated and recrystallized from EtOAc / hexanes to give 0.418 g of the title compound as a white solid.
[404] Physical properties are as follows.
[405]
[406] Preparation method 7
[407] N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (hydroxymethyl) -3-quinolinecarboxamide
[408]
[409] Methyl 3-{[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinecarboxylate (150 mg) from Preparation 6 was added to distilled THF (45 mL). Dissolved. The solution was heated to 35 ° C. to solution the starting material and cooled to 18 ° C. to add LiAlH ₄ (27.0 mg). After 2 hours, further LiAlH ₄ (27.0 mg) was added as the complete conversion to the product did not proceed much. Complete conversion to the product was achieved within 6.5 hours. The reaction was quenched by adding 0.1 mL of H ₂ O and 0.1 mL of 15% NaOH to the reaction mixture. The reaction mixture was filtered to remove precipitated aluminum salts. The filtrate was concentrated to give a green residue. Adsorbed on the blue residue was purified on silica, chromatography was developed with a 3% MeOH in CH ₂ Cl ₂ and 2% MeOH in CH ₂ Cl _2. The homogeneous fractions were concentrated by TLC to give 76.8 mg (55%) of the desired product as a white solid.
[410] Physical properties are as follows.
[411]
[412] Preparation Method 8
[413] Methyl 3-{[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinecarboxylate
[414]
[415] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide (30.0 g), Et ₃ N (19.1 mL), MeOH (110.6) from Preparation 4 in 375 mL of anhydrous DMF. ML), Pd (OAc) ₂ (431 mg), and a solution of 1,3-bis (diphenylphosphino) propane (791.9 mg) were stirred at room temperature until everything dissolved. The CO (g) was slowly bubbled for 2 days and the reaction was kept at 70 ° C. The reaction was cooled to room temperature. 160 ml of 1N HCl was added to the reaction mixture to precipitate the product. An orange solid precipitated out and collected. The solid was triturated with EtOAc, filtered and washed with CH ₂ Cl ₂ to give 23.8 g (93%) of the title compound as an off-white solid.
[416] Physical properties are as follows.
[417]
[418] Recipe 9
[419] N- (4-chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarboxamide
[420]
[421] To a flame dried 1 l three necked round bottom flask was placed methyl 3-{[(4-chlorobenzyl) amino] -carbonyl} -4-hydroxy-6-quinolinecarboxylate (3.0 g) from Preparation 8 It was dissolved in 700 ml of distilled THF. The suspension was heated to 67 ° C. to dissolve the starting material. The reaction was cooled to room temperature and then cooled to 10 ° C. in an ice bath. Lithium aluminum hydride (552.2 mg) was added in one portion. The reaction was stirred at 25 ° C. and monitored by mass spectroscopy for conversion to the desired product. 2 ml H ₂ O, 2 ml 15% NaOH and 2 ml H ₂ O were added to the reaction mixture to quench the reaction. The reaction mixture was filtered to remove precipitated aluminum salts. The filtrate was concentrated to give a yellow green residue. The residue is adsorbed onto silica, 2% MeOH in CH ₂ Cl ₂ (1 L), 3% MeOH in CH ₂ Cl ₂ (2 L), 4% MeOH in CH ₂ Cl ₂ (2 L), CH ₂ Chromatography was developed with 5% MeOH in Cl ₂ (1 L), 6% MeOH in CH ₂ Cl ₂ (1 L) and 7% MeOH in CH ₂ Cl ₂ (2 L). The desired product was developed with 4-7% MeOH in CH ₂ Cl ₂ . The homogeneous fractions were concentrated by TLC to give 1.85 g (67%) of the title compound as yellow crystals.
[422] Physical properties are as follows.
[423]
[424] Preparation Method 10
[425] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[426]
[427] N- (4-chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarboxamide (300 mg), K ₂ CO ₃ (485.1 mg) from Preparation 9 in 4 mL of anhydrous DMF. And a solution of CH ₃ I (0.11 mL) was heated at 90 ° C. for 3 hours. The reaction was cooled to room temperature and diluted with water to dissolve any salts and precipitate the product. The crude product was adsorbed onto silica and chromatographed while developing with 3% methanol in CH ₂ Cl ₂ . The homogeneous fractions were collected and concentrated by TLC to give 154.2 mg (49%) of the title compound as a white solid.
[428] Physical properties are as follows.
[429]
[430] Preparation 11 and Preparation 12
[431] N- (4-chlorobenzyl) -1,4-dihydro-6-[(1Z) -3-hydroxy-1-propenyl] -4-oxo-3-quinolinecarboxamide and N- (4- Chlorobenzyl) -1,4-dihydro-6-[(1E) -3-hydroxy-1-propenyl] -4-oxo-3-quinolinecarboxamide
[432]
[433] N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecar from preparation 5 in 3: 1 CH ₂ Cl ₂ / MeOH (150 mL) A mixture of voxamide (5.48 g) and Pd / C (10%, 0.55 g) was placed on a Parr hydrogenator under H ₂ 50 psi and shaken for 4 hours. After addition of 0.30 g of Pd / C, the resulting mixture was shaken for 2 hours. The reaction mixture was then filtered through celite, 0.55 g of fresh catalyst was added and the resulting mixture was shaken under H _{2 for} 3 hours. The reaction mixture was then filtered through celite and concentrated in vacuo. Polishing from CHCl ₃ / MeOH to give a solid, which was purified by HPLC chromatography on 0.46 × 25 cm chiralcel OD-H column, developing with EtOH at a rate of 0.3 mL / min, to give N- (4-chlorobenzyl) -1 0.383 g of, 4-dihydro-6-[(1Z) -3-hydroxy-1-propenyl] -4-oxo-3-quinolinecarboxamide (cis title compound) and N- (4-chlorobenzyl) 0.492 g of -1,4-dihydro-6-[(1E) -3-hydroxy-1-propenyl] -4-oxo-3-quinolinecarboxamide (trans title compound) was obtained. The cis isomer was crystallized from ethyl acetate to give 0.29 g of the title cis compound as a solid. The trans isomer was crystallized from CH ₂ Cl ₂ / MeOH to give 0.289 g of the title trans compound as a solid.
[434] Physical Properties of N- (4-Chlorophenyl) -1,4-dihydro-6-[(1Z) -3-hydroxy-1-propenyl] -4-oxo-3-quinolinecarboxamide (Preparation 11) Is as follows.
[435]
[436] Physical Properties of N- (4-chlorobenzyl) -1,4-dihydro-6-[(1E) -3-hydroxy-1-propenyl] -4-oxo-3-quinolinecarboxamide (Manufacturing 12) Is as follows.
[437]
[438] Preparation 13
[439] Ethyl 8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate
[440]
[441] Ethyl 8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylate (18.1 g) prepared as intermediate in Preparation 1 was dissolved in DMF (430 mL) and K ₂ CO ₃ (36.1 g , 261 mmol) and methyl iodide (3.25 mL, 52.3 mmol) were added. The reaction mixture was heated to 95 ° C. for 6 h and then stirred at rt overnight. The mixture was divided into 2 portions. The first portion was poured into water and extracted five times with 100 mL of CH ₂ Cl ₂ . The combined organic layers were washed five times with 200 mL of water, dried over magnesium sulfate, filtered and concentrated in vacuo. The treatment was then repeated for the second portion of the reaction mixture to give a total of 15.8 g of the title compound.
[442] Physical properties are as follows.
[443]
[444] Preparation 14
[445] N- (4-chlorobenzyl) -8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[446]
[447] Ethyl 8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate (15.8 g) from Preparation 13 in p-chlorobenzylamine (15.4 mL) The solution of was warmed to 190 ° C. The mixture was then cooled to room temperature and nucleic acid was added. The resulting precipitate was collected by filtration to give the title compound as a solid. Analytical samples were prepared by recrystallization from EtOH.
[448] Physical properties are as follows.
[449]
[450] Preparation 15
[451] N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide
[452]
[453] CuI (0.010 g) to a mixture of N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (0.466 g) in 15 mL of diethylamine ) And (Ph ₃ P) ₂ PdCl ₂ (0.035 g) were added. Propargyl alcohol (0.058 mL) was then added and the reaction was stirred at rt overnight. Diethylamine was removed under vacuum. The residue was partitioned between EtOAc and water. Insoluble material was collected by filtration. The organic layer was washed with brine, dried and concentrated. The residue was combined with insoluble material, adsorbed onto silica and chromatographed while developing with 3% MeOH / CH ₂ Cl ₂ . The homogeneous fractions were combined by TLC and concentrated to give 0.192 g of the desired product as a tan solid.
[454] Physical properties are as follows.
[455]
[456] Preparation 16
[457] Ethyl 6-[[2- (acetyloxy) ethyl] (ethyl) amino] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate
[458]
[459] 2- (ethylamino) -1-ethanol (10.7 g) was added to a pressure tube containing 1-fluoro-4-nitrobenzene (5.3 mL). The reaction was tightly sealed and heated to 135 ° C. with stirring. After 1 hour the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dried in vacuo. The residue was chromatographed on silica running with ethyl acetate. The product containing fractions were evaporated to give 10.1 g of 2- (ethyl-4-nitroanilino) -1-ethanol as an orange solid.
[460] Acetic anhydride (5.0) in a flask containing 2- (ethyl-4-nitroanilino) -1-ethanol (4.2 g) and 4-dimethylaminopyridine (0.12 g) in pyridine (20 mL) at 0 ° C. under dry tube. Ml) was added dropwise. The reaction mixture was allowed to warm to rt overnight. The reaction mixture was diluted with ethyl acetate and partitioned over saturated aqueous sodium carbonate. The layers were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was azeotropically distilled three times with toluene to remove the remaining pyridine. The residue was adsorbed on silica and chromatographed on silica running with 50% ethyl acetate in heptane. The product-containing fractions were evaporated to give 4.9 g of 2- (ethyl-4-nitroanilino) ethyl acetate as a yellow oil.
[461] 10% palladium on carbon (0.11 g) was added to a Parr bottle containing 2- (ethyl-4-nitroanilino) ethyl acetate (2.5 g) and ethyl acetate (25 mL). The reaction mixture was shaken under 50 psi of hydrogen gas for 1 hour. The reaction mixture was filtered through celite washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was treated with diethyl ethoxymethylenemalonate (2.4 mL) and heated to 140 ° C. under argon gas flow. After 1 hour the reaction was cooled to room temperature, adsorbed onto silica and chromatographed on silica running with 50% ethyl acetate in heptane. The product-containing fractions were evaporated to give crude diethyl 2-({4-[[2- (acetyloxy) ethyl] (ethyl) amino] anilino} methylene) malonate as an orange oil.
[462] Diphenyl ether (15 mL) was added to a flask containing crude diethyl 2-({4-[[2- (acetyloxy) ethyl] (ethyl) amino] anilino} methylene) malonate (2.2 g). . The reaction mixture was heated to 260 ° C. at room temperature under argon gas flow for 45 minutes. After 1 h at 260 ° C. the hot reaction was slowly and carefully added to stirred diethyl ether (150 mL). The resulting precipitate was filtered off and washed repeatedly with heptane. The residue was adsorbed on silica and chromatographed on silica running with 3% to 10% methanol in dichloromethane. The product containing fractions were evaporated to yield 0.68 g of ethyl 6-[[(2-acetyloxy) ethyl] (ethyl) amino] -4-hydroxy-3-quinolinecarboxylate as a brown solid.
[463] Potassium carbonate (0.21 g) in a flask containing ethyl 6-[[(2-acetyloxy) ethyl] (ethyl) amino] -4-hydroxy-3-quinolinecarboxylate (0.17 g) in DMF (5 mL) ) And iodomethane (0.05 mL) were added. The reaction was tightly sealed with a lid and heated to 90 ° C. After 3 hours the reaction was cooled to room temperature, diluted with dichloromethane, filtered and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 4% to 8% methanol in dichloromethane. The product containing fractions were evaporated to give 0.22 g of the title compound as an orange solid.
[464] Physical properties are as follows.
[465]
[466] Preparation 17
[467] N-cyclopropyl-4-iodoaniline
[468] To the flask containing 4-iodoaniline (2.19 g) was added methanol (25 mL) and sieved dozens of dry molecules (3A). The mixture was treated with acetic acid (6 mL) followed by [(1-ethoxycyclopropyl) oxy] trimethylsilane (2.5 mL). After 1 h, the reaction mixture was carefully treated with sodium cyanoborohydride (2.8 g) and heated to reflux overnight under a nitrogen atmosphere. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqueous sodium hydroxide (2N). The aqueous was back extracted once with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 3% to 9% ethyl acetate in heptane. The product-containing fractions were combined and evaporated to give 1.85 g of the title compound as a tan oil.
[469] Physical properties are as follows.
[470]
[471] Preparation 18
[472] Diethyl 2-[(cyclopropyl-4-iodoanilino) methylene] malonate
[473] To a flask containing N-cyclopropyl-iodoaniline (0.85 g) from Preparation 17 was added diethyl ethoxymethylenemalonate (0.9 mL) and pyridine (0.5 mL). The flask was tightly sealed with a lid and heated to 130 ° C. overnight. The reaction was cooled to room temperature and azeotropically distilled (3 ×) with toluene under reduced pressure. The residue was dissolved in dichloromethane, washed with brine, dried and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 25% to 75% ethyl acetate in heptane. The product containing fractions were evaporated to yield 0.78 g of the title compound as a tan solid.
[474] Physical properties are as follows.
[475]
[476] Preparation 19
[477] Ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate
[478] Polyphosphoric acid (1.4 g) was added to a flask containing diethyl 2-[(cyclopropyl-4-iodoanilino) methylene] malonate (2.2 g) from Preparation 18. The reaction mixture was capped and heated to 120 ° C. for 1 hour. After 2 h the 120 ° C. reaction was cooled to rt, treated with ice and partitioned between dichloromethane and saturated aqueous bicarbonate. The base aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 0.19 g of the title compound as a tan solid.
[479] Physical properties are as follows.
[480]
[481] Preparation 20
[482]
[483] N- (4-chlorobenzyl) -1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[484] P-chlorobenzylamine (1.0 mL) in a flask containing ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.19 g) from Preparation 19 Was added. The reaction was tightly sealed with a lid and heated to 180 ° C. for 1 hour. The reaction was cooled to room temperature and partitioned between dichloromethane and dilute hydrochloric acid containing methanol. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 2% to 6% methanol in dichloromethane. The product-containing fractions were evaporated to yield 0.10 g of the title compound as a tan solid.
[485] Physical properties are as follows.
[486]
[487] Preparation 21
[488] 4- (4-nitrobenzyl) morpholine
[489] To a flask containing 4-nitrobenzyl bromide (21.6 g) in dry acetone (100 mL) was added potassium carbonate (34.5 g) and morpholine (10 mL). The mixture was refluxed under drying tube overnight. The reaction was partitioned between ethyl acetate and water and separated. The basic aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated under reduced pressure to give 21.3 g of the title compound as a solid.
[490] Physical properties are as follows.
[491]
[492] Preparation 22
[493] 4- (4-aminobenzyl) morpholine
[494] To a solution of 4- (4-nitrobenzyl) morpholine (0.89 g) from Preparation 21 in ethyl acetate (10 mL) was added 5% platinum on carbon (0.04 g). The reaction was shaken under 30 psi of hydrogen gas for 1 hour. The mixture was filtered while washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give 0.71 g of the title compound as a yellow solid.
[495] Physical properties are as follows.
[496]
[497] Preparation 23
[498] N-cyclopropyl-4- (4-morpholinylmethyl) aniline
[499] Methanol (12 ml) was added to a flask containing 4- (4-aminobenzyl) morpholine (0.96 g) from Preparation 22, and dozens of dry molecules were sieved (3A). The mixture was treated with acetic acid (3 mL) followed by [(1-ethoxycyclopropyl) oxy] trimethylsilane (1.25 mL). After 15 minutes, the reaction mixture was carefully treated with sodium cyanoborohydride (1.4 g) and heated to reflux overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered while washing with methanol, and concentrated under reduced pressure. The residue was diluted with diethyl ether and washed with aqueous sodium hydroxide (2N). The aqueous was back extracted once with diethyl ether and once with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 2% to 8% methanol in dichloromethane. The product containing fractions were evaporated to give 0.13 g of the title compound as a pink solid.
[500] Physical properties are as follows.
[501]
[502] Preparation 24
[503] Diethyl 2-{[cyclopropyl-4- (4-morpholinylmethyl) anilino] methylene} malonate
[504] To a flask containing N-cyclopropyl-4- (4-morpholinylmethyl) aniline (0.55 g) from Preparation 23 was added diethyl ethoxymethylenemalonate (0.45 mL) and pyridine (0.33 mL). The flask was tightly sealed with a lid and heated to 145 ° C. for 2 hours. The reaction was cooled to room temperature and azeotropically distilled with toluene under reduced pressure (3 ×). The residue was dissolved in dichloromethane, washed with brine, dried and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 2% to 6% methanol in dichloromethane. The product containing fractions were evaporated to give 0.77 g of the title compound as an oil.
[505] Physical properties are as follows.
[506]
[507] Recipe 25
[508] Ethyl 1-cyclopropyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate
[509]
[510] Polyphosphoric acid (4.4 g) was added to a flask containing diethyl 2-{[cyclopropyl-4- (4-morpholinylmethyl) anilino] methylene} malonate (0.77 g) from Preparation 24. The reaction mixture was tightly sealed with a lid and heated to 120 ° C. After 1 hour the reaction was cooled to room temperature. The reaction mixture was carefully added to a mixture of vigorously stirred dichloromethane and saturated aqueous bicarbonate. The layers were separated and the basic aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 3% to 15% methanol in dichloromethane to give 0.38 g of the title compound as a yellow solid.
[511] Physical properties are as follows.
[512]
[513] Preparation 26
[514] tert-butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6-iodo-4-oxo-1 (4H) -quinolinyl] acetate
[515]
[516] Potassium carbonate in a flask containing N- (4-chlorobenzyl) -6-iodo-4-hydroxy-3-quinolinecarboxamide (0.22 g) produced as described in Preparation 4 in DMF (5 mL) (0.21 g) and tert-butylbromoacetate (0.11 mL) were added. After stirring overnight the reaction was diluted with dichloromethane and partitioned against water. The organic phase was washed with brine, dried over sodium sulfate, concentrated under reduced pressure and dried under vacuum to give 0.26 g of the title compound as a white solid.
[517] Physical properties are as follows.
[518]
[519] Example 1
[520] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-isopropyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[521]
[522] N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (366 mg) and potassium carbonate (276 mg) from Preparation 5 Dissolved in DMF (5 mL). 2-bromopropane (470 μl) was added and the mixture was heated to 100 ° C. for 1 hour. The reaction mixture was poured into water (25 mL), cooled to room temperature and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with saturated aqueous brine (10 mL). The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (EtOAc / heptane, 1/1 to 1/10) and recrystallized from ethanol to give 70 mg (17%) of the title compound as a white solid.
[523] Physical properties are as follows.
[524]
[525] Example 2
[526] 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[527]
[528] N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (366 mg) and potassium carbonate (276 mg) from Preparation 5 Dissolved in DMF (5 mL). 2-iodobutane (575 μL) was added and the mixture was heated to 100 ° C. for 1 hour. The reaction mixture was poured into water (25 mL), cooled to room temperature and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with saturated aqueous brine (10 mL). The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol, 100/1; 50/1; 20/1) to give 80 mg (19%) of the title compound as a white solid.
[529] Physical properties are as follows.
[530]
[531] Example 3
[532] 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -8-methoxy-4-oxo-1,4-dihydro-3-quinoline Carboxamide
[533]
[534] N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8-methoxy-3-quinolinecarboxamide (300 mg) from Preparation 3 and potassium carbonate (310 mg) was dissolved in DMF (5 mL). 2-iodobutane (345 μl) was added and the mixture was heated to 120 ° C. for 4 hours. Additional 2-iodobutane (200 μl) and potassium carbonate (100 mg) were added and the mixture was heated for 16 hours. The reaction mixture was poured into water (75 mL), cooled to room temperature and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with saturated aqueous brine (10 mL). The aqueous layer was back extracted with ethyl acetate (20 mL). The combined organic layers were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (EtOAc / heptane, 30/1; 10/1) to give 60 mg (18%) of the title compound as a white solid.
[535] Physical properties are as follows.
[536]
[537] Example 4
[538] N- (4-chlorobenzyl) -8- (2-hydroxyethoxy) -6- (3-hydroxypropyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides
[539]
[540] Sodium hydride (60% oil suspension) in a suspension of N- (4-chlorobenzyl) -8-fluoro-6-iodo-3-quinolinecarboxamide (2.28 g) from Preparation 1 in DMF (75 mL); 0.600 g) was added followed by 2-benzyloxyethanol (1.42 mL). The reaction was heated to 135 ° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature and poured into saturated aqueous ammonium chloride (200 mL). The aqueous layer was extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (dichloromethane / methanol, 98/2). The homogeneous fractions were combined by TLC and concentrated in vacuo to give a yellow solid which was recrystallized from ethanol to give 1.568 g (53%) of the intermediate amide as an off-white solid. To a suspension of this material (1.149 g) in diethylamine (24 mL) was added copper iodide (0.111 g) and Pd (PPh ₃ ) ₂ Cl ₂ (0.069 g), followed by propargyl alcohol (0.16 mL). It was. The reaction was stirred for 3 days at room temperature. The reaction mixture was concentrated in vacuo and partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting brown solid was purified by column chromatography (dichloromethane / methanol, 98/2). The homogeneous fractions were combined by TLC and concentrated in vacuo to give a tan solid which was recrystallized from ethanol to give 0.181 g (18%) of propargyl compound as a tan crystalline solid. To a solution of this material (0.394 g) in DMF (3 mL) was added potassium carbonate (0.317 g) followed by iodomethane (0.14 mL). The reaction was heated to 90 ° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography (dichloromethane; dichloromethane / methanol, 98/2). The homogeneous fractions were combined by TLC and concentrated in vacuo to give a yellow solid which was recrystallized from ethanol to give 0.273 g (67%) of N-methyl pyridone as a yellow solid. Pyridone (0.350 g) was dissolved in 1/1 dichloromethane / ethanol (100 mL) and hydrogenated at 35 psi on 10% Pd / C (53 mg) for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting yellow oil was dissolved in methanol (60 mL) and hydrogenated over Pd Black (35 mg) for 4 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting yellow oil was purified by column chromatography (dichloromethane / methanol, 98/2; 95/5). The homogeneous fractions were combined by TLC and concentrated in vacuo to give a pale yellow solid which was recrystallized from ethyl acetate to give 0.104 g (35%) of the title compound as a pale yellow solid.
[541] Physical properties are as follows.
[542]
[543] Example 5
[544] N- (4-chlorobenzyl) -8- [2-hydroxy-1- (hydroxymethyl) ethoxy] -6- (3-hydroxypropyl) -1-methyl-4-oxo-1,4- Dihydro-3-quinolinecarboxamide
[545]
[546] Sodium hydride (60% oil suspension) in a suspension of N- (4-chlorobenzyl) -8-fluoro-6-iodo-3-quinolinecarboxamide (2.28 g) from Preparation 1 in DMF (75 mL); 0.600 g) was added followed by 1,3-dibenzyloxy-2-propanol (2.47 mL). The reaction was heated to 135 ° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous ammonium chloride (200 mL). The aqueous layer was extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting brown oil was purified by column chromatography (dichloromethane / methanol, 98/2). The mixed fractions were combined and refined (ethyl acetate / heptane, 1/1). The homogeneous fractions were combined by TLC and concentrated in vacuo to give a yellow solid which was recrystallized from ethyl acetate to give 1.701 g (48%) of intermediate amide as a pale yellow solid. To a suspension of this material (1.330 g) in diethylamine (23 mL) was added copper iodide (0.107 g) and Pd (PPh ₃ ) ₂ Cl ₂ (0.066 g), followed by addition of propargyl alcohol (0.15 mL). It was. The reaction was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo. The resulting brown solid was purified by column chromatography (dichloromethane, dichloromethane / methanol, 98/2). The homogeneous fractions were combined by TLC and concentrated in vacuo to give an orange solid which was recrystallized from diethyl ether / ethyl acetate to give 0.727 g (61%) of propargyl derivative as off white solid. Potassium carbonate (0.325 g) was added to a solution of the material (0.500 g) in DMF (3 mL) followed by iodomethane (0.15 mL). The reaction was heated to 90 ° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (dichloromethane / methanol, 98/2). The homogeneous fractions were combined by TLC and concentrated in vacuo to give a yellow solid which was recrystallized from ethyl acetate / methanol to give 0.383 g (75%) of N-methyl pyridone as a yellow solid. A solution of pyridone (0.310 g) in 1/1 dichloromethane / ethanol (30 mL) was hydrogenated at 35 psi over 10% Pd / C (62 mg) for 5.5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting yellow oil was purified by column chromatography (dichloromethane / methanol; 98/2, 95/5, 90/10). The homogeneous fractions were combined by TLC and concentrated in vacuo to give a pale yellow solid which was recrystallized from ethyl acetate / methanol to give 0.050 g (22%) of the title compound as a white solid.
[547] Physical properties are as follows.
[548]
[549] Example 6
[550] N- (4-chlorobenzyl) -8-fluoro-6- (hydroxymethyl) -4-oxo-1- [3- (tetrahydro-2H-pyran-2-yloxy) propyl] -1,4 -Dihydro-3-quinolinecarboxamide
[551]
[552] To a suspension of NaH (60% suspension in oil, 11.1 mg) in 2.5 mL of anhydrous DMF, N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (hydroxymethyl)-from Preparation 7- 3-quinolinecarboxamide (100 mg) was added. The reaction mixture was stirred for 15-20 minutes at room temperature, then 2- (3-bromopropoxy) tetrahydro-2H-pyran (89.4 mg) was added. The reaction was stirred at rt for 3 days. The reaction mixture was treated with aqueous NaHCO ₃ , and then extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were washed with 15% K ₂ CO ₃ and water (2 ×), dried over sodium sulfate and concentrated to give a yellow residue. The residue was chromatographed with development with 2% MeOH in CH ₂ Cl ₂ . The homogeneous fractions were combined by TLC and concentrated to give 34.0 mg (24%) of the title compound as a white solid.
[553] Physical properties are as follows.
[554]
[555] Example 7
[556] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propenyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide
[557]
[558] N- (4-chlorobenzyl) -1,4-dihydro-6- [3-hydroxy-1-propenyl] -4-oxo-3-quinolinecarboxamide (0.52 g) from Preparations 11 and 12 Was dissolved in DMF (4 mL) and potassium carbonate (0.78 g) and N- (2-chloroethyl) morpholine hydrochloride (0.52 g) were added. The mixture was heated at 90 ° C. for 2 h and then partitioned between water and chloroform. The organic layer was concentrated in vacuo to give a brown oil. Column chromatography (developed with 1-7% MeOH / CHCl ₃ ) and then crystallized from EtOAc / hexanes gave the title compound as a mixture of isomers. The mixture was then purified by HPLC chromatography on a 0.46 × 25 cm chiralcel OD-H column, developing with EtOH at a rate of 0.5 ml / min. This resulted in 0.161 g of an alkene mixture as about a 2: 1 mixture of trans: cis isomers which was crystallized from ethyl acetate to give 0.13 g of the title compound as a hydrate.
[559] Physical properties are as follows.
[560]
[561] Example 8
[562] N- (4-chlorobenzyl) -8-fluoro-6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[563]
[564] N- (4-chlorobenzyl) -8-fluoro-6-iodo-1-methyl-4-oxo-1 from diethyl amine (42.5 mL) and CH ₂ Cl ₂ (50 mL) from Preparation 14, 4-dihydro-3-quinolinecarboxamide (0.600 g), propargyl alcohol (0.11 mL, 1.90 mmol), CuI (0.048 g, 0.25 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.178 g, 0.25 mmol) was warmed to 65 ° C. overnight. The reaction mixture was then concentrated in vacuo. Column chromatography (developed with 5-10% MeOH / CH ₂ Cl ₂ ) afforded the title compound as a solid.
[565] Physical properties are as follows.
[566]
[567] Example 9
[568] N- (4-chlorobenzyl) -8-fluoro-6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinoline Carboxamide
[569]
[570] N- (4-chlorobenzyl) -8-fluoro-1,4-dihydro-6- (3-hydroxy-1 from Example 8 in MeOH (10 mL) and CH ₂ Cl ₂ (10 mL) A mixture of -propynyl) -1-methyl-4-oxo-3-quinolinecarboxamide (0.200 g) and Pd / C (10%, 0.040 g) was placed for 6 hours at 50 pis of hydrogen in a Parr stirrer. The reaction mixture was filtered through celite and concentrated in vacuo. Recrystallization from EtOAc gave the title compound as a solid.
[571] Physical properties are as follows.
[572]
[573] Example 10
[574] N- (4-chlorobenzyl) -1- [2- (diethylamino) ethyl] -8-fluoro-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-di Hydro-3-quinolinecarboxamide
[575]
[576] A solution of N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.96 g) from Preparation 15 was prepared. It was dissolved in DMF (7 mL) and K ₂ CO ₃ (1.38 g) and 2-bromo-N, N-diethylethylamine hydrobromide (1.30 g) were added. The reaction mixture was heated to 95 ° C for 16 h. Water was added, an oily solid was formed and it was isolated by tilting the liquid. Column chromatography (developed with 1-3% MeOH / CHCl ₃ ) gave 0.373 g of the title compound, which was crystallized from ethyl acetate to give 0.163 g of solid.
[577] Physical properties are as follows.
[578]
[579] Example 11
[580] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-propyl-1,4-dihydro-3-quinolinecarboxamide
[581]
[582] N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.50 g) from preparation 5 in DMF, potassium carbonate (0.76 g ) And 1-iodopropane (0.47 g) were heated to 100 ° C. for 6 h and stirred at rt overnight. The reaction mixture was filtered and the solution was evaporated under reduced pressure to give a light brown solid. The solid was stirred with ethyl acetate for 1 hour and filtered. The solvent was evaporated from the filtrate under reduced pressure to give 0.12 g of the title compound as a yellow-white solid.
[583] Physical properties are as follows.
[584]
[585] Example 12
[586] N- (4-chlorobenzyl) -1- [2- (diethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[587]
[588] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.616 g) from Preparation 5 was added to DMF (4 mL). It was dissolved in and K ₂ CO ₃ (0.93 g, 6.72 mmol) and 2-bromo-N, N-diethylethylamine hydrobromide (0.88 g, 3.35 mmol) were added. The reaction mixture was heated at 90 ° C. for 16 h. The mixture was partitioned between CHCl ₃ and water. The organic layer was concentrated in vacuo to give an oil. Column chromatography (developed with 1-5% MeOH / CHCl ₃ ) gave 0.10 g of a brown oil. Crystallization from ethyl acetate / hexanes gave 0.013 g of the title compound as a solid.
[589] Physical properties are as follows.
[590]
[591] Example 13
[592] N- (4-chlorobenzyl) -1- [2- (dimethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecar Voxamide, hydrochloride salt
[593]
[594] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.515 g) from Preparation 5 was added to DMF (10 mL). Dissolved in K ₂ CO ₃ (0.778 g) and diisopropylaminoethyl chloride-hydrochloride (0.56 g) were added. The reaction mixture was heated at 95 ° C. for 14 h and then stirred at rt overnight. Thereafter, the mixture was poured into water, and when oil was formed, it was isolated by tilting the liquid. The oil was dissolved in MeOH / CH ₂ Cl ₂ and etheric HCl was added to adjust the pH to 2. The mixture was concentrated in vacuo to afford the title compound as the hydrochloride salt.
[595] Physical properties are as follows.
[596]
[597] Example 14
[598] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (1-piperidinyl) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide
[599]
[600] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.367 g) from Preparation 5 was added to DMF (10 mL). It was dissolved in and K ₂ CO ₃ (0.55 g, 4.0 mmol) and 1- (2-chloroethyl) piperidine hydrochloride (0.375 g, 2.0 mmol) were added. The reaction mixture was heated at 90 ° C. for 3 hours and then stirred at room temperature for 48 hours. Water was added and a precipitate formed. The precipitate was filtered off, dried at room temperature and dried under reduced pressure to give 0.171 g of solid. The solid was dissolved in CHCl ₃ and filtered. The filtrate was concentrated in vacuo and crystallized from ethyl acetate to give 0.066 g of the title compound as a solid.
[601] Physical properties are as follows.
[602]
[603] Example 15
[604] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [3- (1-piperidinyl) propyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide
[605]
[606] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.367 g) from Preparation 5 was added to DMF (10 mL). Was dissolved in and K ₂ CO ₃ (0.55 g) and N- (3-chloropropyl) piperidine hydrochloride (0.408 g) were added. The reaction mixture was heated at 90 ° C. for 10 hours and then stirred at room temperature for 38 hours. Water was added and a precipitate formed. The precipitate was filtered off, dried at room temperature and dried under reduced pressure to give 0.187 g of solid. The solid was dissolved in CHCl ₃ and filtered to remove 0.045 g of precipitate. The filtrate was concentrated in vacuo and crystallized from ethyl acetate to give 0.065 g of the title compound as a solid.
[607] Physical properties are as follows.
[608]
[609] Example 16
[610] N- (4-chlorobenzyl) -1,4-dihydro-6- (3-hydroxy-1-propynyl) -1- [2- (1-methyl-2-pyrrolidinyl) ethyl] -4 Oxo-3-quinolinecarboxamide
[611]
[612] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.458 g) from Preparation 5 was added to DMF (10 mL). Dissolved in K ₂ CO ₃ (0.69 g, 5.0 mmol) and 3-chloromethyl-1-methylpiperidine hydrochloride (0.47 g, 2.5 mmol) were added. The reaction mixture was heated to 90 ° C. for 2.5 h. Water was added and a precipitate formed. The precipitate was filtered off and dried at room temperature to give 0.41 g of solid. The solid was triturated with CHCl ₃ and filtered to give 0.33 g of the title compound as a solid.
[613] Physical properties are as follows.
[614]
[615] Example 17
[616] N- (4-chlorobenzyl) -1- [2- (diisopropylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide
[617]
[618] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.458 g) from Preparation 5 was added to DMF (10 mL). Dissolved in K ₂ CO ₃ (0.69 g) and 2- (diisopropylamino) ethyl chloride hydrochloride (0.50 g) were added. The reaction mixture was heated to 90 ° C. for 2 h and then stirred at rt overnight. A small amount of water was added and the mixture was heated for 20 hours. Additional 2- (diisopropylamino) ethyl chloride hydrochloride (0.25 g, 1.25 mmol) was added and the mixture was heated at 100 for 5 h and then stirred at rt overnight. Water was added to form an oily solid, which was separated by tilting the liquid. Column chromatography (developed with 1-2% MeOH / CHCl ₃ ) gave 0.45 g of solid. It was dissolved in CH ₂ Cl ₂ containing a small amount of MeOH and added to a 1: 1 solution of pentane / Et ₂ O to crystallize to yield 0.22 g of the title compound as a solid.
[619] Physical properties are as follows.
[620]
[621] Example 18
[622] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (1-pyrrolidinyl) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide
[623]
[624] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.458 g) from Preparation 5 was added to DMF (10 mL). Dissolved in K ₂ CO ₃ (0.69 g) and 1- (2-chloroethyl) pyrrolidine hydrochloride (0.425 g). The reaction mixture was heated to 90 ° C. for 3 hours. Water was added to form a blackish solid, which was separated by tilting the liquid. Column chromatography (developed with 1-5% MeOH / CHCl ₃ ) gave 0.17 g of solid. It was dissolved in CH ₂ Cl ₂ containing a small amount of MeOH and added to a 1: 1 solution of pentane / Et ₂ O to crystallize to yield 0.153 g of the title compound as a solid.
[625] Physical properties are as follows.
[626]
[627] Example 19
[628] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide
[629]
[630] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.458 g) from Preparation 5 was added to DMF (10 mL). Dissolved in K ₂ CO ₃ (0.69 g) and 4- (2-chloroethyl) morpholine hydrochloride (0.47 g). The reaction mixture was heated to 90 ° C. for 2 hours. Water was added to form a blackish solid, which was separated by tilting the liquid. Column chromatography (developed with 1-5% MeOH / CHCl ₃ ) gave 0.183 g of solid. It was dissolved in CH ₂ Cl ₂ containing a small amount of MeOH and added to a 1: 1 solution of pentane / Et ₂ O to crystallize to yield 0.13 g of the title compound as a solid.
[631] Physical properties are as follows.
[632]
[633] Example 20
[634] N- (4-chlorobenzyl) -1- [3- (dimethylamino) propyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecar Voxamide
[635]
[636] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.458 g) from Preparation 5 was added to DMF (10 mL). Dissolved in K ₂ CO ₃ (0.69 g) and 3-dimethylaminopropyl chloride hydrochloride (0.42 g) were added. The reaction mixture was heated to 90 ° C. for 6 hours. Water was added to form a blackish solid, which was isolated by tilting the liquid. Column chromatography (developed with 1-20% MeOH / CHCl ₃ ) gave 0.103 g of solid. It was dissolved in CH ₂ Cl ₂ containing a small amount of MeOH and added to a 1: 1 solution of pentane / Et ₂ O to crystallize to afford 0.072 g of the title compound as a solid.
[637] Physical properties are as follows.
[638]
[639] Example 21
[640] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-vinyl-1,4-dihydro-3-quinolinecarboxamide
[641]
[642] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (1.83 g) from Preparation 5 was added to DMF (25 mL). Dissolved in K ₂ CO ₃ (1.38 g) and 1,2-dibromoethane (4.3 mL) were added. The reaction mixture was heated to 90 ° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate and then with chloroform. The combined organic layers were concentrated in vacuo to give 2.5 g of a blackish oil. Column chromatography (developed with 1-3% MeOH / CHCl ₃ ) 1- (1-bromoethyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl)- 0.378 g of 4-oxo-1,4-dihydro-3-quinolinecarboxamide was obtained as a solid and used without further purification. 1- (1-bromoethyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.347 g) was suspended in 1: 1 THF / CH ₃ CN (15 mL), sodium carbonate (0.16 g) and ethylamine (0.4 mL) were added and the mixture was refluxed for 16 h. Additional ethylamine (0.80 mL) was added and the mixture was refluxed for 16 h. Additional ethylamine (0.80 mL) and DMF (5 mL) were added and the mixture was heated at 100 ° C. for 6 hours and then at room temperature for 48 hours. Potassium carbonate (0.193 g) was added and the mixture was heated at 100 ° C. for 3 hours. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was concentrated in vacuo to give 0.60 g of oil. Column chromatography (developed with 1-5% MeOH / CHCl ₃ ) gave 0.118 g of the title compound as a solid.
[643] Physical properties are as follows.
[644]
[645] Example 22
[646] N- (4-chlorobenzyl) -6-[(E) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[647]
[648] N- (4-chlorobenzyl) -6-[(1E) -3-hydroxy-1-propenyl] -4-hydroxy-3-quinolinecarboxamide (0.184) from Preparation 12 in DMF (2 mL) g), a mixture of K ₂ CO ₃ (0.276 g) and iodomethane (0.062 mL) were heated in a stopper flask at 90 ° C. for 1 h. Water was added, the mixture was cooled and at room temperature while a precipitate formed Stir for 16 hours. The precipitate was filtered off and dried in vacuo at 60 ° C. for 48 hours to give 0.164 g of the title compound as a solid.
[649] Physical properties are as follows.
[650]
[651] Example 23
[652] N- (4-chlorobenzyl) -6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[653]
[654] N- (4-chlorobenzyl) -6-[(1Z) -3-hydroxy-1-propenyl] -4-hydroxy-3-quinolinecarboxamide (0.184) from Preparation 11 in DMF (2 mL) g), a mixture of K ₂ CO ₃ (0.276 g) and iodomethane (0.062 mL) were heated in a stopper flask at 90 ° C. for 1 hour. Water was added, the mixture was cooled and stirred for 16 hours at room temperature while a precipitate formed. The precipitate was filtered off and dried in vacuo at 60 ° C. for 48 hours to give a solid. It was dissolved in CH ₂ Cl ₂ containing a small amount of MeOH and added to a 1: 1 solution of pentane / Et ₂ O to crystallize to yield 0.085 g of the title compound as a solid.
[655] Physical properties are as follows.
[656]
[657] Example 24
[658] N- (4-chlorobenzyl) -6- [ethyl (2-hydroxyethyl) amino] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[659]
[660] Ethyl 6-[[2- (acetyloxy) ethyl] (ethyl) amino] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.22 g) from Preparation 16 P-chlorobenzylamine (1.0 mL) was added to the flask. The reaction was tightly sealed with a lid and heated to 190 ° C. overnight. The reaction was cooled to room temperature. The residue was adsorbed on silica and chromatographed on silica running with 4% to 8% methanol in dichloromethane. The product containing fractions were evaporated to give 0.12 g of the title compound as off white solid.
[661] Physical properties are as follows.
[662]
[663] Example 25
[664] N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[665]
[666] 0.24 g of N- (4-chlorobenzyl) -1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 20 under an atmosphere of argon gas, copper iodide Diethylamine (1.5 mL) and propargyl alcohol (0.04 mL) were added to a dry flask containing (I) 0.01 g and 0.04 g of dichlorobis (triphenylphosphine) palladium (II). After 3 hours the reaction was diluted with DMF (0.5 mL) and stirred overnight. The reaction was concentrated under reduced pressure, diluted with dichloromethane containing a small amount of methanol and partitioned over water. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 2% to 6% methanol in dichloromethane. The product containing fractions were combined and concentrated under reduced pressure to give 0.17 g of the title compound as a solid.
[667] Physical properties are as follows.
[668]
[669] Example 26
[670] N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[671]
[672] N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1 from Example 25 in THF (3 mL) and methanol (3 mL) Platinum oxide (0.01 g) was added to a solution of, 4-dihydro-3-quinolinecarboxamide (0.17 g). The mixture was placed under an atmosphere of hydrogen gas. After 1 hour the mixture was filtered through celite washing with THF: methanol. The filtrate was concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 2% to 4% methanol in dichloromethane. The product containing fractions were concentrated under reduced pressure to give 0.13 g of the title compound as a white solid.
[673] Physical properties are as follows.
[674]
[675] Example 27
[676] N- (4-chlorobenzyl) -1-cyclopropyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[677]
[678] 4-Chloro in a flask containing ethyl 1-cyclopropyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.38 g) from Preparation 25 Benzylamine (2.0 mL) was added. The reaction was tightly sealed with a lid and heated to 165 ° C. overnight. The reaction was cooled to room temperature, adsorbed onto silica and chromatographed on silica running with 1% to 6% methanol in dichloromethane. The product containing fractions were evaporated to give a solid, which was dissolved in a minimum amount of dichloromethane. The solution was added to 1: 1 diethyl ether: pentane to precipitate the title compound as a white solid. This solid was collected by filtration and dried in vacuo to give 0.36 g of the title compound.
[679] Physical properties are as follows.
[680]
[681] Example 28
[682] tert-butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinolinyl] acetate
[683]
[684] Tert-butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6-iodo-4-oxo-1 (4H) -quinolinyl] acetate from preparation 26 under an atmosphere of argon gas To a dry flask containing 0.23 g, 0.01 g of copper (I) iodide and 0.03 g of dichlorobis (triphenylphosphine) palladium (II) was added diethylamine (2.0 mL) and propargyl alcohol (0.03 mL). . After 1 hour the reaction was diluted with DMF (1.0 mL) and stirred overnight. The reaction was concentrated under reduced pressure, diluted with dichloromethane containing a small amount of methanol and partitioned over water. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica running with 2% to 4% methanol in dichloromethane. The product containing fractions were combined and concentrated under reduced pressure to give 0.13 g of the title compound as a solid.
[685] Physical properties are as follows.
[686]
[687] Example 29
[688] 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinolinyl] acetic acid
[689]
[690] Tert-butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4- from dichloromethane (1 mL) To a suspension of oxo-1 (4H) -quinolinyl] acetate (0.07 g) was added trifluoroacetic acid (1 mL). After 3 hours, the resulting solution was concentrated under reduced pressure. The residue was dissolved in a small amount of dichloromethane: methanol: DMF and added slowly to vigorously stirred 1: 1 diethyl ether: pentane. The resulting precipitate was collected by filtration to give 0.05 g of the title compound as a solid.
[691] Physical properties are as follows.
[692]
[693] Example 30
[694] N- (4-chlorobenzyl) -1- (2-hydroxyethyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[695]
[696] Potassium carbonate (in a flask containing N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.37 g) from Preparation 5 2.75 g) and bromoethanol (0.71 mL) were added. The flask was tightly sealed with a lid and heated to 100 degrees. After 4 hours, the reaction was cooled to room temperature and partitioned between dichloromethane and water containing methanol. The organic layer was washed twice with water, brine, dried and concentrated under reduced pressure. The residue was adsorbed on silica and chromatographed on silica, developing with 2% to 10% methanol in dichloromethane to afford 0.09 g of the title compound as a white solid.
[697] Physical properties are as follows.
[698]
[699] Example 31
[700] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[701]
[702] 6.90 g of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide from Preparation 5 in 40 ml of DMF, 10.4 g of potassium carbonate and 2.3 ml of methyl iodide suspension was stirred at 90 ° C. for 4 hours, then cooled and diluted with 350 ml of water. The resulting solid was filtered, washed with water and dried in vacuo. The solid was flash chromatographed on silica with 3-5% methanol in dichloromethane to give 6.02 g of the title compound as a yellow solid.
[703] Physical properties are as follows.
[704]
[705] Preparation 27
[706] N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[707]
[708] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-di from Example 31 in 20 ml 1: 1 THF-methanol A mixture of 0.50 g of hydro-3-quinolinecarboxamide and 50 mg of 5% platinum catalyst on carbon was stirred under 1 atmosphere of hydrogen for 3 hours and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residual solid was flash chromatographed on silica with 4-5% methanol in dichloromethane to give 0.45 g of the title compound as a yellow solid. The solid was further purified by recrystallization from 15 ml of acetonitrile.
[709] Physical properties are as follows.
[710]
[711] Example 32
[712] Di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl phosphate
[713]
[714] N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1-methyl-4-oxo-1,4-dihydro from Preparation 27 in 2 ml of 1: 1 chloroform-THF stirred under argon. To a suspension of 77 mg of 3-quinolinecarboxamide and 25 mg of 1H-tetrazole, 90 μl of di-tert-butyl diethyl phosphoramidite was added. After 18 hours, the solution was cooled to 0 ° C. and a slight excess of m-CPBA (about 110 mg) was added. After 10 minutes, the mixture was partitioned between ethyl acetate and aqueous NaHSO ₃ . The organic phase was washed with dilute aqueous HCl, water and aqueous NaHCO ₃ , dried over sodium sulphate and concentrated under reduced pressure. The residue was flash chromatographed on silica with 2% methanol in dichloromethane to give 111 mg of the title compound as a white crystalline solid.
[715] Physical properties are as follows.
[716]
[717] Example 33
[718] 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl dihydrogen phosphate
[719]
[720] Di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1, from Example 32 in 1 ml 1: 1 TFA-dichloromethane, A solution of 77.8 mg of 4-dihydro-6-quinolinyl) propyl phosphate was stirred for 1 hour and then slowly added to 20 ml of rapidly stirred 1: 1 ether-hexane. The precipitated solid was filtered off, washed with hexanes and dried under vacuum to give 67 mg of the title compound as a white solid.
[721] Physical properties are as follows.
[722]
[723] Example 34
[724] Di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl phosphate
[725]
[726] N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarbox according to a method analogous to that described in Example 32. The title compound was prepared from amide (Example 26).
[727] Physical properties are as follows.
[728]
[729] Example 35
[730] Sodium 2-[{8- [3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propoxy ] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate
[731]
[732] 77 mg of N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 27 in 1 ml of DMF , 0.46 mL of a 0.65 M solution of triethylammonium salt of triglyceride ammonium in acetonitrile, 27 mg of DMAP and 38 μl of DIC were stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The residue was flash chromatographed on silica with 5-20% methanol in dichloromethane to give a solid which was dissolved in chloroform and butanol. The solution was stirred with 25 ml of saturated aqueous sodium sulfate, filtered through anhydrous sodium sulfate and concentrated under reduced pressure to give 113 mg of the title compound as a white solid.
[733] Physical properties are as follows.
[734]
[735] Example 36
[736] Sodium 2-[{8- [3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl) prop Foxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate
[737]
[738] N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarbox according to a method analogous to that described in Example 35 The title compound was prepared from amide (Example 26).
[739] Physical properties are as follows.
[740]
[741] Example 37
[742] Sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl)- 2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate
[743]
[744] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3- according to a method analogous to that described in Example 35 The title compound was prepared from quinolinecarboxamide (Example 31).
[745] Physical properties are as follows.
[746]
[747] Example 38
[748] Sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate
[749]
[750] N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 according to a method analogous to that described in Example 35 The title compound was prepared from -quinolinecarboxamide (Example 25).
[751] Physical properties are as follows.
[752]
[753] Preparation 28
[754] 2-Fluoro-5-iodobenzoic acid
[755] 67 ml of a 1.6M solution of butyllithium 1.6M in hexane was added dropwise to a solution covered with 16.8 ml of diisopropylethylamine in stirred argon in 200 ml of THF cooled at -78 ° C. The solution was warmed to 0 ° C and then recooled to -78 ° C. To this solution was added dropwise 11.5 ml of 4-fluoroiodobenzene in 10 ml of THF. The solution was stirred at −78 ° C. for 90 minutes and then passed quickly on a dry ice-ether slurry. The mixture was allowed to warm up to room temperature and then extracted with 300 mL 0.3M NaOH. The aqueous phase was cooled with ice and acidified with 40 mL 6N HCl. The precipitate was extracted twice with ether and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 19.57 g of the title compound as a white needle. The mother liquor residue was recrystallized to give 3.78 second yield.
[756] Physical properties are as follows.
[757]
[758] Preparation 29
[759] Ethyl 3- (2-fluoro-5-iodophenyl) -3-oxopropanoate
[760] 3.9 g of carbonyldiimidazole were added to a solution of 5.32 g of 2-fluoro-5-iodobenzoic acid from Preparation 28 in 20 mL of stirred THF under argon. In a fractionation flask 2.8 ml of chlorotrimethylsilane was added to a mixture of 3.74 g of potassium ethyl malonate in 20 ml of acetonitrile. The mixture was stirred under argon for 18 hours, then cooled to 0 ° C. and 6.6 mL DBU was added dropwise. After the mixture was stirred at 0 ° C. for 3 hours, the acyl imidazolide solution prepared above was added via cannula. After 2 hours, the mixture was partitioned between ether and excess dilute HCl and the organic phase was washed with dilute HCl and brine and dried over magnesium sulfate. Solvent was removed under reduced pressure to give a colorless oil, which was flash chromatographed on silica with 10% ethyl acetate in hexane to give 5.07 g of the title compound as a pink dense prism.
[761] Physical properties are as follows.
[762]
[763] Preparation 30
[764] Ethyl 1- (tert-butyl) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate
[765] A solution of 2.36 g of ethyl 3- (2-fluoro-5-iodophenyl) -3-oxopropanoate, 2.0 mL of triethyl orthoformate and 15 mL of acetic anhydride from Preparation 29 was refluxed under argon for 2 hours. After evaporation, the solvent was evaporated off under reduced pressure. 10 ml of dry tert-butanol and 0.74 ml of tert-butylamine were added to the residual oil, and the solution was stirred at 80 ° C for 2 hours. Then potassium tert-butoxide (0.87 g) was added and stirring continued at 80 ° C. under argon for 18 hours. The mixture was then cooled and partitioned between dilute HCl and chloroform-methanol. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed on silica with 2-4% methanol in dichloromethane to give 1.32 g of the title compound as off-white solid.
[766] Physical properties are as follows.
[767]
[768] Preparation 31
[769] 1- (tert-butyl) -N- (4-chlorobenzyl) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[770]
[771] A slurry of 1.11 g of ethyl 1- (tert-butyl) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from formula 30 in 2.0 g of 4-chlorobenzylamine under argon Heated at 160 ° C. for 8 hours, then cooled to room temperature and polished with 1N HCl. The solid was filtered off, washed with water and dried under vacuum. Flash chromatography using 20% ethyl acetate in dichloromethane gave 1.22 g of the title compound as a white solid.
[772] Physical properties are as follows.
[773]
[774] Example 39
[775] 1- (tert-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[776]
[777] 1- (tert-butyl) -N- (4-chlorobenzyl) -6-iodo-4-oxo-1,4-dihydro-3-quinoline from preparation 31 in 23 ml of stirred diethylamine under argon 0.16 ml of propargyl alcohol was added to a slurry of 1.15 g of carboxamide, 156 mg of copper iodide and 66 mg of dichlorobis (triphenylphosphine) palladium (II). The mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was partitioned between water and chloroform-methanol and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed on silica with 2-4% methanol in dichloromethane to give 977 mg of a tan solid. Recrystallization from ethanol gave 850 mg of the title compound as a beige solid.
[778] Physical properties are as follows.
[779]
[780] Preparation 32
[781] 1- (tert-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[782]
[783] 1- (tert-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1 from Example 39 in 10 ml 1: 1 THF-methanol A mixture of 303 mg of 4-dihydro-3-quinolinecarboxamide and 15 mg of platinum oxide was stirred for 3 hours under 1 atmosphere of hydrogen gas, then filtered through diatomaceous earth and concentrated under reduced pressure. The mixture was purified by flash chromatography on silica using 2-3% methanol in dichloromethane to give 294 mg of the title compound.
[784] Physical properties are as follows.
[785]
[786] Example 40
[787] Sodium 2-[{8- [3- (1- (tert-butyl) -3-{[(4-chlorobenzyl) amino] -carbonyl} -4-oxo-1,4-dihydro-6-qui Nolinyl) propoxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate
[788]
[789] 1- (tert-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3- according to a method analogous to that described in Example 35 The title compound was prepared from quinolinecarboxamide (Preparation 32).
[790] Physical properties are as follows.
[791]
[792] Example 41
[793] Sodium 2-[(8-{[3- (1- (tert-butyl) -3-{[(4-chlorobenzyl) amino] -carbonyl} -4-oxo-1,4-dihydro-6- Quinolinyl) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate
[794]
[795] 1- (tert-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-di according to a method analogous to that described in Example 35 The title compound was prepared from hydro-3-quinolinecarboxamide (Example 39).
[796] Physical properties are as follows.
[797]
[798] Example 42
[799] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[800]
[801] The title compound was obtained from ethyl 1- (tert-butyl) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate according to methods analogous to those described in Preparation 30-31 and Example 39. Prepared.
[802] Physical properties are as follows.
[803]
[804] Preparation 32b
[805] 4- (aminomethyl) benzonitrile
[806] A mixture of 4- (bromomethyl) benzonitrile (7.1 g) and sodium azide (2.6 g) in DMF (40 mL) was stirred for 19 h. Then the reaction mixture was diluted with water (150 mL) and extracted with ether (2 × 50 mL). The organic phases were combined, washed with water (50 mL) and brine (50 mL) and dried over magnesium sulfate. Filtration and evaporation of the solvent gave 5.5 g of 4- (azidomethyl) benzonitrile as a clear colorless oil.
[807] Triphenylphosphine (7.67 g) was added to a solution of 4- (azidomethyl) benzonitrile (4.19 g) in THF (30 mL) and stirred for 1 hour. Water (10 mL) was added and the solution stirred for 16 h. The reaction mixture was diluted with ether (50 mL) and extracted with HCl (3N, 3 × 25 mL) and water (1 × 25 mL). The aqueous phases were combined and washed with ether (50 mL). Sodium hydroxide was added until pH was 12. After extraction with ether (2 x 50 mL), the solution was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting crude mixture was then purified via bulb to bulb distillation at 150 ° C. 1 Torr to afford 1.74 g (50%) of the title compound as a clear colorless oil.
[808] Physical properties are as follows.
[809]
[810] Example 43
[811] N- (4-cyanobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[812]
[813] Ethyl 4-hydroxy-6-iodo-3-quinolinecarboxylate (5.0 g), potassium carbonate (10.4 g) and methyl iodide (0.94 mL) prepared as intermediate in Preparation 4 were added to DMF (100 mL). Suspended and heated at 95 ° C. under a nitrogen atmosphere for 6.5 h. After the mixture was cooled to room temperature, potassium carbonate was filtered off and the solvent was evaporated under reduced pressure until a white solid precipitate precipitated in solution. The white solid was filtered off, washed with water and dried in the air stream. The solid sample (2.0 g) was suspended in ethanol (12 mL) and sodium hydroxide (8 mL, 3N) was added. The mixture was stirred overnight. Then the mixture was acidified with 3N HCl. The resulting solid was filtered, washed with water (3 × 30 mL) and dried in air stream. The solid sample (1.0 g) and 1,1′-carbonyldiimidazole (1.0 g) were suspended in DMF (20 mL) and heated at 70 ° C. for 2 hours. The mixture was cooled to rt and treated with water (0.054 mL). A solution of 0.42 g of 4- (aminomethyl) benzonitrile from Preparation 32b in 10 ml of DMF was added to the mixture and stirred at room temperature for 24 hours. Diluted with 30 ml of water precipitated a white solid from the solution. The solid was filtered off and washed with 1: 1 DMF: water (3 × 20 mL). The white solid (0.5 g) was suspended in diethylamine (17 mL) and treated with copper iodide (0.06 g), bis-triphenylphosphine palladium chloride (0.04 g) and propargyl alcohol (0.08 mL). . The reaction was stirred at rt overnight and evaporated under reduced pressure to reduce volume to give a brown viscous oil. The oil was diluted with CH ₂ Cl ₂ to give an off white solid. The solid was filtered off and then dissolved in hot acetic acid. Insoluble impurities were filtered out of the still hot solution and the solution was cooled to precipitate the product. The solid was filtered off, washed with water (3 × 25 mL) and dried in an air stream on a fritted funnel. This method yielded 0.31 g of the title compound as an off-white solid.
[814] Physical properties are as follows.
[815]
[816] Example 44
[817] 6-{[bis (2-hydroxyethyl) amino] methyl} -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[818]
[819] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (9.5 mL) ( 200 mg), methanesulfonyl chloride (0.048 mL) was added to a cooled (0 ° C.) solution of DMAP (11.5 mg) and 2,4,6-collidine (0.087 mL). The mixture was stirred at room temperature until the starting material was consumed and diethanolamine (0.54 mL) was added. The reaction mixture was heated to 56 ° C. for 1.5 h. The reaction mixture was cooled to room temperature and partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted three times with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a yellow residue. The resulting solid was adsorbed onto silica and chromatographed (1% MeOH in CH ₂ Cl ₂ (1 L), 2% MeOH in CH ₂ Cl ₂ (1 L), 3% MeOH in CH ₂ Cl ₂ (1 L)). ), Developed with 4% MeOH (2 L) in CH ₂ Cl ₂ ). The homogeneous fractions were combined by TLC and concentrated to give 69.3 mg (28%) of the title compound as a white solid.
[820] Physical properties are as follows.
[821]
[822] Example 45
[823] N- (4-chlorobenzyl) -6-{[(2-hydroxyethyl) (methyl) amino] methyl} -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[824]
[825] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (14 mL) ( Methanesulfonyl chloride (0.065 mL) was added to a cooled (0 ° C.) solution of 0.27 g), DMAP (0.017 g) and 2,4,6-collidine (0.12 mL). The mixture was stirred at rt overnight and 2- (methylamino) ethanol (0.61 mL) was added. The reaction mixture was stirred at rt for 2 h, poured into water and extracted three times with CH ₂ Cl ₂ . The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ / MeOH and adsorbed on silica. Chromatography (CH ₂ Cl ₂ (1 L), 1.5% MeOH in CH ₂ Cl ₂ (1 L), 2.5% MeOH in CH ₂ Cl ₂ (1 L), 3.5% MeOH in CH ₂ Cl ₂ (1 L)) , Developed with 5% MeOH in CH ₂ Cl ₂ (1 L), 6% MeOH in CH ₂ Cl ₂ (1 L)) to afford the product as a clear residue. The residue was added CH ₂ Cl ₂ / hexanes and then crystallized by removing the solvent in vacuo to yield 0.21 g (69%) of the title compound as a white solid.
[826] Physical properties are as follows.
[827]
[828] Preparation 33
[829] 1,4-oxa plate
[830] Sodium azide (4.42 mL) was added portionwise to a solution of tetrahydro-4H-pyran-4-one (4.19 mL) in stirred concentrated HCl (23 mL) cooled to 0 ° C. After all additions, the reaction was stirred at room temperature for 4 hours. Sodium carbonate solid was added little by little until the solution became slightly alkaline (pH = 9). Water was added while sodium carbonate was added to dissolve the salt. The alkaline solution was diluted with CHCl ₃ (125 mL) and the phases separated. The aqueous layer was extracted with CHCl ₃ (2 × 75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2.5 g (48%) of 1,4-oxazepan-5-one as an orange-brown residue. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.66, 3.80, 3.35, 2.72.
[831] To a solution of 1,4-oxazepan-5-one (2.5 g) in distilled THF (86 mL) cooled to 0 ° C. was added dropwise a solution of LiAlH ₄ in THF (1M, 21.9 mL). The reaction mixture was stirred for 2.5 h at which additional LiAlH ₄ (11 mL) was added. Water (4 mL), 15% NaOH (4 mL) and water (4 mL) were added sequentially to quench the reaction. The reaction mixture was filtered, the filtrate was dried over sodium sulfate, filtered and concentrated to give 963 mg (44%) of 1,4-oxazepan as a residue.
[832] Physical properties are as follows.
[833]
[834] Example 46
[835] N- (4-chlorobenzyl) -1-methyl-6- (1,4-oxazepan-4-ylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[836]
[837] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (15.7 mL) ( 330 mg), DMAP (19.1 mg) and 2,4,6-collidine (0.14 mL) were added methanesulfonyl chloride (0.080 mL) to a cooled (0 ° C.) solution. The mixture was stirred at room temperature until the starting material was consumed and a solution of 1,4-oxepan (0.963 g) from Preparation 33 in anhydrous DMF (3 mL) was added. The reaction mixture was heated to 56 ° C. for 1.5 h. The mixture was cooled to rt and water (125 mL) was added to precipitate the product. The solid was adsorbed on silica and column chromatography (100% CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (2 L), 1.5% MeOH in CH ₂ Cl ₂ (1 L), CH Purified with 2% MeOH (3 L) in ₂ Cl ₂ ). The homogeneous fractions were combined by TLC and concentrated to give 124.5 mg (31%) of the title compound as a white solid.
[838] Physical properties are as follows.
[839]
[840] Preparation 34
[841] 1,4-thiazepan
[842] To a solution of tetrahydrothiopyran-4-one (4.74 g) in stirred concentrated HCl (20.7 mL) cooled to 0 ° C. was added sodium azide (3.98 g, 61.2 mmol) in portions. After all additions, the reaction was stirred at room temperature for 4 hours. Thereafter, sodium carbonate solid was added little by little until the solution became slightly alkaline (pH = 9). Water was added while sodium carbonate was added to dissolve the salt. The alkaline solution was diluted with CHCl ₃ (125 mL) and the phases separated. The aqueous layer was extracted with CHCl ₃ (2 × 75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from CH ₂ Cl ₂ / hexanes to give 4.30 g (81%) of 1,4-thiazepan-5-one as a white solid.
[843] Physical properties are as follows.
[844]
[845] To a solution of 1,4-thiazepan-5-one (3.0 g) in distilled THF (90 mL) cooled to 0 ° C. was added dropwise a solution of LiAlH ₄ (1M solution, 22.9 mL) in THF. The mixture was stirred at rt for 2 h. Water (2 mL), 15% NaOH (2 mL) and water (2 mL) were added sequentially to quench the reaction. The reaction mixture was filtered to remove precipitated aluminum salts. The filtrate was dried over sodium sulfate, filtered and concentrated to give 2.63 g (98%) of 1,4-thiazephan as a yellow residue.
[846] Physical properties are as follows.
[847]
[848] Example 47
[849] N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (1,4-thiazepan-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide
[850]
[851] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (19 mL) ( Methanesulfonyl chloride (0.096 mL) was added to a cooled (0 ° C.) solution of 400 mg), DMAP (23 mg) and 2,4,6-collidine (0.17 mL). The mixture was stirred at room temperature until the starting material was consumed and 1,4-thiazephan (1.13 g) from Preparation 34 was added. The reaction mixture was heated to 65 ° C. for 1.5 h. The mixture was cooled to rt and water (125 mL) was added to precipitate the product. The solid was adsorbed onto silica and column chromatography (100% CH ₂ Cl ₂ (1 L), 0.5% MeOH in CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (1 L), CH)). Purified with 1.5% MeOH (2.5 L) in ₂ Cl ₂ ). The homogeneous fractions were combined by TLC and concentrated to give 338.7 mg (66%) of the title compound as a white solid.
[852] Physical properties are as follows.
[853]
[854] Example 48
[855] N- (4-chlorobenzyl) -1-methyl-6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide
[856]
[857] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (12 mL) ( Methanesulfonyl chloride (0.06 mL) was added to a cooled (0 ° C.) solution of 250 mg), DMAP (14.4 mg) and 2,4,6-collidine (0.11 mL). The mixture was stirred at room temperature until the starting material was consumed. (1S, 4S)-(+)-2-aza-5-oxabicyclo [2.2.1] heptane hydrochloride (475.9 mg) and Et ₃ N (0.49 mL) were added to the solution. The reaction mixture was heated to 65 ° C. overnight. The mixture was cooled to room temperature and filtered to remove the precipitated salt from the solution. The filtrate was diluted with water (125 mL) to precipitate the product. The solid was adsorbed on silica and column chromatography (1% MeOH in CH ₂ Cl ₂ (1 L), 2% MeOH in CH ₂ Cl ₂ (1 L), 3% MeOH in CH ₂ Cl ₂ (2.5 L)). Developed into). The homogeneous fractions were combined by TLC, concentrated and recrystallized from CH ₂ Cl ₂ / hexanes to give 164.0 mg (53%) of the title compound as a white solid.
[858] Physical properties are as follows.
[859]
[860] Example 49
[861] N- (4-chlorobenzyl) -6- (2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl) -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[862]
[863] To a cooled (0 ° C.) solution of (2H) 1,4-benzoxazin-3 (4H) -one (5.04 g) in freshly distilled THF (110 mL) was added LiAlH ₄ (34 mL, THF via funnel Solution in 1M) was added dropwise. LiAlH ₄ was added while maintaining the reaction temperature below 10 ° C. The mixture was stirred at rt for 2 h, then water (5 mL), 15% NaOH (5 mL) and water (5 mL) were added sequentially to quench the reaction. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ , dried over sodium sulfate, filtered and concentrated to give the product benzomorpholine as a yellow oil, which was used without further purification in the next step.
[864] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (15 mL) ( Methanesulfonyl chloride (0.10 mL) was added to a cooled (0 ° C.) solution of 0.41 g), DMAP (0.030 g) and 2,4,6-collidine (0.19 mL). The mixture was stirred at rt for 12 h and then benzomorpholine (1.60 g) was added. The reaction mixture was stirred at rt for 2 h and then heated to 65 ° C. overnight. The mixture was cooled to room temperature and poured water. The solid was dissolved in CH ₂ Cl ₂ / MeOH and adsorbed onto silica. Purified by column chromatography (CH ₂ Cl ₂ (1 L), developed with 1% MeOH in CH ₂ Cl ₂ (2 L)), and then recrystallized from CH ₂ Cl ₂ / hexanes to give 0.56 g (100 of the title compound). %) Was obtained as a pale golden solid.
[865] Physical properties are as follows.
[866]
[867] Example 50
[868] 6-((benzyl (2-hydroxyethyl) amino) methyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[869]
[870] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (20 mL) ( 357 mg), DMAP (20 mg) and 2,4,6-collidine (0.33 mL) were added methanesulfonyl chloride (0.193 mL). The mixture was stirred at rt for 3 h and then N-benzylethanolamine (1.42 mL) was added. The reaction mixture was stirred at rt for 20 h, poured into water (60 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (CH ₂ Cl ₂ / methanol, 100/1; 50/1) to give 0.35 g (71%) of the title compound as a white solid.
[871] Physical properties are as follows.
[872]
[873] Preparation 35
[874] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[875]
[876] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation 10 in anhydrous DMF (48 mL) ( 1.0 g), collidine (0.44 mL) and a solution of DMAP (57.9 mg) were cooled to 0 ° C. Methanesulfonyl chloride (0.24 mL) was added dropwise. The reaction was stirred at rt. The crude product was precipitated by addition of water and filtered. The resulting solid was adsorbed on silica and purified by chromatography (developed with 100% CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (1 L)). Product containing fractions were combined and concentrated to give 948.8 mg (90%) of the title compound as a white solid.
[877] Physical properties are as follows.
[878]
[879] Example 51
[880] 6- (azidomethyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[881]
[882] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (200 from Preparation 35 in anhydrous DMF (7 mL) Mg) and sodium azide (176.8 mg) were heated at 60 ° C. overnight. The reaction was cooled to room temperature and poured into water to precipitate the product. The solid was adsorbed onto silica and developed with chromatography (100% CH ₂ Cl ₂ (1 L), 0.5% MeOH in CH ₂ Cl ₂ (1 L) and 1% MeOH in CH ₂ Cl ₂ (1 L)). Purified). The homogeneous fractions were combined by TLC and concentrated to give 182.7 mg (90%) of the title compound as a white solid.
[883] Physical properties are as follows.
[884]
[885] Preparation 36
[886] t-butyl-4,4-difluoro-1-piperidinecarboxylate and t-butyl-4-fluoro-3,6-dihydro-1 [2H] -pyridinecarboxylate
[887] To a solution of 1- (t-butoxycarbonyl) -4-piperidone in distilled THF (41 mL) was added diethylamino sulfur trifluoride (4.39 mL). The reaction was heated at 60 ° C. for 6 hours and then cooled to room temperature overnight. The reaction mixture was poured into 120 mL of ice water. The phases were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give yellow crystals. The crude product was adsorbed on silica and purified by chromatography (developed with 1% EtOAc in hexanes (1 L), 2% EtOAc in hexanes (1 L), 3% EtOAc in hexanes (1 L)). The homogeneous fractions were combined by TLC and concentrated to give a mixture of both products. The product was isolated by HPLC to give 543.8 mg (16%) of t-butyl-4,4-difluoro-1-piperidine-carboxylate [ ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.56, 1.94, 1.48] as a white solid, t-butyl-4-fluoro-3,6-dihydro-1 [2H] -pyridinecarboxylate 196 mg (7%) [ ¹ H NMR (300 MHz, CDCl ₃ ) δ5 .21, 3.93, 3.62, 2.31, 1.48] were obtained as a yellow residue.
[888] Preparation 37
[889] 4,4-difluoropiperidine
[890] To a solution of t-butyl-4,4-difluoro-1-piperidinecarboxylate (510 mg) from Preparation 36 in CH ₂ Cl ₂ (2 mL) was added trifluoroacetic acid (0.71 mL). It was. The reaction was stirred at rt for 2.5 h and then partitioned between saturated NaHCO ₃ and CH ₂ Cl ₂ . The aqueous layer was extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were dried over sodium sulphate, filtered and concentrated until the product began to evaporate (visible to bubbling violently). More than 50 mg (18%) of 4,4-difluoropiperidine was obtained as a clear liquid.
[891] Physical properties are as follows.
[892]
[893] Example 52
[894] N- (4-chlorobenzyl) -6-[(4,4-difluoro-1-piperidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides
[895]
[896] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4-dihydro-3 from Production 35 in 1-methyl-2-pyrrolidinone (3 mL) To a solution of -quinolinecarboxamide (50 mg) was added N, N-diisopropylethylamine (0.03 mL) and 4,4-difluoropiperidine (50 mg) from Preparation 37. The reaction mixture was stirred overnight at room temperature and then heated at 50 ° C. for 4 hours. The mixture was cooled to room temperature and poured into water to precipitate the product. The crude solid was recrystallized from CH ₂ Cl ₂ / hexanes to give 51.5 mg (84%) of the title compound as a white solid.
[897] Physical properties are as follows.
[898]
[899] Preparation 38
[900] 4-fluoro-1,2,3,6-tetrahydropyridine hydrochloride
[901] On the surface of a cooled (0 ° C.) solution of t-butyl-4-fluoro-3,6-dihydro-1 [2H] -pyridinecarboxylate (196 mg) from Preparation 36 in MeOH (3 mL). Pass dry HCl for 1 minute. The reaction mixture was capped and stirred at 0 ° C. for 15 minutes and then at room temperature for 15 minutes. The mixture was concentrated to give 119 mg (100%) of 4-fluoro-1,2,3,6-tetrahydropyridine hydrochloride as an orange-brown residue.
[902] Example 53
[903] N- (4-chlorobenzyl) -6-((4-fluoro-3,6-dihydro-1 (2H) -pyridinyl) methyl) -1-methyl-4-oxo-1,4-dihydro -3-quinolinecarboxamide
[904]
[905] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4-dihydro-3 from Production 35 in 1-methyl-2-pyrrolidinone (3 mL) To a solution of -quinolinecarboxamide (60 mg) N, N-diisopropylethylamine (0.075 mL) and 4-fluoro-1,2,3,6-tetrahydropyridine hydrochloride from Preparation 38 (119 Mg) was added. The reaction mixture was stirred at rt overnight, then heated at 60 ° C. for 4 h. The mixture was cooled to room temperature and poured into water to precipitate the product. The crude solid was adsorbed onto silica and chromatographed (100% CH ₂ Cl ₂ (1 L), 0.25% MeOH in CH ₂ Cl ₂ (1 L), 0.5% MeOH in CH ₂ Cl ₂ (1 L), CH ₂ 0.75% MeOH in Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (1 L), 1.25% MeOH in CH ₂ Cl ₂ (1 L), 1.5% MeOH in CH ₂ Cl ₂ (2 L) Developed). The homogeneous fractions were combined by TLC and concentrated to give 32.2 mg (46%) of the desired product as a white solid.
[906] Physical properties are as follows.
[907]
[908] Preparation 39
[909] N- (4-chlorobenzyl) -6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[910]
[911] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide (12.07 g) and potassium carbonate (5.70 g) from Preparation 4 were dissolved in DMF (90 mL). Iodomethane (2.1 mL) was added and the mixture was stirred at rt for 1 h. The resulting suspension was poured into water (500 mL) and filtered. The crude solid was washed with water (50 mL) and diethyl ether (100 mL) and then recrystallized from ethanol to give 10.6 g (85%) of the title compound as a white solid.
[912] Physical properties are as follows.
[913]
[914] Example 54
[915] N- (4-chlorobenzyl) -1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinolinecarboxamide
[916]
[917] N- (4-chlorobenzyl) -6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.45 g) and PdCl ₂ (PPh ₃ ) from Preparation 39 _To a solution of ₂ (70 mg) tributylvinylstanan (0.32 mL) was added. The mixture was stirred at rt for 1 h and then heated at 60 ° C. for 30 min. After cooling to room temperature, the reaction mixture was poured into water (60 mL), filtered and washed with water (20 mL) and diethyl ether (20 mL). The crude product was purified by recrystallization from acetonitrile to give 0.20 g (57%) of the title compound as a white solid.
[918] Physical properties are as follows.
[919]
[920] Recipe 40
[921] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide
[922]
[923] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarboxamide (1.71 g) from Preparation 9 in DMF (50 mL) was dried under a 0 ° C dry tube. Treated with 4-dimethylaminopyridine (0.12 g), 2,4,6-collidine (1.05 mL) and methanesulfonylchloride (0.60 mL). The mixture was allowed to slowly warm up to room temperature overnight. The reaction mixture was then treated with morpholine (8.0 mL) and stirred for 4 hours. The reaction mixture was poured into water (250 mL) and extracted with dichloromethane (5 x 50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization from methanol-acetonitrile (1/1, 150 mL) to give 1.7 g of the title compound as a white solid.
[924] Physical properties are as follows.
[925]
[926] Example 55
[927] N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[928]
[929] Solution of N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide (0.37 g) from DMF (10 mL) Was treated with potassium carbonate (2.75 g), potassium iodide (1.66 g) and 2- (2-chloroethoxy) ethanol (1.0 mL). The mixture was tightly sealed with a lid and heated to 100 ° C. for 48 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane. The layers were separated and the aqueous layer was reextracted with dichloromethane containing a small amount of methanol and finally extracted again with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography developing with 3% to 15% methanol in dichloromethane and then recrystallized from methanol to give 82 mg of the title compound as a light yellow solid.
[930] Physical properties are as follows.
[931]
[932] Example 56
[933] N- (4-chlorobenzyl) -1- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide
[934]
[935] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (165 mg), triethylene glycol monomethyl ether (0.10 mL) and diethyl azodicarboxylate (0.10 mL) were added to the containing dry flask. The mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 2% to 8% methanol in dichloromethane and then purified by recrystallization from ethyl acetate-heptane to give 164 mg of the title compound as a white solid.
[936] Physical properties are as follows.
[937]
[938] Example 57
[939] N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[940]
[941] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (165 mg), triethylene glycol (0.20 mL) and diethyl azodicarboxylate (0.10 mL) were added to the containing dry flask. The mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography, developing with 10% to 40% methanol in ethyl acetate, and then recrystallized from ethyl acetate to give 68 mg of the title compound as a white solid.
[942] Physical properties are as follows.
[943]
[944] Example 58
[945] N- (4-chlorobenzyl) -1- [2- (2-ethoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[946]
[947] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (164 mg), 2-ethoxy- (2-ethoxy) ethanol (0.09 mL) and diethyl azodicarboxylate (0.10 mL) were added to the containing dry flask. The mixture was stirred at rt overnight. The reaction mixture was again treated with triphenylphosphine (164 mg), 2-ethoxy- (2-ethoxy) ethanol (0.09 mL) and diethyl azodicarboxylate (0.10 mL). After 4 hours, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography developing with acetone and then recrystallized from ethyl acetate-heptane to give 0.18 g of the title compound as a white solid.
[948] Physical properties are as follows.
[949]
[950] Example 59
[951] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (2-propynyl) -1,4-dihydro-3-quinolinecarboxamide
[952]
[953] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (393 mg), propargyl alcohol (0.09 mL) and diethyl azodicarboxylate (0.18 mL) were added to the containing dry flask. The mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and adsorbed onto silica gel. The crude product was subjected to flash column chromatography developing with 2% to 6% methanol in dichloromethane and then purified by recrystallization from acetonitrile to give 0.20 g of the title compound as a white solid.
[954] Physical properties are as follows.
[955]
[956] Example 60
[957] N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[958]
[959] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (393 mg), ethyl 2-hydroxyethylsulfide (0.16 mL) and diethyl azodicarboxylate (0.18 mL) were added to the containing dry flask. The mixture was stirred at rt overnight, then concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 2% to 6% methanol in dichloromethane and then purified by recrystallization from ethanol-cyclohexane to give 0.21 g of the title compound as a white solid.
[960] Physical properties are as follows.
[961]
[962] Example 61
[963] N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[964]
[965] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (396 mg), 3-methylthiolpropanol (0.16 mL) and diethyl azodicarboxylate (0.18 mL) were added to the containing dry flask. The mixture was stirred at rt for 48 h and then concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 2% to 6% methanol in dichloromethane and then recrystallized from toluene-cyclohexane to give 0.14 g of the title compound as a white solid.
[966] Physical properties are as follows.
[967]
[968] Example 62
[969] N- (4-chlorobenzyl) -1- (4-hydroxy-2-butynyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides
[970]
[971] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (393 mg), 1,4-butyne diol (0.45 g) and diethyl azodicarboxylate (0.18 mL) were added to the containing dry flask. The mixture was stirred at rt overnight, then concentrated under reduced pressure and adsorbed onto silica gel. The crude product was subjected to flash column chromatography developing with 2% to 6% methanol in dichloromethane and then purified by recrystallization from methanol-acetonitrile to give 0.16 g of the title compound as a white solid.
[972] Physical properties are as follows.
[973]
[974] Example 63
[975] N- (4-chlorobenzyl) -6-{[(2-hydroxy-2-phenylethyl) (methyl) amino] methyl} -1-methyl-4-oxo-1,4-dihydro-3-quinoline Carboxamide
[976]
[977] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4 from preparation 35 in dry NMP (2 mL) containing diisopropylethylamine (0.04 mL) A solution of dihydro-3-quinolinecarboxamide (0.06 g) was treated with α- (methylaminomethyl) -benzyl alcohol (0.04 g). The reaction mixture was shaken for 3 days at room temperature and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The separated organic layer was washed twice with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was adsorbed on silica and flash column chromatography developing with 2% to 6% methanol in dichloromethane and then recrystallized from ethyl acetate-hexane to afford 0.05 g of the title compound as a white solid.
[978] Physical properties are as follows.
[979]
[980] Example 64
[981] 1- {2- [bis (2-hydroxyethyl) amino] ethyl} -N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[982]
[983] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (363 mg), triethanolamine (1.3 mL) and diethyl azodicarboxylate (0.18 mL) were added to the containing dry flask. The mixture was stirred at rt for 4 days. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography running with 3% to 9% methanol in dichloromethane. The product fractions were concentrated under reduced pressure, dissolved in a small amount of ethyl acetate-diethyl ether and excess hexane was added dropwise. The resulting precipitate was collected by filtration, washed with diethyl ether and then with hexane to afford 0.04 g of the title compound as a white solid.
[984] Physical properties are as follows.
[985]
[986] Example 65
[987] N- (4-chlorobenzyl) -1- [3- (methylsulfinyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[988]
[989] N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4- from Example 61 in dichloromethane (2 mL) at 0 ° C P-toluenesulfonic acid hydrate (0.04 g) was added to a solution of oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 g), followed by m-chloroperoxybenzoic acid (˜85%) (0.045 g). Was added. The mixture was stirred for 0.5 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography developing with 3% to 9% methanol in dichloromethane. The product fractions were combined and recrystallized from ethyl acetate-methanol-hexane to give 0.07 g of the title compound as a white solid.
[990] Physical properties are as follows.
[991]
[992] Example 66
[993] N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[994]
[995] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (314 mg), 3,3'-thiodipropanol (0.7 mL) and diethyl azodicarboxylate (0.18 mL) were added to the containing dry flask. The mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography developing with 5% to 15% methanol in dichloromethane. The product fractions were concentrated under reduced pressure and recrystallized from ethyl acetate-hexane to give 0.20 g of the title compound as a white solid.
[996] Physical properties are as follows.
[997]
[998] Example 67
[999] N- (4-chlorobenzyl) -1- [3- (methylsulfonyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1000]
[1001] N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4- from Example 61 in dichloromethane (2 mL) at 0 ° C P-toluenesulfonic acid hydrate (0.04 g) was added to a solution of oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 g), followed by m-chloroperoxybenzoic acid (~ 85%) (0.09 g) Was added. The mixture was stirred for 0.5 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography developing with 3% to 6% methanol in dichloromethane to afford 0.07 g of the title compound as a white solid.
[1002] Physical properties are as follows.
[1003]
[1004] Example 68
[1005] N- (4-chlorobenzyl) -1- [2- (ethylsulfinyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1006]
[1007] N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4- from Example 60 in dichloromethane (2 mL) at 0 ° C P-toluenesulfonic acid hydrate (0.04 g) was added to a solution of oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 g), followed by m-chloroperoxybenzoic acid (~ 85%) (0.045 g) Was added. The mixture was stirred for 0.5 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 3% to 9% methanol in dichloromethane and then purified by recrystallization from acetonitrile to give 0.05 g of the title compound as a white solid.
[1008] Physical properties are as follows.
[1009]
[1010] Example 69
[1011] N- (4-chlorobenzyl) -1- [2- (ethylsulfonyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1012]
[1013] N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4- from Example 60 in dichloromethane (2 mL) at 0 ° C P-toluenesulfonic acid hydrate (0.04 g) was added to a solution of oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 g), followed by m-chloroperoxybenzoic acid (~ 85%) (0.085 g) Was added. The mixture was stirred for 0.5 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from acetonitrile to give 0.08 g of the title compound as a white solid.
[1014] Physical properties are as follows.
[1015]
[1016] Example 70
[1017] N- (4-chlorobenzyl) -1- (3-[(3-hydroxypropyl) sulfinyl] propyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[1018]
[1019] N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholi) from Example 66 in dichloromethane (5 mL) at 0 ° C. P-toluenesulfonic acid hydrate (0.10 g) was added to a solution of nilmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.27 g), followed by m-chloroperoxybenzoic acid (˜85). %) (0.10 g) was added. The mixture was stirred for 0.5 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography developing with 3% to 25% methanol in dichloromethane to give 0.17 g of the title compound as a white solid.
[1020] Physical properties are as follows.
[1021]
[1022] Example 71
[1023] N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfonyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[1024]
[1025] N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholi) from Example 66 in dichloromethane (5 mL) at 0 ° C. P-toluenesulfonic acid hydrate (0.10 g) was added to a solution of nilmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.27 g), followed by m-chloroperoxybenzoic acid (˜85). %) (0.20 g) was added. The mixture was stirred for 0.5 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 3% to 9% methanol in dichloromethane and then purified by recrystallization from acetonitrile to afford 0.08 g of the title compound as a white solid.
[1026] Physical properties are as follows.
[1027]
[1028] Example 72
[1029] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- [2- (phenylsulfanyl) ethyl] -1,4-dihydro-3-quinolinecarboxamide
[1030]
[1031] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.20 g) from preparation 40 in dry THF (5 mL) under argon atmosphere. Triphenylphosphine (284 mg), 2-hydroxyethyl phenyl sulfide (0.27 mL) and diethyl azodicarboxylate (0.17 mL) were added to the containing dry flask. The mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography developing with 5% to 15% methanol in dichloromethane. The product fractions were concentrated under reduced pressure and recrystallized from acetonitrile to give 0.21 g of the title compound as a white solid.
[1032] Physical properties are as follows.
[1033]
[1034] Example 73
[1035] N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1036]
[1037] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.21 g) from Preparation 40 in DMF (4 mL) was cesium carbonate (0.33 g) and chloromethyl methyl sulfide (0.05 mL). The mixture was tightly sealed with a lid and stirred at room temperature for 3 hours and then heated to 90 ° C. for 1 hour. The reaction mixture was cooled to rt, diluted with dichloromethane (50 mL), washed with water (2 ×), brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 2% to 4% methanol in dichloromethane and then purified by recrystallization from acetonitrile to give 0.1 g of the title compound as a white solid.
[1038] Physical properties are as follows.
[1039]
[1040] Example 74
[1041] N- (4-chlorobenzyl) -6-([[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) -amino] methyl) -1-methyl-4-oxo-1,4 -Dihydro-3-quinolinecarboxamide
[1042]
[1043] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4 from preparation 35 in dry DMF (2 mL) containing diisopropylethylamine (0.07 mL) A solution of dihydro-3-quinolinecarboxamide (0.09 g) was treated with cinephrine (0.05 g). The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (2 × 10 mL), brine (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography, evolving with 3% to 6% methanol in dichloromethane and then purified by recrystallization from toluene to afford 0.09 g of the title compound as a tan solid.
[1044] Physical properties are as follows.
[1045]
[1046] Example 75
[1047] N- (4-chlorobenzyl) -6-[(3-hydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1048]
[1049] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4 from preparation 35 in dry NMP (2 mL) containing diisopropylethylamine (0.14 mL) A solution of dihydro-3-quinolinecarboxamide (0.09 g) was treated with 3-azetidinol hydrochloride (0.04 g, prepared as described in Helv. Chim. Acta 1988, 1035). The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (2 × 10 mL), brine (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was flash column chromatographed while developing with 5% to 20% methanol in dichloromethane and then purified by recrystallization from methanol-acetonitrile to afford 0.08 g of the title compound as off-white solid.
[1050] Physical properties are as follows.
[1051]
[1052] Example 76
[1053] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] -1,4-dihydro-3-quinolinecarboxamide
[1054]
[1055] A solution of N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.21 g) from Preparation 40 in DMF (4 mL) was cesium carbonate (0.30 g) and chloromethyl phenyl sulfide (0.08 mL). The mixture was tightly sealed with a lid and heated to 75 ° C. for 8 hours. The reaction mixture was cooled to rt, diluted with dichloromethane (50 mL), washed with water (2 × 10 mL), brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 2% to 4% methanol in dichloromethane and then purified by recrystallization from ethyl acetate-hexane to give 0.19 g of the title compound as a white solid.
[1056] Physical properties are as follows.
[1057]
[1058] Example 77
[1059] N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl] (methyl) amino] methyl} -1-methyl-4-oxo -1,4-dihydro-3-quinolinecarboxamide
[1060]
[1061] N- (4-chlorobenzyl) -6- (chloromethyl) -1-methyl-4-oxo-1,4 from preparation 35 in dry DMF (2 mL) containing diisopropylethylamine (0.18 mL) A solution of dihydro-3-quinolinecarboxamide (0.09 g) was treated with dl-methaneprin hydrochloride (0.12 g). The reaction mixture was stirred at rt for 3 days. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (2 × 10 mL), brine (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography developing with 2% to 5% methanol in dichloromethane and then purified by recrystallization from methanol-toluene to afford 0.08 g of the title compound as an off-white solid.
[1062] Physical properties are as follows.
[1063]
[1064] Example 78
[1065] N- (4-chlorobenzyl) -6-[(3,3-dihydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides
[1066]
[1067] N- (4-chlorobenzyl) -6-[(3-hydroxy-1-azetidinyl) methyl] -1 from Example 75 in dry DMSO (3 mL) containing triethylamine (0.35 mL) A solution of -methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 g) was treated with pyridine-sulfur trioxide complex (0.25 g). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water (2 ×), brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from acetonitrile to afford 0.06 g of the title compound as a tan solid.
[1068] Physical properties are as follows.
[1069]
[1070] Example 79
[1071] N- (4-chlorobenzyl) -1-[(methylsulfinyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1072]
[1073] N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo- from Example 73 in dichloromethane (4 mL) at 0 ° C. P-toluenesulfonic acid hydrate (0.06 g) was added to a solution of 1,4-dihydro-3-quinolinecarboxamide (0.14 g), followed by m-chloroperoxybenzoic acid (˜85%) (0.06 g). It was. The mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization from methanol-acetonitrile to give 0.11 g of the title compound as a white solid.
[1074] Physical properties are as follows.
[1075]
[1076] Example 80
[1077] N- (4-chlorobenzyl) -1-[(methylsulfonyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1078]
[1079] N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo- from Example 73 in dichloromethane (4 mL) at 0 ° C. To a solution of 1,4-dihydro-3-quinolinecarboxamide (0.14 g) was added p-toluenesulfonic acid hydrate (0.06 g), followed by m-chloroperoxybenzoic acid (˜85%) (0.13 g). It was. The mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 3% to 9% methanol in dichloromethane and then purified by recrystallization from ethyl acetate-hexane to afford 0.08 g of the title compound as a white solid.
[1080] Physical properties are as follows.
[1081]
[1082] Example 81
[1083] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfinyl) -methyl] -1,4-dihydro-3-quinolinecarboxamide
[1084]
[1085] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] from Example 76 in dichloromethane (2 mL) at 0 ° C. P-toluenesulfonic acid hydrate (0.03 g) was added to a solution of -1,4-dihydro-3-quinolinecarboxamide (0.08 g), followed by m-chloroperoxybenzoic acid (˜85%) (0.03 g). Was added. The mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization from acetonitrile to afford 0.06 g of the title compound as a white solid.
[1086] Physical properties are as follows.
[1087]
[1088] Example 82
[1089] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfonyl) -methyl] -1,4-dihydro-3-quinolinecarboxamide
[1090]
[1091] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] from Example 76 in dichloromethane (4 mL) at 0 ° C. P-toluenesulfonic acid hydrate (0.03 g) was added to a solution of -1,4-dihydro-3-quinolinecarboxamide (0.08 g), followed by m-chloroperoxybenzoic acid (˜85%) (0.06 g). Was added. The mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization from acetonitrile to afford 0.07 g of the title compound as a white solid.
[1092] Physical properties are as follows.
[1093]
[1094] Example 83
[1095] N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecar Voxamide
[1096]
[1097] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy)-which is the product of Example 42 according to the method described in Preparation 27 The title compound was prepared from ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide.
[1098] Preparation 41
[1099] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1100]
[1101] N- (4-chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarboxamide (3.3 g), from cesium carbonate (6.33 g from stirred 9 in DMF (10 mL) ) And 2- (2-methoxyethoxy) ethyl p-toluenesulfonate (4.0 g) were heated at 50 ° C. for 18 hours, then cooled and partitioned between ethyl acetate and dilute HCl. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed on silica with 4% to 5% methanol in dichloromethane to give 3.0 g of the title compound.
[1102] Physical properties are as follows.
[1103]
[1104] Example 84
[1105] N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[1106]
[1107] N- (4-chlorobenzyl) -6- (hydroxymethyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1 from Preparation 41 in stirred DMF (1 mL) To a solution of, 4-dihydro-3-quinolinecarboxamide (197 mg) was added 2,4,6-collidine (0.14 mL) and DMAP (8 mg). The solution was cooled to 0 ° C. and methanesulfonyl chloride (69 μl) was added. After 18 hours, the mixture was added to 20 ml of water containing 0.75 ml of rapidly stirred 1N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give N- (4-chlorobenzyl) -6- (chloromethyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo 183 mg of -1,4-dihydro-3-quinolinecarboxamide was obtained.
[1108] To a solution of the chloride (93 mg) in DMF (1 mL) was added morpholine (53 μl). The solution was stirred for 18 hours and then concentrated under reduced pressure. The residue was flash chromatographed on silica with 3% -4% methanol in dichloromethane to give 98.7 mg of the title compound as a white crystalline solid. Analytical samples can be prepared by recrystallization from ethyl acetate in hexanes.
[1109] Physical properties are as follows.
[1110]
[1111] Example 85
[1112] N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-6-[(4-oxo-1-piperidinyl) methyl] -1,4- Dihydro-3-quinolinecarboxamide
[1113]
[1114] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1115]
[1116] Example 86
[1117] N- (4-chlorobenzyl) -6-{[(cyanomethyl) (methyl) amino] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4- Dihydro-3-quinolinecarboxamide
[1118]
[1119] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1120]
[1121] Example 87
[1122] N- (4-chlorobenzyl) -6-{[(3R) -3-hydroxypyrrolidinyl] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1, 4-dihydro-3-quinolinecarboxamide
[1123]
[1124] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1125]
[1126] Example 88
[1127] N- (4-chlorobenzyl) -6-{[[(1R, 2S) -2-hydroxy-1-methyl-2-phenylethyl] (methyl) -amino] methyl} -1- [2- (2 -Methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1128]
[1129] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1130]
[1131] Example 89
[1132] N- (4-chlorobenzyl) -6-{[(2-hydroxy-2-phenylethyl) (methyl) amino] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4- Oxo-1,4-dihydro-3-quinolinecarboxamide
[1133]
[1134] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1135]
[1136] Example 90
[1137] N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) amino] -methyl} -1- [2- (2-methoxy Methoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1138]
[1139] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1140]
[1141] Example 91
[1142] 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[1143]
[1144] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1145]
[1146] Example 92
[1147] 1- {2- [2- (tert-butoxy) ethoxy] ethyl} -N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (Methyl) amino] methyl} -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1148]
[1149] The title compound was prepared in a similar manner as described in Example 84. Physical properties are as follows.
[1150]
[1151] Example 93
[1152] N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6-[(methylsulfanyl) methyl] -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[1153]
[1154] N- (4-chlorobenzyl) -6- (chloromethyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo prepared as described in Example 84 in DMF (1.5 mL) To a suspension of -1,4-dihydro-3-quinolinecarboxamide (175 mg) was added sodium thiomethoxide (40 mg). The mixture was stirred for 18 hours and then added to 25 ml of rapidly stirred water. The solid was filtered, washed with water, dried in vacuo and recrystallized from acetonitrile to give 139 mg of the title compound as pale yellow crystals.
[1155] Physical properties are as follows.
[1156]
[1157] Preparation 42
[1158] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboximidoyl chloride
[1159]
[1160] A suspension of N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide (0.75 g) from Preparation 4 in dichloroethane (15 mL) was heated to 65 ° C. Phosphorus pentachloride (0.57 g) was added in one portion. After 1.25 hours, the reaction mixture was cooled to room temperature and the solvent was evaporated under nitrogen flow. Dichloromethane (20 mL) was added followed by toluene (6 mL) and the resulting solid was filtered and dried to give N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecart. Voximidoyl chloride (0.77 g) was obtained.
[1161] Physical properties are as follows.
[1162]
[1163] Preparation 43
[1164] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarbothioamide
[1165]
[1166] Hydrogen sulfide was bubbled in a solution of anhydrous pyridine (40 mL) cooled to 0 ° C. for 30 minutes. N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboximidoyl chloride (1.14 g) from Preparation 42 was added in one portion. After 15 minutes, the ice bath was removed and the reaction stirred for 18 hours at room temperature with continued bubbling of hydrogen sulfide. The reaction mixture was poured into ice water and the resulting solid was filtered and dried. The solid is dissolved in CH ₂ Cl ₂ / MeOH, adsorbed on silica, chromatography (CH ₂ Cl ₂ (1 L), 0.5% MeOH in CH ₂ Cl ₂ (1 L), 0.75% in CH ₂ Cl ₂ ) Purified with MeOH (6 L)) to give N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.90 g) as a yellow solid.
[1167] Physical properties are as follows.
[1168]
[1169] Preparation 44
[1170] N- (4-chlorobenzyl) -6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide
[1171]
[1172] N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.20 g) and triphenylphosphine from preparation 43 in freshly distilled tetrahydrofuran (5 mL) MeOH (0.027 mL) was added to a suspension of (0.15 g), followed by diethyl azodicarboxylate. After the initial exothermic reaction, the reaction was stirred at room temperature for 3 hours. Additional triphenylphosphine (0.030 g), methanol (0.010 mL) and diethyl azodicarboxylate (0.020 mL) were added to terminate the reaction. The reaction was stirred at rt overnight. The reaction was concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ and adsorbed on silica. Purification by chromatography (CH ₂ Cl ₂ (1 L), developed with 1% MeOH in CH ₂ Cl ₂ (1 L)) N- (4-chlorobenzyl) -6-iodo-1-methyl-4 -Oxo-1,4-dihydro-3-quinolinecarbothioamide (0.065 g) was obtained as a yellow solid.
[1173] Physical properties are as follows.
[1174]
[1175] Example 94
[1176] N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide
[1177]
[1178] N- (4-Chlorobenzyl) -6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide (0.20) from Preparation 44 in diethylamine (10 mL) g), a suspension of propargyl alcohol (0.030 mL), copper iodide (0.028 g) and bis (triphenylphosphine) palladium (II) chloride (0.0095 g) was stirred at room temperature for 18 hours. The solid in the reaction mixture was filtered, dissolved in CH ₂ Cl ₂ / MeOH and adsorbed onto silica. Purification by chromatography (developed with 1% MeOH in CH ₂ Cl ₂ (1 L), 2% MeOH in CH ₂ Cl ₂ (1 L)) gave 0.12 g of the title compound as a yellow solid.
[1179] Physical properties are as follows.
[1180]
[1181] Preparation 45
[1182] Methyl 3-{[(4-chlorobenzyl) amino] carbothioyl} -4-hydroxy-6-quinolinecarboxylate
[1183]
[1184] Dimethylformamide (anhydride, 5 mL) was added to the flame dried flask. The solution was purged with nitrogen for 15 minutes. To this solution was added N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.25 g), methanol (0.90 mL), triethylamine (0.16 mL) from Preparation 44. ) And dichlorobis (triphenylphosphine) palladium (0.068 g) were added. The reaction was placed under a CO balloon and stirred at 70 ° C. for 3 hours. The reaction was cooled to rt and poured into 1N HCl (40 mL). The resulting solid was filtered and dried. The solid was dissolved in CH ₂ Cl ₂ / MeOH and adsorbed onto silica. Purified by chromatography (developed with CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (2 L), 3% MeOH in CH ₂ Cl ₂ (1 L)), methyl 3-{[( 4-chlorobenzyl) amino] carbothioyl} -4-hydroxy-6-quinolinecarboxylate (0.090 g) was obtained as a yellow solid.
[1185] Physical properties are as follows.
[1186]
[1187] Preparation 46
[1188] N- (4-chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarbothioamide
[1189]
[1190] Room temperature in a suspension of methyl 3-{[(4-chlorobenzyl) amino] carbothioyl} -4-hydroxy-6-quinolinecarboxylate (0.062 g) from preparation 45 in freshly distilled THF (8 mL) Lithium aluminum hydride (1M in THF, 0.34 mL) was added dropwise. After 45 minutes the reaction was quenched sequentially with 1 mL of water, 1 mL of 15% NaOH and 1 mL of water. The reaction mixture was concentrated in vacuo. The residue was adsorbed onto silica. Purified by chromatography (developed by 1% MeOH in CH ₂ Cl ₂ (1 L), 2% MeOH in CH ₂ Cl ₂ (1 L) and 3% MeOH in CH ₂ Cl ₂ (1 L)). (4-Chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarbothioamide (0.038 g) was obtained.
[1191] Physical properties are as follows.
[1192]
[1193] Preparation 47
[1194] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarbothioamide
[1195]
[1196] N- (4-chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarbothioamide from preparation 46 in anhydrous dimethylformamide (4 mL) in a flame dried flask (0.082 g) To a solution of dimethylaminopyridine (0.011 g), 2,4,6-collidine (0.035 mL) and methanesulfonyl chloride (0.017 mL) were added. After the reaction mixture was stirred at room temperature for 1 hour, thin layer chromatography confirmed that the starting material was almost consumed. Morpholine (0.20 mL) was added in one portion. The reaction was stirred for 1.5 hours and then poured into water. The aqueous solution was extracted twice with CH ₂ Cl ₂ and twice with 3% MeOH: CH ₂ Cl ₂ . The organics were combined, dried over sodium sulfate, filtered and concentrated. Residual DMF was removed on a vacuum pump. The residue was dissolved in CH ₂ Cl ₂ and hexanes were added to give a solid (starting material) which was filtered and dried. This filtrate was evaporated overnight to give a second solid. This solid was dissolved in CH ₂ Cl ₂ and adsorbed onto silica. Chromatography (CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (1 L), 2% MeOH in CH ₂ Cl ₂ (1 L), 2.5% MeOH in CH ₂ Cl ₂ (1 L)) , Developed with 3% MeOH (2 L) in CH ₂ Cl ₂ ) N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarbo 0.028 g of thioamide was obtained as a yellow solid.
[1197] Physical properties are as follows.
[1198]
[1199] Example 95
[1200] N- (4-chlorobenzyl) -1-methyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbothioamide
[1201]
[1202] In a flame-dried flask, N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarbothioamide (0.060 g), triphenylphosphine (from production 47 0.045 g) and freshly distilled THF (1.5 mL). To this solution was added methanol (8.00 μL) and diethyl azodicarboxylate (28.00 μL). The reaction was stirred at rt for 18 h. The morning of reacting left a large amount of starting material. Additional PPh ₃ (0.025 g), methanol (5.00 μl) and diethyl azodicarboxylate (14.00 μl) were added and the reaction stirred for 18 hours. Morninglighting of the reaction resulted in addition of 10 equivalents of PPh ₃ , methanol and diethyl azodicarboxylate, respectively, as some starting material still remained. An exothermic reaction was observed after adding diethyl azodicarboxylate. The reaction was immediately monitored by TLC and the starting material was consumed. Solvent was removed and the residue was dissolved in CH ₂ Cl ₂ / MeOH and adsorbed on silica. Column chromatography (CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (1 L), 2% MeOH in CH ₂ Cl ₂ (2 L), 4% MeOH in CH ₂ Cl ₂ (1 L) ), Developed with 7% MeOH (1 L) in CH ₂ Cl ₂ ) to give the title compound containing triphenylphosphine oxide. These fractions were combined, concentrated and the residue was again adsorbed on silica. Second chromatography (1: 1 hexanes: ethyl acetate (1 L), 45:55 hexanes: ethyl acetate (1 L), 4: 6 Hexane: ethyl acetate (1 L), 35:65 hexanes: ethyl acetate (1 L), 1: 3 hexanes: ethyl acetate (1 L), 2: 8 hexanes: ethyl acetate (1 L), 1: 9 hexanes: Purification with ethyl acetate (1 L), 100% ethyl acetate (1 L), developed with 2% MeOH in CH ₂ Cl ₂ (1 L), 4% MeOH in CH ₂ Cl ₂ (1 L)) Was obtained as a light yellow residue. The residue was dissolved in CH ₂ Cl ₂ and hexanes added until cloudy. After the solution was placed in the freezer overnight, the title compound as a solid was filtered and dried (0.020 g).
[1203] Physical properties are as follows.
[1204]
[1205] Preparation 48
[1206] N- (4-chlorobenzyl) -8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1207]
[1208] A solution of 2-iodoaniline (8.22 g) and diethyl ethoxymethylenemalonate (8.00 mL) was heated at 130 ° C. for 1 hour. The reaction was cooled to room temperature. Diphenylether (100 mL) was added and the reaction heated at 250 ° C. for 1.25 h. The reaction was cooled to room temperature and the resulting solid was filtered, washed with hexanes and dried to give ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate (6.84 g).
[1209] The resulting ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate (4.01 g) and 4-chlorobenzylamine (20.00 mL) were heated at 180 ° C. for 1.5 h. The reaction was cooled to room temperature. After addition of ethyl acetate, hexanes were added, the solids were filtered off, washed with hexanes and dried to give N- (4-chlorobenzyl) -4-hydroxy-8-iodo-3-quinolinecarboxamide (3.98 g )
[1210] N- (4-chlorobenzyl) -4-hydroxy-8-iodo-3-quinolinecarboxamide (0.88 g), K ₂ C0 ₃ (1.12 g) and iodine in anhydrous dimethylformamide (25 mL) A suspension of domethane (0.14 mL) was heated at 90 ° C. until the reaction was shown to be terminated by TLC. The reaction mixture was cooled to room temperature and poured into water (150 mL). The resulting solid was filtered off and dried. The solid was dissolved in CH ₂ Cl ₂ / MeOH and adsorbed onto silica. Chromatography (CH ₂ Cl ₂ (1 L), 0.5% MeOH in CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (1 L), 1.5% MeOH in CH ₂ Cl ₂ (1 L)) , Developed with ₂ % MeOH (1 L) in CH ₂ Cl ₂ ) to afford 0.50 g of the title compound as a white solid.
[1211] Physical properties are as follows.
[1212]
[1213] Example 96
[1214] N- (4-chlorobenzyl) -8- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1215]
[1216] N- (4-chlorobenzyl) -8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.21 g from Preparation 48 in diethylamine (15 mL) ), A solution of copper iodide (0.029 g), bis (triphenylphosphine) palladium (II) chloride (0.012 g) and propargyl alcohol (0.035 mL) was stirred at room temperature for 18 hours. Dichloromethane was added to the reaction mixture, followed by hexane. The resulting solid was filtered off, washed with hexanes and dried. The solid was dissolved in CH ₂ Cl ₂ / MeOH and adsorbed onto silica. Chromatography (CH ₂ Cl ₂ (1 L), 0.5% MeOH in CH ₂ Cl ₂ (1 L), 1% MeOH in CH ₂ Cl ₂ (1 L), 1.5% MeOH in CH ₂ Cl ₂ (1 L)) , Developed with ₂ % MeOH in CH ₂ Cl ₂ (1 L), 3% MeOH in CH ₂ Cl ₂ (1 L)) to give 0.13 g of the title compound as a yellow solid.
[1217] Physical properties are as follows.
[1218]
[1219] Example 97
[1220] N- (4-chlorobenzyl) -8- (4-hydroxy-1-butynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1221]
[1222] N- (4-chlorobenzyl) -8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.22 g from Preparation 48 in diethylamine (15 mL) ), A solution of copper iodide (0.029 g), bis (triphenylphosphine) palladium (II) chloride (0.013 g) and 3-butyn-1-ol (0.040 mL) was stirred at room temperature for 18 hours. Hexane was added to the reaction mixture, and the resulting solid was filtered and dried. The solid was dissolved in CH ₂ Cl ₂ / MeOH and adsorbed onto silica. Chromatography (CH ₂ Cl ₂ (1 L), 1.5% MeOH in CH ₂ Cl ₂ (1 L), 2% MeOH in CH ₂ Cl ₂ (2 L), 3% MeOH in CH ₂ Cl ₂ (1 L)) Developed as) to give 0.16 g of the title compound as a light yellow solid.
[1223] Physical properties are as follows.
[1224]
[1225] Preparation 49
[1226] (4-nitrobenzyl) triphenylphosphonium bromide
[1227] 4-nitrobenzylbromide (12.96 g) was added to a triphenylphosphine solution in Et ₂ O (150 mL). The solution was stirred overnight and the resulting solid was filtered and dried to give 10.95 g of (4-nitrobenzyl) triphenylphosphonium bromide as a white solid.
[1228] Physical properties are as follows.
[1229]
[1230] Recipe 50
[1231] 4- (4-nitrobenzylidene) tetrahydro-2H-pyran
[1232] To a 100 ml flask under N ₂ was added NaH (0.40 g of a 60% solution in mineral oil) and anhydrous DMSO (7 ml). The resulting solution was heated at 80 ° C. for 1 hour and then cooled in an ice water bath. To this was added a suspension of phosphonium bromide (4.78 g) from Preparation 49 in warmed DMSO (40 mL). The mixture was stirred at rt for 10 min. Then tetrahydro-4H-pyran-4-one (0.92 mL) was added dropwise. The mixture was stirred overnight at room temperature and then at 80 ° C. for 8 hours. The mixture was poured onto ice and extracted with Et ₂ O. Extracts were combined and concentrated. The crude product was chromatographed (developed with Biotage flash 40M, gradient 60/40 CH ₂ Cl ₂ / hexanes) to give 0.464 g of 4- (4-nitrobenzylidene) tetrahydro-2H-pyran yellow. Obtained as a solid.
[1233] Physical properties are as follows.
[1234]
[1235] Preparation 51
[1236] Ethyl 4-hydroxy-6- (tetrahydro-2H-pyran-4-ylmethyl) -3-quinolinecarboxylate
[1237]
[1238] A mixture of 4- (4-nitrobenzylidene) tetrahydro-2H-pyran (400 mg) and platinum (IV) (40 mg) from Preparation 50 in MeOH (40 mL) was added at 40 psi of hydrogen for 4 hours. Hydrogenated. The reaction mixture was filtered through celite and concentrated. Then CH ₂ Cl ₂ (50 mL) and diethyl ethoxymethylenemalonate (0.37 mL) were added to the residue and the mixture was concentrated at 40 ° C. Then diphenyl ether (20 mL) was added to this residue. The mixture was heated to 250 ° C. for 1 hour. Then the mixture was cooled down and diluted with hexanes. The resulting product was collected, washed with hexanes and dried to afford 0.453 g of ethyl 4-hydroxy-6- (tetrahydro-2H-pyran-4-ylmethyl) -3-quinolinecarboxylate.
[1239] Physical properties are as follows.
[1240]
[1241] Preparation 52
[1242] N- (4-chlorobenzyl) -4-hydroxy-6- (tetrahydro-2H-pyran-4-ylmethyl) -3-quinolinecarboxamide
[1243]
[1244] A solution of ethyl 4-hydroxy-6- (tetrahydro-2H-pyran-4-ylmethyl) -3-quinolinecarboxylate (0.315 g) and 4-chlorobenzylamine (0.61 mL) from Preparation 51 was prepared. Heated to 180 ° C. over time. The reaction mixture was cooled to 65 ° C. and diluted with CH ₂ Cl ₂ . Hexane was added to start precipitation of the product. The resulting solid was collected and 0.33 g of N- (4-chlorobenzyl) -4-hydroxy-6- (tetrahydro-2H-pyran-4-ylmethyl) -3-quinolinecarboxamide was obtained as off-white solid.
[1245] Physical properties are as follows.
[1246]
[1247] Example 98
[1248] N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (tetrahydro-2H-pyran-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide
[1249]
[1250] N- (4-chlorobenzyl) -4-hydroxy-6- (tetrahydro-2H-pyran-4-ylmethyl) -3-quinolinecarboxamide (0.200 g from Preparation 52 in anhydrous DMF (10 mL) ) Was added K ₂ CO ₃ (0.269 g) and CH ₃ I (0.04 mL). The mixture was stirred for 15 minutes. Then water (10 mL) was added and the resulting solid was collected and dried. The crude product was chromatographed (developed with biotag flash 40S, CH ₂ Cl ₂ , 1% MeOH / CH ₂ Cl ₂ , 2% MeOH / CH ₂ Cl ₂ ) to give 0.161 g of the title compound as a white solid.
[1251] Physical properties are as follows.
[1252]
[1253] Example 99
[1254] N- (4-chlorobenzyl) -6-{[3- (hydroxyimino) -1-azetidinyl] methyl} -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides
[1255]
[1256] N- (4-chlorobenzyl) -6-[(3-hydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1, from example 75 in methyl sulfoxide (3 mL), A suspension of 4-dihydro-3-quinolinecarboxamide (0.09 g) was treated with triethylamine (0.35 mL) and cooled in a water bath. The mixture was treated with sulfur trioxide pyridine complex (0.25 g) and stirred for 2 hours. The mixture was diluted with diethyl ether containing a small amount of methanol and dichloromethane. The organic phase was washed three times with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was suspended in ethanol (95%, 2 mL) and treated with hydroxylamine hydrochloride (0.03 g) and sodium hydroxide (0.02 g). The flask was tightly sealed with a lid and heated at 65 ° C. overnight. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and methanol containing methanol. The aqueous phase was extracted with dichloromethane and dichloromethane containing methanol. The combined organic phases were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was developed by flash column chromatography on silica gel, developing with a small amount of methanol in dichloromethane, and then purified by recrystallization with acetonitrile-methanol to give 14 mg of the title compound as a tan solid.
[1257] Physical properties are as follows.
[1258]
[1259] Example 100
[1260] N- (4-chlorobenzyl) -1- {2- [2- (4-morpholinyl) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1,4-di Hydro-3-quinolinecarboxamide
[1261]
[1262] N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl)-from Example 57 in pyridine (2 mL) at 0 ° C. A solution of 4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 g) and 4-dimethylaminopyridine (0.002 g) was treated with tosyl chloride (0.05 g). The mixture was allowed to warm to rt overnight. The mixture was treated with additional tosyl chloride (0.05 g), stirred for 4 h, then with morpholine (0.20 mL) and stirred overnight. The mixture was concentrated under reduced pressure and residual pyridine was removed by azeotropic distillation with toluene. The residue was subjected to flash column chromatography on silica gel, developing with ammonia containing 2% to 10% methanol in dichloromethane, and then purified by recrystallization with ethyl acetate-hexane to give 29 mg of the title compound as a white solid.
[1263] Physical properties are as follows.
[1264]
[1265] Example 101
[1266] N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[1267]
[1268] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.25 g) and cesium carbonate (0.39) from Preparation 40 in DMF (3 mL) g) suspension was treated with chloromethyl 4-chlorophenyl sulfide (0.13 mL). The mixture was tightly sealed with a lid and heated to 105 ° C. for 2 hours. The reaction mixture was cooled to rt, diluted with dichloromethane (50 mL), washed with water (2 × 10 mL), brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was developed with 1% to 3% methanol in dichloromethane, flash column chromatography and then purified by ethyl acetate to afford 0.26 g of the title compound as a white solid.
[1269] Physical properties are as follows.
[1270]
[1271] Example 102
[1272] N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfinyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[1273]
[1274] N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) from Example 101 in dichloromethane (2 mL) at 0 ° C. Treatment of a solution of -4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.11 g) with p-toluenesulfonic acid hydrate (0.04 g) followed by m-chloroperoxybenzoic acid (~ 85%) (0.04 g). The mixture was stirred for 0.75 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from acetonitrile to give 0.10 g of the title compound as a white solid.
[1275] Physical properties are as follows.
[1276]
[1277] Example 103
[1278] N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfonyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamide
[1279]
[1280] N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) from Example 101 in dichloromethane (2 mL) at 0 ° C. Treatment of a solution of -4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.11 g) with p-toluenesulfonic acid hydrate (0.04 g) followed by m-chloroperoxybenzoic acid (~ 85%) (0.09 g). The mixture was stirred for 0.75 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from acetonitrile to give 0.09 g of the title compound as a white solid.
[1281] Physical properties are as follows.
[1282]
[1283] Example 104
[1284] N- (4-chlorobenzyl) -1-[(4-chlorophenoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1285]
[1286] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.21 g) and cesium carbonate (0.33) from Preparation 40 in DMF (2 mL) g) suspension was treated with α, 4-dichloroanisole (0.13 g). The mixture was tightly sealed with a lid and heated to 100 ° C. for 3 hours. The reaction mixture was cooled to rt, diluted with dichloromethane (50 mL) and washed with water. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 1% to 4% methanol in dichloromethane and then purified by recrystallization with acetonitrile to give 0.20 g of the title compound as a white solid.
[1287] Physical properties are as follows.
[1288]
[1289] Example 105
[1290] N- (4-chlorobenzyl) -1-[(2-methoxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides
[1291]
[1292] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.21 g) and cesium carbonate (0.34) from Preparation 40 in DMF (2 mL) g) suspension was treated with 2-methoxyethoxymethyl chloride (0.07 mL). The mixture was tightly sealed with a lid and heated to 100 ° C. for 3 hours. The reaction mixture was cooled to rt, diluted with dichloromethane and washed with water. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 1% to 5% methanol in dichloromethane and then recrystallized from acetonitrile to give 0.08 g of the title compound as a white solid.
[1293] Physical properties are as follows.
[1294]
[1295] Example 106
[1296] 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] methoxy} ethyl benzoate
[1297]
[1298] N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide (0.41 g) and cesium carbonate (0.65) from Preparation 40 in DMF (5 mL) g) suspension was treated with benzoyloxyethylchloromethyl ether (˜85%, 0.31 mL). The mixture was tightly sealed with a lid and heated to 110 ° C. for 3 hours. The reaction mixture was cooled to rt, diluted with dichloromethane and washed with water (3 ×). The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 2% to 6% methanol in dichloromethane and then recrystallized from acetonitrile to give 0.08 g of the title compound as a white solid.
[1299] Physical properties are as follows.
[1300]
[1301] Example 107
[1302] N- (4-chlorobenzyl) -1-[(2-hydroxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides
[1303]
[1304] 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] meth from Example 106 The flask containing oxy} ethyl benzoate (0.12 g) was treated with methanol (5 mL) saturated with ammonia. The mixture was tightly sealed with a lid and stirred for 3 days at room temperature. The reaction mixture was concentrated under reduced pressure. The crude product was subjected to flash column chromatography developing with 2% to 10% methanol in dichloromethane and then purified by recrystallization with acetonitrile to afford 0.07 g of the title compound as a white solid.
[1305] Physical properties are as follows.
[1306]
[1307] Example 108
[1308] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinolinecarboxamide (Formula W-5; Z = O)
[1309]
[1310] The flask containing 4- (4-aminobenzyl) morpholine (0.48 g) from Preparation 22 was treated with methanol (5 mL) and dozens of dry molecules were sieved (3x). The mixture was treated with acetic acid (1 mL) and tetrahydro-4H-pyran-4-one (0.24 mL). After 1 h, the mixture was carefully treated with sodium cyanoborohydride (0.6 g) and heated to reflux under a nitrogen atmosphere. After 1 hour, the mixture was cooled to room temperature and filtered while washing with methanol. The filtrate was diluted with diethyl ether and washed with aqueous sodium hydroxide (2N). The aqueous was back extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was flash column chromatography on silica running with 2% to 5% methanol in dichloromethane. The product-containing fractions were combined and evaporated to yield 0.34 g of N- [4- (4-morpholinylmethyl) phenyl] tetrahydro-2H-pyran-4-amine as a white solid.
[1311] A flask containing 0.34 g of N- [4- (4-morpholinylmethyl) phenyl] tetrahydro-2H-pyran-4-amine was transferred to diethyl ethoxymethylenemalonate (0.30 mL) and pyridine (0.20 mL). Treated. The flask was tightly sealed with a lid and heated to 140 ° C. for 2 hours. The reaction was cooled to room temperature and azeotropically distilled (3 ×) with toluene under reduced pressure. The residue was dissolved in dichloromethane, washed with water, brine, dried and concentrated under reduced pressure. The residue was chromatographed on silica running with 2% to 6% methanol in dichloromethane. The product-containing fractions were evaporated to yield 0.41 g of diethyl 2-{[4- (4-morpholinylmethyl) (tetrahydro-2H-pyran-4-yl) anilino] methylene} malonate as a tan oil.
[1312] A flask containing 0.41 g of diethyl 2-{[4- (4-morpholinylmethyl) (tetrahydro-2H-pyran-4-yl) anilino] methylene} malonate was treated with polyphosphoric acid (1.5 g) It was. The reaction mixture was heated to 100 ° C. under a stream of nitrogen gas. After 1 hour, the reaction was cooled to room temperature. The reaction mixture was carefully added to a mixture of vigorously stirred dichloromethane and saturated aqueous bicarbonate. The layers were separated and the basic aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica, developing with 2% to 6% methanol in dichloromethane to ethyl 6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl- 0.24 g of 1,4-dihydro-3-quinolinecarboxylate was obtained as a tan solid.
[1313] A flask containing 0.21 g of ethyl 6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinolinecarboxylate 4 Treated with -chlorobenzylamine (2.0 mL). The reaction was tightly sealed with a lid and heated to 190 ° C. for 1 hour. The reaction was cooled to room temperature, adsorbed onto silica, chromatographed on silica, developing with 2% to 6% methanol in dichloromethane, and then recrystallized from ethyl acetate to give 0.14 g of the title compound.
[1314] Physical properties are as follows.
[1315]
[1316] Example 109
[1317] N- (4-chlorobenzyl) -1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox Amides (Formula W-5; Z = NMe)
[1318]
[1319] The flask containing 4- (4-aminobenzyl) morpholine (0.48 g) from Preparation 22 was treated with tetrahydrofuran (10 mL) and N-methyl-4-piperidone (0.37 mL) under an argon atmosphere. The solution was treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture was partitioned into saturated aqueous sodium bicarbonate containing diethyl ether and sodium hydroxide. The aqueous was back extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica, developing with 2% to 5% methanol, saturated with ammonia in dichloromethane, 1-methyl-N- [4- (4-morpholinylmethyl) phenyl] -4 0.52 g of piperidineamine was obtained as a tan solid.
[1320] The flask containing 0.52 g of 1-methyl-N- [4- (4-morpholinylmethyl) phenyl] -4-piperidineamine was treated with diethyl ethoxymethylenemalonate (0.55 mL). The flask was tightly sealed with a lid and heated to 150 ° C. for 1 hour. The reaction was cooled to rt, treated with diethyl ethoxymethylenemalonate (0.55 mL) and heated to 180 ° C. for 2 h. The reaction was cooled to room temperature and flash column chromatography on silica running with 5% to 20% methanol in dichloromethane. The product-containing fractions were evaporated to yield 0.75 g of diethyl 2-{[(1-methyl-4-piperidinyl-4- (4-morpholinylmethyl) anilino] methylene} malonate as a tan solid.
[1321] A flask containing 0.36 g of 2-{[(1-methyl-4-piperidinyl-4- (4-morpholinylmethyl) anilino] methylene} malonate was treated with polyphosphoric acid (1.8 g). The mixture was heated under a flow of nitrogen gas to 130 ° C. After 4 hours, the reaction was cooled to room temperature The reaction mixture was carefully added to a mixture of vigorously stirred dichloromethane and saturated aqueous bicarbonate. The basic aqueous layer was extracted three times with dichloromethane The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give crude ethyl 1- (1-methyl-4-piperidinyl) -6- (4-mor 0.32 g of polyylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate was obtained as a tan solid.
[1322] Flask containing 0.31 g of crude ethyl 1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate Was treated with 4-chlorobenzylamine (2.0 mL). The reaction was tightly sealed with a lid and heated to 165 ° C. overnight. The reaction was cooled to room temperature, adsorbed onto silica, chromatographed on silica, developing with 2% to 10% methanol saturated with ammonia in dichloromethane, and then recrystallized from ethyl acetate-hexane to give 0.11 g of the title compound. Got it.
[1323] Physical properties are as follows.
[1324]
[1325] Example 110
[1326] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide (Formula W -5; Z = NH)
[1327]
[1328] A flask containing 4- (4-aminobenzyl) morpholine (0.48 g) from Preparation 22 was placed under an argon atmosphere with tetrahydrofuran (10 mL) and tert-butyl 4-oxo-1-piperidinecarboxylate ( 0.60 g). The solution was treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring for 3 days, the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and dilute aqueous sodium hydroxide. The aqueous was back extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was developed by flash column chromatography on silica gel, developing with 2% to 6% methanol in dichloromethane, tert-butyl 4- [4- (4-morpholinylmethyl) anilino] -1-piperidinecar 0.96 g of carboxylate was obtained as a tan solid.
[1329] The flask containing 0.94 g of tert-butyl 4- [4- (4-morpholinylmethyl) anilino] -1-piperidinecarboxylate was treated with diethyl ethoxymethylenemalonate (1.0 mL). The flask was tightly sealed with a lid and heated to 150 ° C. for 2 hours. The reaction was then heated to 175 ° C. for 2 hours. The reaction was cooled to room temperature and flash column chromatography on silica running with 2% to 5% methanol in dichloromethane. The product containing fractions were evaporated to diethyl 2-{[[1- (tert-butoxycarbonyl) -4-piperidinyl] -4- (4-morpholinylmethyl) anilino] methylene} malonate 0.78 g was obtained as a tan solid.
[1330] 0.36 g of diethyl 2-{[[1- (tert-butoxycarbonyl) -4-piperidinyl] -4- (4-morpholinylmethyl) anilino] methylene} malonate in toluene (2 mL) The flask containing the solution of was treated with polyphosphoric acid (2.1 g). The reaction mixture was heated to 120 ° C. under a stream of nitrogen gas. After 1 hour, the reaction was cooled to room temperature. The reaction mixture was carefully added to a mixture of vigorously stirred dichloromethane and saturated aqueous bicarbonate. The layers were separated and the basic aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford crude ethyl 6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro 0.14 g of 3-quinolinecarboxylate was obtained as a tan oil.
[1331] 4-chloro flask containing 0.14 g of crude ethyl 6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxylate Treated with benzylamine (1.0 mL). The reaction was tightly sealed with a lid and heated to 180 ° C. for 2 hours. The reaction was cooled to room temperature, flash column chromatographed on silica, developing with 2% to 10% methanol saturated with ammonia in dichloromethane, and then recrystallized from acetonitrile to give 0.10 g of the title compound as a white solid.
[1332] Physical properties are as follows.
[1333]
[1334] Example 111
[1335] N- (4-chlorobenzyl) -1- (1,1-dioxohexahydro-thiopyran-4-yl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro 3-quinolinecarboxamide (Formula W-5; Z = SO ₂ )
[1336]
[1337] The flask containing 4- (4-aminobenzyl) morpholine (0.48 g) from Preparation 22 was treated with tetrahydrofuran (10 mL) and tetrahydrothiopyran-4-one (0.35 g) under an argon atmosphere. The solution was treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and dilute aqueous sodium hydroxide. The aqueous was back extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica, developing with 2% to 6% methanol in dichloromethane, and then purified by recrystallization from cyclohexane to give N- [4- (4-morpholinylmethyl) phenyl] tetrahydro 0.53 g of -2H-thiopyran-4-amine was obtained as a tan solid.
[1338] The flask containing 0.44 g of N- [4- (4-morpholinylmethyl) phenyl] tetrahydro-2H-thiopyran-4-amine was treated with diethyl ethoxymethylenemalonate (0.35 mL). The flask was tightly sealed with a lid and heated to 160 ° C. for 2 hours. The reaction was cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0.35 mL) and pyridine (0.35 mL) and heated to 150 ° C. for 1 hour in a tightly sealed flask. The reaction was cooled to room temperature and azeotropically distilled with toluene under reduced pressure (3 ×). The residue was flash column chromatography on silica gel running with ethyl acetate. The product containing fractions were evaporated to yield 0.59 g of diethyl 2-{[4- (4-morpholinylmethyl) (tetrahydro-2H-thiopyran-4-yl) anilino] methylene} malonate as a tan solid .
[1339] Diethyl 2-{[4- (4-morpholinylmethyl) (tetrahydro-2H-thiopyran-4-yl) anilino] methylene} malonate (0.30 g) in dichloromethane (5 mL) at 0 ° C The solution of was treated with p-toluenesulfonic acid hydrate (0.57 g) followed by m-chloroperoxybenzoic acid (˜85%) (0.32 g). The mixture was stirred for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was subjected to flash column chromatography on silica gel, developing with 2% to 6% methanol in dichloromethane, to obtain 4- [4- (4-morpholinylmethyl) anilino] tetrahydrothiopyran-1,1 (2H 0.12 g of) -dione was obtained as a white solid.
[1340] A flask containing 0.11 g of 4- [4- (4-morpholinylmethyl) anilino] tetrahydrothiopyran-1,1 (2H) -dione was treated with diethyl ethoxymethylenemalonate (0.15 mL). . The flask was tightly sealed with a lid and heated to 155 ° C. for 2 hours. The reaction was cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0.15 mL) and pyridine (0.15 mL) and heated to 120 ° C. for 2 hours in a tightly sealed flask. The reaction was cooled to room temperature and azeotropically distilled with toluene under reduced pressure (3 ×). The residue was treated with diethyl ethoxymethylenemalonate (0.5 mL) and heated to 190 ° C. After 2 hours, the reaction was cooled to room temperature and flash column chromatography on silica gel running with 2% to 6% methanol in dichloromethane. The product-containing fractions were evaporated to give 0.11 g of diethyl 2-{[(1,1-dioxohexahydrothiopyran-4-yl) -4- (4-morpholinylmethyl) anilino] methylene} malonate Obtained as a tan solid.
[1341] Toluene (2 mL) contains 0.11 g of diethyl 2-{[(1,1-dioxohexahydrothiopyran-4-yl) -4- (4-morpholinylmethyl) anilino] methylene} malonate The flask was treated with polyphosphoric acid (1.5 g). The reaction mixture was heated to 120 ° C. under a stream of nitrogen gas. After 2 hours, the reaction was cooled to room temperature. The reaction mixture was carefully added to a mixture of vigorously stirred dichloromethane and saturated aqueous bicarbonate. The layers were separated and the basic aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, developing with 2% to 10% methanol in dichloromethane to give crude ethyl 1- (1,1-dioxohexahydro-thiopyran-4-yl) -6- 0.06 g of (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate was obtained as off-white solid.
[1342] Ethyl 1- (1,1-dioxohexahydro-thiopyran-4-yl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate 0.06 The flask containing g was treated with 4-chlorobenzylamine (0.6 mL). The reaction was tightly sealed with a lid and heated to 190 ° C. for 2 hours. The reaction was cooled to room temperature, adsorbed onto silica gel and flash column chromatography on silica running with 2% to 10% methanol in dichloromethane. The product containing fractions were concentrated under reduced pressure and triturated with diethyl ether. The resulting residue was dissolved in a small amount of dichloromethane and added dropwise to stirred diethyl ether (40 mL). The resulting precipitate was collected by suction filtration to give 0.05 g of the title compound as off white solid.
[1343] Physical properties are as follows.
[1344]
[1345] Preparation 53
[1346] 4- (3-bromo-4-fluorobenzyl) morpholine
[1347] To a solution of 3-bromo-4-fluorobenzaldehyde (2.03 g) in dichloroethane (40 mL) was added morpholine (0.96 mL) and acetic acid (0.57 mL). Sodium triacetoxyborohydride (3.18 g) was added portionwise for 1 hour and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with 1N NaOH solution (10 mL) and diluted with CH ₂ Cl ₂ (100 mL). The organic layer was washed with 1N NaOH (3 × 35 mL). The aqueous layer was back extracted with CH ₂ Cl ₂ (20 mL). The combined organic layers were extracted with 0.1N HCl (6 × 25 mL). The combined aqueous layers were basified with 2N NaOH (pH = 12) and the product was extracted with CH ₂ Cl ₂ (6 × 25 mL). The combined organic layers were washed with brine (20 mL) and dried over magnesium sulfate. The solution was concentrated in vacuo to give 2.23 g (82%) of the title compound as a clear, colorless oil.
[1348] Physical properties are as follows.
[1349]
[1350] Preparation 54
[1351] 1- [2-fluoro-5- (4-morpholinylmethyl) phenyl] -1-ethanone
[1352] A solution of 4- (3-bromo-4-fluorobenzyl) morpholine (35.5 g) from Preparation 53 in THF (400 mL) was cooled to -75 ° C and added while maintaining a temperature below -65 ° C. N-butyllithium was added through a funnel. A solution of N-methyl-N-methoxyacetamide (prepared as described in Tetrahedron Lett. 1983, 24, 1857) in THF (50 mL) while maintaining a temperature below −65 ° C. It was added via an addition funnel. The reaction was stirred at -75 [deg.] C. for 1 hour and then warmed to room temperature overnight. The reaction mixture was quenched with 1N HCl (150 mL) and diluted with ethyl acetate (400 mL). The layers were separated and the aqueous layer was basified with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with saturated sodium bicarbonate (2 × 100 mL) and brine (50 mL). The aqueous layer was back extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo to a yellow oil. The oil was purified by fractional distillation at 135-140 ° C./0.3 Torr to give 19.7 g (64%) of the title compound as a clear, colorless oil.
[1353] Physical properties are as follows.
[1354]
[1355] Preparation 55
[1356] Ethyl 3- [2-fluoro-5- (4-morpholinylmethyl) phenyl] -3-oxopropanoate
[1357] A solution of 1- [2-fluoro-5- (4-morpholinylmethyl) phenyl] -1-ethanone (19.6 g) of Preparation 54 in diethyl carbonate (150 mL) was cooled to 0 ° C and , Sodium hydride (60% suspension, 6.6 g) was added slowly to the reaction mixture. The reaction was stirred at 0 ° C. for 3 hours and then warmed to room temperature overnight. The reaction mixture was quenched with acetic acid (10 mL), diluted with water (200 mL) and basified with saturated sodium carbonate. Then the solution was extracted with ether (3 × 200 mL). The combined organic layers were washed with saturated sodium bicarbonate (100 mL) and brine (50 mL). The combined aqueous layers were back extracted with ether (50 mL). The combined organic layers were then dried over sodium sulphate and concentrated in vacuo to an orange oil. The crude product was purified in two batches by column chromatography (heptane / IPA, 8/1; 4/1) to give 20.2 g (79%) of the title compound as a yellow oil.
[1358] Physical properties are as follows.
[1359]
[1360] Preparation 56
[1361] Ethyl 1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate
[1362]
[1363] Ethyl 3- [2-fluoro-5- (4-morpholinylmethyl) phenyl] -3-oxopropanoate (10.0 g), triethylorthoformate (10.8 ml) and acetic anhydride (from preparation 55 10.7 mL) were combined in a flask equipped with a Dean-Stark trap and concentrator. The reaction was heated to 150 ° C. for 3.5 h. Excess acetic anhydride and triethylorthoformate were distilled off at 100 ° C. and 0.2 torr to yield ethyl 3-ethoxy-2- [2-fluoro-5- (4-morpholinylmethyl) benzoyl] -2-prop A burgundy oil containing a mixture of the E- and Z- isomers of phenoate was obtained.
[1364] The crude mixture was dissolved in ethanol (50 mL) and 4-aminomorpholine (4.7 mL) was added. The reaction mixture was stirred at rt for 2.5 h and concentrated in vacuo. The resulting burgundy oil was purified in two batches by column chromatography (MeOH / CH ₂ Cl ₂ : 1%, 2%, 5%) to give ethyl (E)-and (Z) -2- [2-fluoro-5 -(4-morpholinylmethyl) benzoyl] -3- (4-morpholinylamino) -2-propenoate was obtained as a yellow oil.
[1365] The crude enamine was dissolved in THF and sodium hydride was slowly added to this solution. After the mixture was heated to 70 ° C. for 2 hours, the reaction was quenched with water (5 mL) and concentrated in vacuo to a burgundy slurry. Additional water (100 mL) was added and the remaining THF was removed in vacuo. The resulting yellow precipitate suspended in aqueous solution was filtered on a frit funnel and washed twice with water and once with ether to give 5.9 g (55%) of the title compound as a yellow powdery solid.
[1366] Physical properties are as follows.
[1367]
[1368] Example 112
[1369] N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1370]
[1371] Ethyl 1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (5.0 g) and 4- from Preparation 56 Chlorobenzylamine (7.6 mL) was combined and heated to 190 ° C for 7 h. After cooling to room temperature, the mixture was solidified. The solid was triturated with a 10: 1 mixture of EtOAc / MTBE (30 mL) and filtered over frit. The crude solid was again ground with a 10: 1 hot mixture of EtOAc / MTBE (110 mL). The suspension was cooled to rt and filtered on frit to give 4.9 g (79%) of the title compound as a white solid.
[1372] Physical properties are as follows.
[1373]
[1374] Example 113
[1375] N- (4-chlorobenzyl) -1- (4-methyl-1-piperazinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides
[1376]
[1377] The title compound was prepared using 1-amino-4-methylpiperazine and Example 112 according to a similar method as described in Preparation 56. The crude product was purified by recrystallization in EtOH to give 0.87 g of the title compound as a white solid.
[1378] Physical properties are as follows.
[1379]
[1380] Example 114
[1381] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide
[1382]
[1383] The title compound was prepared using 1-aminopiperadine and Example 112 following a similar method as described in Preparation 56. The crude product was purified by recrystallization in acetonitrile to give 0.73 g of the title compound as a white solid.
[1384] Physical properties are as follows.
[1385]
[1386] Example 115
[1387] N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-pyrrolidinyl) -1,4-dihydro-3-quinolinecarboxamide
[1388]
[1389] The title compound was prepared using 1-aminopyrrolidine and Example 112 following a similar method as described in Preparation 56. The crude product was purified by recrystallization in methanol to give 0.39 g of the title compound as a white solid.
[1390] Physical properties are as follows.
[1391]
[1392] Example 116
[1393] N- (4-chlorobenzyl) -1-[(2R) -2- (methoxymethyl) pyrrolidinyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide
[1394]
[1395] The title compound was prepared using (R)-(+)-1-amino-2- (methoxymethyl) pyrrolidine and Example 112 following a similar method as described in Preparation 56. The crude product was purified by column chromatography (MeOH / CH ₂ Cl ₂ : 0.5%, 1.5%, 2.5%) and triturated with ether to give 0.79 g of the title compound as a white solid.
[1396] Physical properties are as follows.
[1397]
[1398] Example 117
[1399] N- (4-chlorobenzyl) -1- (dimethylamino) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1400]
[1401] The title compound was prepared using 1,1-dimethylhydrazine and Example 112 according to a similar method as described in Preparation 56. The crude product was purified by recrystallization in methanol to give 0.2 g of the title compound as a white solid.
[1402] Physical properties are as follows.
[1403]
[1404] Preparation 57
[1405] 1-amino-N- (4-chlorobenzyl) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1406]
[1407] A suspension of N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide (2.0 g) and potassium carbonate (2.0 g) of Preparation 4 in DMF (40 mL) at room temperature After stirring for 5 hours, it was treated with O- (mesitylsulfonyl) hydroxylamine (1.5 g). After 24 hours, the solvent was evaporated under reduced pressure and the residue was diluted with water (150 mL). The resulting solid was filtered and washed with water (3 ×) and ether (2 ×). Recrystallization from hot acetic acid / water gave 1.35 g of the title compound as a tan solid.
[1408] Physical properties are as follows.
[1409]
[1410] Example 118
[1411] 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1412]
[1413] 1-amino-N- (4-chlorobenzyl) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.25 g) from Preparation 57, copper iodide (I) ( 32 mg) and bis (triphenylphosphine) palladium (II) chloride (19 mg) were suspended in diethylamine (8 mL). Propargyl alcohol (39 μl) was added and the mixture was stirred at rt for 16 h. The mixture was diluted with ethanol and then concentrated in vacuo. The crude solid was triturated with dichloromethane and recrystallized in acetic acid to give 76 mg of the title compound as a beige solid.
[1414] Physical properties are as follows.
[1415]
[1416] Example 119
[1417] 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1418]
[1419] 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide from Example 118 ( 0.21 g) was dissolved in a 1: 1 mixture of methanol / DMF. To the solution was added 5% platinum on carbon (0.11 g) and acetic acid (0.5 mL). The reaction was shaken for 4.5 h under hydrogen atmosphere (35 psi). The catalyst was removed by filtration through celite. The filtrate was concentrated in vacuo and the resulting white solid was triturated with dichloromethane. The crude product was then purified by column chromatography (MeOH / CH ₂ Cl ₂ : 3%, 5%) to give 0.10 g of the title compound as a white solid.
[1420] Physical properties are as follows.
[1421]
[1422] Preparation 58
[1423] Butyl 1- (dimethylamino) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate
[1424]
[1425] A solution of TBDMS ketene acetal (8.1 g) and triethylamine (5.6 mL) of butyl acetate in THF (20 mL) was added at one time to a solution of 2-chloro-5-iodobenzoyl chloride in THF (40 mL). After the mixture was stirred for 24 hours, the solvent was evaporated under nitrogen flow. The residue was diluted with ether (30 mL) and filtered. The resulting filtrate was concentrated to give 8.2 g of oil, which was dissolved in THF (100 mL) and treated with 3N hydrochloric acid (10 mL). After 5 hours, the volume of the solution was reduced to 2/3 by evaporation under reduced pressure. The residue was diluted with dichloromethane (100 mL). The phases were separated and the organic layer was dried over magnesium sulfate. The mixture was filtered and dissolved in toluene. The solvent was evaporated and the process repeated until TBDMS was not detected by ¹ H NMR in the mixture. The residual oil was purified by column chromatography (30-45% dichloromethane in hexanes) to give 7.9 g of butyl 3- (2-chloro-5-iodophenyl) -3-oxopropanoate as an orange oil.
[1426] A mixture of the ketoester (3.3 g) and ethyl orthoformate (2.2 mL) in acetic anhydride (2 mL) was refluxed for 2 hours. Excess triethyl orthoformate and acetic anhydride were removed by evaporation under reduced pressure, then concentrated from xylene (75 mL) to butyl 2- (2-chloro-5-iodobenzoyl) -3-ethoxy-2-propeno Eight was obtained as crude oil.
[1427] Dimethylhydrazine (1.1 mL) was added to a solution of the crude enol ether (4.0 g) in ethanol (10 mL). The mixture was stirred for 4 hours. The reaction mixture was then concentrated to give 4 g of butyl 2- (2-chloro-5-iodobenzoyl) -3-ethoxy- (2,2-dimethylhydrazino) -2-propenoate as an amber oil. .
[1428] The hydrazide was dissolved in dioxane (50 mL) and treated with sodium hydride (0.6 g, 60% in mineral oil). The mixture was refluxed for 2 hours, cooled to room temperature and filtered while washing with concentrated ethanol (2 × 10 mL). The combined filtrates and washes were refluxed with 5 g of DARCO and the solution was filtered through celite. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (5-15% ethyl acetate in dichloromethane) to give 1.2 g of the title compound as a white solid.
[1429] Physical properties are as follows.
[1430]
[1431] Example 120
[1432] N- (4-chlorobenzyl) -1- (dimethylamino) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1433]
[1434] Butyl 1- (dimethylamino) -6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.50 g) and 4-chlorobenzylamine (0.29 mL) from Preparation 58 Heated to 170 ° C. for hours. The reaction was cooled to room temperature and the crude solid was recrystallized in acetic acid to give 0.54 g of amide. The resulting amide (0.25 g), copper iodide (I) (30 mg) and bis (triphenylphosphine) palladium chloride (II) chloride (18 mg) were suspended in diethylamine (8 mL). Propargyl alcohol (36 μl) was added and the mixture was stirred at rt for 16 h. The mixture was diluted with ethanol and then concentrated in vacuo. The crude solid was triturated with dichloromethane and purified by column chromatography (2% MeOH / CH ₂ Cl ₂ ) to give 9 mg of the title compound as a beige solid.
[1435] Physical properties are as follows.
[1436]
[1437] Preparation 59
[1438] Ethyl 1- (dimethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate
[1439]
[1440] Ethyl 3- (2-fluorophenyl) -3-oxopropanoate (15.0 g) was refluxed with triethylorthoformate (17.8 mL) in acetic anhydride (16.8 mL) for 4 hours. The reaction mixture was diluted with xylene (75 mL) and concentrated under reduced pressure to give 19.1 g of amber oil. A solution of oil (4.0 g) in ethanol (10 mL) was treated with 1,1-dimethylhydrazine (1.1 mL) and stirred for 10 minutes. The reaction mixture was concentrated and shaken with 4: 1 hexanes / ether. The solvent was decanted and the last remaining solvent was removed in high vacuum to give ethyl 3- (2,2-dimethylhydrazino) -2- (2-fluorobenzoyl) -2-propanoate as an amber oil.
[1441] The resulting hydrazide (4.0 g) was dissolved in dioxane (20 mL) and treated with 60% sodium hydride (0.60 g) in oil. The mixture was refluxed under nitrogen for 2 hours and then cooled to 25 ° C. The reaction mixture was diluted with ethanol (10 mL) and water (75 mL) and then extracted with ethyl acetate (3 × 75 mL). The organic phases were combined, washed with brine, dried over calcium chloride and filtered. Evaporate under reduced pressure to reduce the volume of the filtrate and dry to dilute the residue with diethyl ether (150 mL). The solid was filtered and washed with diethyl ether (2 × 20 mL) to give 0.75 g of ethyl 1- (dimethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate as an orange solid.
[1442] Physical properties are as follows.
[1443]
[1444] Example 121
[1445] N- (4-chlorobenzyl) -1- (dimethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1446]
[1447] Ethyl 1- (dimethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.21 g) and 4-chlorobenzylamine (1.2 mL) of Preparation 59 were prepared at 180 ° C. under nitrogen for 10 hours. Heated to. Dilution with a mixture of toluene and hexanes precipitated the product from the cooled reaction mixture. The crude product was then recrystallized from aqueous acetic acid to afford 0.030 g of the title compound.
[1448] Physical properties are as follows.
[1449]
[1450] Recipe 60
[1451] Ethyl 1- (allyloxy) -4-oxo-1,4-dihydro-3-quinolinecarboxylate
[1452]
[1453] O-allylhydroxylamine hydrate (1.52 g) was dissolved in ethanol (50 mL) and treated with 3N aqueous sodium hydroxide until a phenolphthalene end point was obtained. Ethyl 3-ethoxy-2- (2-fluorobenzoyl) -2-propenoate (3.7 g, prepared from ethyl 3- (2-fluorophenyl) -3-oxopropanoate as in Preparation 59 ) Was added and the mixture was stirred for 3 hours. The mixture was filtered and the resulting filtrate was concentrated. The crude enamine intermediate was treated with sodium hydride in reflux dioxane according to a similar method as described in Preparation 58. The crude product was purified by column chromatography (30-40% ethyl acetate in dichloromethane). Fractions containing the main product were combined and concentrated under reduced pressure. The residue was dissolved in a minimum volume of ethyl acetate and stored overnight at −15 ° C., then ether (20 mL) and cyclohexane (20 mL) were added. The solid was collected by filtration and washed twice with ether to yield 1.0 g of the title compound as a pale yellow solid.
[1454] Physical properties are as follows.
[1455]
[1456] Example 122
[1457] 1- (allyloxy) -N- (4-chlorobenzyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1458]
[1459] Ethyl 1- (allyloxy) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.5 g) of Preparation 60 was treated with sodium hydroxide (3N, 2 mL) in ethanol (2 mL) , Stirred for 30 minutes. The reaction mixture was neutralized with hydrochloric acid, filtered and the filtrate was washed with water (3 ×) and ether (1 ×). The crude carboxylic acid was dried under a stream of air to give 0.31 g of a white powder, which was suspended in DMF (15 mL) and treated with 1,1'-carbonyldiimidazole (0.46 g). The reaction mixture was heated to 65 ° C. for 5 hours, cooled and treated with water (0.03 mL). After 5 minutes, 4-chlorobenzylamine (0.19 mL) was added. The mixture was stirred for 3 days, diluted with water (15 mL) and filtered to give 0.19 g of the title compound as a white solid.
[1460] Physical properties are as follows.
[1461]
[1462] Example 123
[1463] N- (4-chlorobenzyl) -1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1464]
[1465] Ethyl 3-ethoxy-2- (2-fluorobenzoyl) -2-propenoate (4.0 g, prepared from ethyl 3- (2-fluorophenyl) -3-oxopropanoate as in Preparation 59 ) And O-methylhydroxylamine (16 mmol, prepared by mixing 1 equivalent of O-methylhydroxylamine hydrochloride and 1 equivalent of sodium ethoxide in ethanol) in ethanol (20 mL) for 1 hour at room temperature I was. The mixture was concentrated, diluted with dioxane (75 mL) and reconcentrated to remove remaining ethanol. The resulting enamine was diluted in dioxane (70 mL) and sodium hydride (60% suspension, 0.64 g) was added. The mixture was heated to reflux for 2.5 hours, cooled to room temperature and concentrated in vacuo. The remaining residue was partially dissolved in ethanol (100 mL) and filtered. The filtrate was concentrated in vacuo and chromatographed (7% MeOH / CH ₂ Cl ₂ ). The combined fractions were concentrated and the residue was recrystallized in a 1: 1 ether / hexane mixture to give ethyl 1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (melting point 120-121 ° C.) 0.95 g was obtained as a white solid.
[1466] The resulting carboxylate ester (0.48 g) was stirred with a solution of 3N NaOH (aq, 5 mL) in ethanol (6 mL) for 15 minutes. The reaction mixture was neutralized with 3N HCl, filtered and washed with ethanol to give carboxylic acid as a white solid. Carboxylic acid (0.16 g) and N, N'-carbonyldiimidazole (0.18 g) were dissolved in DMF (10 mL) and heated to 65 ° C for 5 h. The reaction mixture was cooled to 0 ° C., quenched with water (0.01 mL) and stirred for 5 minutes. After warming to room temperature, 4-chlorobenzylamine (0.10 mL) was added. Thereafter, the reaction mixture was stirred for 16 hours at room temperature. Water (15 mL) was added and the precipitate was filtered off and washed with 1: 1 DMF / H ₂ O (2 × 25 mL) and water (2 × 25 mL) to give 50 mg of the title compound as a white solid.
[1467] Physical properties are as follows.
[1468]
[1469] Example 124
[1470] N- (4-bromobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1471]
[1472] 4-bromobenzylamine hydrochloride (2.22 g) was suspended in water (5 mL) and neutralized with 2N aqueous NaOH (5 mL). The free amine was extracted with dichloromethane (2 × 25 mL). The organic layers were combined, washed with brine (5 mL) and dried over sodium sulfate. The solution was concentrated in vacuo to give 1.48 g of a clear, colorless solution, which was ethyl 1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4 from preparation 56. Combined with dihydro-3-quinolinecarboxylate (0.48 g) and heated to 190 ° C. for 3 hours. The reaction mixture was cooled to room temperature, the resulting solid was recrystallized in ethyl acetate and 0.44 g of the title compound was obtained as a white solid.
[1473] Physical properties are as follows.
[1474]
[1475] Example 125
[1476] N- (4-fluorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide
[1477]
[1478] Ethyl 1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.33 g) and 4- from Preparation 56 Fluorobenzylamine (0.55 mL) was combined and heated to 180 ° C. for 3 hours. The reaction was cooled to room temperature. The crude solid was triturated with ether, filtered and recrystallized in methanol to give 0.14 g of the title compound as a white solid.
[1479] Physical properties are as follows.
[1480]
[1481] All publications, patents, and patent documents cited are hereby incorporated by reference as if each were incorporated by reference. The present invention has been described in terms of various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications are possible within the spirit and scope of the invention.

权利要求:
Claims (81)
[1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof.
<Formula I>

Wherein X is a) 0 or b) S;
W is a) R ² , b) NR ⁷ R ⁸ , C) OR ⁹ or d) SO _i R ⁹ ;
R ¹ is a) Cl, b) F, c) Br, d) CN or e) N0 ₂ ;
R ² is a) (CH ₂ CH ₂ 0) _m R ¹⁰ ,
b) het bound via a carbon atom,
C) OC _2- which may be partially unsaturated and substituted by NR ⁷ R ⁸ , R ¹¹ , CN, SO _i R ⁹ , or further by het, OR ^1O , OC (═O) aryl or NR ⁷ R ⁸ C _1-7 alkyl optionally substituted by one or more substituents selected from the group consisting of ₄ alkyl, or
d) optionally unsaturated by C _1-7 alkyl which may be partially unsaturated and optionally substituted by R ¹¹ , NR ⁷ R ⁸ , SO _i R ⁹ , or optionally R ¹¹ , NR ⁷ R ⁸ or SO _i R ⁹ C _3-8 cycloalkyl;
R ³ is a) H, b) halo or c) C _1-4 alkyl optionally substituted by one to three halo;
R ⁴ is a) H, b) aryl, c) het, d) S0 ₂ NHR ¹² , e) CONHR ¹² , f) NR ⁷ R ⁸ , g) NHCOR ¹² , h) NHS0 ₂ R ¹² , i) optionally- OC _2-7 alkyl substituted by OH, j) SC _2-7 alkyl optionally substituted by OH, or
k) C _1-8 which may be partially unsaturated and optionally substituted by one or more substituents selected from the group consisting of N ₃ , OR ¹⁰ , NR ⁷ R ⁸ , halo, SO _i R ⁹ , OR ¹³ or R ¹¹ Alkyl;
R ⁵ is a) H, b) halo, c) C≡CR ¹⁴ , d) NR ⁷ R ⁸ , e) S0 ₂ NHR ¹² , f) het or g) C _1-7 alkyl optionally substituted by OH; ;
R ⁶ is a) H, b) halo, c) SC _1-7 alkyl,
e) C _1-7 alkoxy optionally substituted by one or more halo or OH, or
f) OC _1-7 alkyl which may be partially unsaturated and further substituted with halo, NR ¹⁰ R ¹⁰ , (CH ₂ ) _n OR ¹³ , R ¹¹ , or SO _i R ⁹ , NR ⁷ R ⁸ , or het C _1-7 alkyl optionally substituted by;
R ⁷ and R ⁸ are independently a) H, b) aryl,
c) C _1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from the group consisting of NR ¹⁰ R ¹⁰ , CONR ¹⁰ R ¹⁰ , R ¹¹ , SO _i R ⁹ , halo; or
d) R ⁷ and R ⁸ together with the nitrogen bonded to them form a het;
R ⁹ is a) aryl, b) het, c) C _3-8 cycloalkyl, or
d) may be partially unsaturated, optionally one or more OR ¹⁰ , Oaryl, het, aryl, NR ¹⁰ R ¹⁰ , CN, SH, SO _i C _1-6 alkyl, SO _i aryl, halo or CONR ¹⁰ R ¹⁰ C _1-7 alkyl which may be substituted by;
R ¹⁰ is a) H or b) C _1-7 alkyl optionally substituted by OH;
R ¹¹ is a) OR ¹⁰ , b) Ohet, c) Oaryl, d) CO ₂ R ¹⁰ , e) het, f) aryl or g) CN;
R ¹² is a) H, b) het, c) aryl, d) C _3-8 cycloalkyl or e) C _1-7 alkyl optionally substituted by NR ⁷ R ⁸ or R ¹¹ ;
R ¹³ is a) (P = O) (OH) ₂ , b) (P = O) (C _1-7 alkoxy) ₂ , c) CO (CH ₂ ) _n CON (CH ₃ ) (CH ₂ ) _n SO ₃ ^- M ⁺ , d) amino acids, e) C (= 0) aryl, f) C (= 0) C _1-6 alkyl optionally substituted by NR ¹⁰ R ¹⁰ or g) CO (CH ₂ ) _n CO ₂ H;
R ¹⁴ is a) het, b) (CH ₂ ) _n OR ¹³ or
c) C _1-7 alkyl substituted by one or more substituents selected from R ¹¹ , or OC _1-7 alkyl further substituted with SO _i R ⁹ , NR ⁷ R ⁸ , or het;
Aryl is a phenyl radical or ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic;
het contains 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and is optionally 4- (4), 5- (5), 6 fused to a benzene ring or any bicyclic heterocycle group (6) or 7- (7) membered saturated or unsaturated heterocyclic rings;
Wherein any aryl is C _1- which may be substituted by halo, OH, CF ₃ , C _1-6 alkoxy, and further 1 to 3 SR ¹⁰ , NR ¹⁰ R ¹⁰ , OR ¹⁰ or C0 ₂ R ¹⁰ . Optionally substituted by one or more substituents selected from the group consisting of ₆ alkyl;
Wherein any het may be substituted by halo, OH, CF ₃ , C _1-6 alkoxy, oxo, auxin, and further one to three SR ¹⁰ , NR ¹⁰ R ¹⁰ , OR ¹⁰ or C0 ₂ R ¹⁰ . Optionally substituted by one or more substituents selected from the group consisting of C _1-6 alkyl;
i is 0, 1 or 2;
m is 1, 2 or 3;
n is 1, 2, 3, 4, 5 or 6;
M is sodium, potassium or lithium;
Provided that X is O,
R ² is C _1-7 alkyl optionally substituted by R ¹⁵ ;
R ³ is H, methyl or halo;
R ⁴ is H, CONH (C _1-7 alkyl), NR ¹⁶ R ^17, or optionally OR ^10, CN, COOH, or is a C _1-7 alkyl substituted by NR ¹⁶ R ^17;
R ⁵ is H, halo, SO ₂ NHR ¹⁰ , NR ¹⁶ R ¹⁷ , or C _1-7 alkyl optionally substituted by OR ¹⁰ ;
R ⁶ is H, halo, C _1-7 alkoxy, or an optionally halo, OR ^10, CO ₂ R ¹⁰ or is a C _1-7 alkyl substituted by NR ¹⁶ R ^17;
R ¹⁵ is NR ¹⁶ R ¹⁷ , OR ¹⁰ , CN or C0 ₂ R ¹⁰ ;
R ¹⁶ and R ¹⁷ are independently H or C _1-7 alkyl; Or when NR ¹⁶ R ¹⁷ together with the nitrogen to which they are attached form a 5- or 6-membered ring such as pyrrolidine, piperidine, morpholine or piperazine, R ¹ is not Cl, Br, F or CN.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is Cl.
[3" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is F. 3.
[4" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is CN or NO ₂ .
[5" claim-type="Currently amended] The compound of claim 1, wherein R ² is (CH ₂ CH ₂ 0) _m H or (CH ₂ CH ₂ 0) _m C _1-4 alkyl, wherein m is 2 or 3. 3.
[6" claim-type="Currently amended] The compound of claim 1, wherein R ² is optionally substituted by R ¹¹ , NR ⁷ R ⁸ , SO _i R ⁹ , or optionally C _1-7 alkyl substituted by R ¹¹ , NR ⁷ R ⁸ or SO _i R ⁹ . C _3-8 cycloalkyl, wherein R ⁷ , R ⁸ , R ⁹ , R ¹¹ and i are the same as defined in claim 1.
[7" claim-type="Currently amended] The compound of claim 1, wherein R ² is cyclopropyl.
[8" claim-type="Currently amended] The compound of claim 1, wherein R ² is bonded via a carbon atom and is the same het as defined in claim 1.
[9" claim-type="Currently amended] The compound of claim 8, wherein het is tetrahydro-2H-pyranyl, piperidinyl, 1-methyl-piperidinyl or 1,1-dioxo-tetrahydro-2H-thiopyran.
[10" claim-type="Currently amended] The OC _2-4 alkyl of claim 1, wherein R ² is partially unsaturated and is substituted by NR ⁷ R ⁸ , R ¹¹ , SO _i R ⁹ , or further by het, OR ^1O or OC (═O) aryl. And C _2-7 alkyl optionally substituted by R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are the same compounds as defined in claim 1.
[11" claim-type="Currently amended] 11. The method of claim 10 wherein, R ² is (Z or E) -CH = CHR ^1O or a -CC≡CR ^{1O, 1O} wherein R is H, or an optionally C _1-7 alkyl substituted by OH.
[12" claim-type="Currently amended] The compound of claim 1, wherein R ² is NR ⁷ R ⁸ , R ¹¹ , SO _i R ⁹ , or further C substituted by OC _2-4 alkyl substituted by het, OR ¹⁰ or OC (═O) aryl. _1-7 alkyl, wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are the same as defined in claim 1.
[13" claim-type="Currently amended] The compound of claim 1, wherein R ² is further C _1-7 alkyl substituted by het, OH, OC _1-4 alkyl or OC _2-4 alkyl substituted by OC (═O) aryl.
[14" claim-type="Currently amended] The compound of claim 1, wherein R ² is C _1-7 alkyl substituted by SO _i R ⁹ , wherein R ⁹ and i are the same as defined in claim 1.
[15" claim-type="Currently amended] The compound of claim 1, wherein R ² is C _1-7 alkyl substituted by SO _i R ⁹ , wherein R ⁹ is C _1-4 alkyl optionally substituted by OH, or R ⁹ is optionally substituted by Cl Phenyl and i is 0, 1 or 2.
[16" claim-type="Currently amended] The compound of claim 1, wherein R ² is methyl.
[17" claim-type="Currently amended] The compound of claim 1, wherein W is NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are the same as defined in claim 1.
[18" claim-type="Currently amended] The compound of claim 1, wherein W is NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ together with the nitrogen to which they are attached form the same het as defined in claim 1.
[19" claim-type="Currently amended] The compound of claim 18, wherein the het is morpholine, piperidine, pyrrolidine, piperazine, or 4-methyl-piperazine.
[20" claim-type="Currently amended] The compound of claim 1, wherein W is NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently H, or C _1-4 alkyl optionally substituted by OH.
[21" claim-type="Currently amended] The compound of claim 18, wherein het is morpholine.
[22" claim-type="Currently amended] The compound of claim 1, wherein W is OR ⁹ or SO _i R ⁹ , wherein R ⁹ is partially unsaturated and optionally OR ¹⁰ , Oaryl, het, aryl, NR ¹⁰ R ¹⁰ , CN, CONR ¹⁰ R ¹⁰ or halo. C _1-6 alkyl which may be substituted by R ¹⁰ is H or C _1-4 alkyl.
[23" claim-type="Currently amended] The compound of claim 1, wherein R ³ is H. ³ .
[24" claim-type="Currently amended] The compound of claim 1, wherein R ³ is CF ₃ or halo.
[25" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is aryl or het.
[26" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is SO ₂ NHR ¹² , CONHR ¹² , NHCOR ¹² or NHS0 ₂ R ¹² , wherein R ¹² is the same as defined in claim 1.
[27" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is partially unsaturated and is C _2-8 alkyl optionally substituted with OR ¹⁰ , NR ⁷ R ⁸ , halo, SO _i R ⁹ , OR ¹³ or R ¹¹ , wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹³ are the same compounds as defined in claim 1.
[28" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is (Z or E) —CH═CHC _1-4 alkyl, optionally substituted by OH.
[29" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is —C≡CC _1-4 alkyl, optionally substituted by OH or OR ¹³ , wherein R ¹³ is (P═O) (OH) ₂ , (P═O) (C _{1 -7} alkoxy) ₂ or CO (CH ₂ ) ₆ CON (CH ₃ ) (CH ₂ ) _n SO ₃ ^- M ⁺ .
[30" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is C _1-8 alkyl substituted by OR ¹³ , wherein R ¹³ is (P═O) (OH) ₂ , ( _P═O ) (C _1-7 alkoxy) ₂ or _{CO (CH 2) n CON (} CH 3) (CH 2) 6 SO 3 - M + in the compound.
[31" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is C _1-8 alkyl substituted by SO _i R ⁹ , wherein R ⁹ is the same as defined in claim 1.
[32" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are the same as defined in claim 1.
[33" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is C _1-8 alkyl substituted by NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are the same as defined in claim 1.
[34" claim-type="Currently amended] The compound of claim 33, wherein R ⁷ and R ⁸ together with the nitrogen to which they are attached form the same het as defined in claim 1.
[35" claim-type="Currently amended] The compound of claim 33, wherein R ⁷ and R ⁸ are independently OH, C _1-6 alkyl optionally substituted by one or more substituents selected from the group consisting of the same aryl or CN as defined in claim 1.
[36" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is C _1-8 alkyl substituted by N ₃ .
[37" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is C _1-8 alkyl substituted by the same het as defined in claim 1.
[38" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is 4-morpholine methyl.
[39" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is C _1-7 alkyl substituted with the same R ¹¹ as defined in claim 1.
[40" claim-type="Currently amended] The compound of claim 1, wherein R ⁵ is H, or C _1-7 alkyl, optionally substituted by OH.
[41" claim-type="Currently amended] The compound of claim 1, wherein R ⁶ is OC _1-7 alkyl, optionally substituted by one or more OH.
[42" claim-type="Currently amended] The compound of claim 1, wherein R ⁶ is halo.
[43" claim-type="Currently amended] The compound of claim 1, wherein R ⁶ is C≡CC _1-7 alkyl substituted by one or more OH, or C _2-7 alkoxy substituted by one or more OH.
[44" claim-type="Currently amended] The compound of claim 1, wherein R ⁶ is H or C _1-7 alkyl optionally substituted by halo, NR ¹⁰ R ¹⁰ , OH, CO ₂ R ¹⁰ or het, wherein R ¹⁰ and het are defined in claim 1. Same compound as that shown.
[45" claim-type="Currently amended] The compound of claim 1 wherein M is sodium, potassium or lithium.
[46" claim-type="Currently amended] The compound of claim 1, wherein X is S; W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are the same as defined in claim 1.
[47" claim-type="Currently amended] The compound of claim 1, wherein X is O; R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ are the same as defined in claim 1 and W is NR ⁷ R ⁸ , OR ⁹ , SO _i R ⁹ or R ² ; Where R ² is a) (CH ₂ CH ₂ 0) _n R ¹⁰ ,
b) het bound via a carbon atom,
C) C _1-7 alkyl partially unsaturated and optionally substituted by OH,
d) C _3-8 cycloalkyl, or
e) C optionally substituted by one or more substituents selected from Ohet, Oaryl, SO _i R ⁹ , or additionally OC _2-4 alkyl substituted by het, OR ¹⁰ or OC (═O) aryl. _1-7 alkyl; Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and n are the same compounds as defined in claim 1.
[48" claim-type="Currently amended] The compound of claim 1, wherein X is O or S; R ¹ is Cl; R ³ is H; R ⁵ is H; R ⁶ is H or F; R ⁴ is 4-morpholinylmethyl; R ²
a) SO _i R ^9, or added by OH, het, OC _1-4 alkyl or OC (= O) C _1-4 alkyl substituted by a C _1-4 alkoxy substituted by phenyl,
b) (CH ₂ CH ₂ 0) ₂ C _1-4 alkyl,
C) C _1-6 alkyl partially unsaturated and optionally substituted by OH,
d) cyclopropyl,
e) tetrahydro-2H-pyranyl,
f) piperidinyl,
g) morpholinyl,
h) 1-methyl-piperidinyl or
i) 1,1-dioxo-tetrahydro-2H-thiopyran;
Wherein R ⁹ is phenyl optionally substituted by Cl or R ⁹ is C _1-6 alkyl optionally substituted by OH.
[49" claim-type="Currently amended] The compound of claim 1, wherein X is O or S; R ¹ is Cl; R ³ is H; R ⁵ is H; R ⁶ is H or F; R ⁴ is partially unsaturated and C _1-6 alkyl optionally substituted by OH or OR ¹³ ; Or R ⁴ is C _1-4 alkyl substituted by OR ¹³ ; W may be NR ¹⁰ R ¹⁰ , cyclopropyl, (CH ₂ CH ₂ 0) ₂ OR ¹⁰ , or partially unsaturated and optionally OH, morpholinyl, NR ¹⁰ R ¹⁰ , C (═O) OC _1-4 alkyl C _1-6 alkyl substituted by; Wherein R ¹⁰ is H or C _1-4 alkyl; R ¹³ is (P = O) (C _{1-7 alkoxy) 2, CO (CH 2)} n CON (CH 3) (CH 2) n SO 3 - M + , or (P = O) (OH) 2 The compound .
[50" claim-type="Currently amended] The compound of claim 1, wherein X is O or S; R ¹ is Cl; R ³ is H; R ⁵ is H; R ⁶ is C≡CC _1-4 alkyl optionally substituted by OH; R ⁴ is H, or C _1-4 alkyl which is partially unsaturated and may optionally be substituted by OH; W is C _1-4 alkyl optionally substituted by OH.
[51" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[52" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[53" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[54" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[55" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[56" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[57" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[58" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[59" claim-type="Currently amended] The method of claim 1, Phosphorus compounds or pharmaceutically acceptable salts.
[60" claim-type="Currently amended] The compound of claim 1, wherein R ² is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, carboxymethyl, (C _1-7 alkoxy) carbonylmethyl, 2-hydroxyethyl, 2- ( 2-methoxyethoxy) ethyl, 3- (2-tetrahydropyranyloxy) propyl, 2-morpholinoethyl, 2- (diethylamino) ethyl, 2- (dimethylamino) ethyl, 2-piperi Dinoethyl, 3-piperidinopropyl, 2- (1-methylpyrrolidin-2-yl) ethyl, 2- (diisopropylamino) ethyl, 2-pyrrolidin-1-ylethyl, 3- ( Dimethylamino) propyl or vinyl.
[61" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is 3-hydroxy-1-propynyl, 3-hydroxypropyl, hydroxymethyl, cis-4-hydroxy-1-butenyl, trans-4-hydroxy-1- Butenyl, (2-hydroxyethyl) (ethyl) amino, morpholinomethyl, (CH ₂ ) ₂ O (P = O) (OH) ₂ , (CH ₂ ) ₃ O (P = O) (tert- Butoxy) ₂ , 3- [di (tert-butyl) phosphoryl] propyl, 3-phosphorylpropyl, Na ⁺ -OS (O) ₂ CH ₂ CH ₂ N-CH ₃ ) C (= 0) (CH ₂ ) ₆ C (= O) O (CH ₂ ) ₃ or Na ⁺ -OS (O) ₂ CH ₂ CH ₂ N (CH ₃ ) C (= O)-(CH ₂ ) ₆ C (= O) OCH ₂ C ≡C-phosphorus compound.
[62" claim-type="Currently amended] The method of claim 1,
(1) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-isopropyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(2) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(3) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -8-methoxy-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(4) N- (4-chlorobenzyl) -6- [3-hydroxy-1-propenyl] -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(5) N- (4-chlorobenzyl) -8-fluoro-6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecar Boxamide;
(6) N- (4-chlorobenzyl) -8-fluoro-6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(7) N- (4-chlorobenzyl) -1- [2- (diethylamino) ethyl] -8-fluoro-6- (3-hydroxy-1-propynyl) -4-oxo-1, 4-dihydro-3-quinolinecarboxamide;
(8) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-propyl-1,4-dihydro-3-quinolinecarboxamide;
(9) N- (4-chlorobenzyl) -1- [2- (diethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(10) N- (4-chlorobenzyl) -1- [2- (dimethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide hydrochloride;
(11) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-piperidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
(12) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [3- (1-piperidinyl) propyl] -1,4-di Hydro-3-quinolinecarboxamide;
(13) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (1-methyl-2-pyrrolidinyl) ethyl] -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(14) N- (4-chlorobenzyl) -1- [2- (diisopropylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro 3-quinolinecarboxamide;
(15) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-pyrrolidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
(16) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(17) N- (4-chlorobenzyl) -1- [3- (dimethylamino) propyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
(18) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(19) N- (4-chlorobenzyl) -6-[(E) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(20) N- (4-chlorobenzyl) -6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(21) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(22) tert-butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinoli Nil] acetate;
(23) 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinolinyl] acetic acid ;
(24) N- (4-chlorobenzyl) -1- (2-hydroxyethyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(25) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(26) di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl Phosphate;
(27) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl dihydrogen phosphate;
(28) di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl) Propyl phosphate;
(29) sodium 2-[{8- [3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinoli Nil) propoxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate;
(30) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinoli Nil) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
(31) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinoli Nil) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
(32) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-qui Nolinyl) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
(33) 1- (tert-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(34) sodium 2-[{8- [3- (1- (tert-butyl) -3-{[(4-chlorobenzyl) amino] -carbonyl} -4-oxo-1,4-dihydro- 6-quinolinyl) propoxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate;
(35) sodium 2-[(8-{[3- (1- (tert-butyl) -3-{[(4-chlorobenzyl) amino] -carbonyl} -4-oxo-1,4-dihydro -6-quinolinyl) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
(36) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy) -ethyl] -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(37) N- (4-cyanobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(38) N- (4-chlorobenzyl) -1-methyl-6- (1,4-oxazepan-4-ylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(39) N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (1,4-thiazepan-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide;
(40) N- (4-chlorobenzyl) -1-methyl-6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) -4-oxo-1,4-dihydro 3-quinolinecarboxamide;
(41) N- (4-chlorobenzyl) -6- (2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl) -1-methyl-4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(42) 6- (azidomethyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(43) N- (4-chlorobenzyl) -1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(44) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(45) N- (4-chlorobenzyl) -1- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(46) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide:
(47) N- (4-chlorobenzyl) -1- [2- (2-ethoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(48) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (2-propynyl) -1,4-dihydro-3-quinolinecarboxamide;
(49) N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(50) N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(51) N- (4-chlorobenzyl) -1- (4-hydroxy-2-butynyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(52) N- (4-chlorobenzyl) -6-{[(2-hydroxy-2-phenylethyl) (methyl) amino] methyl} -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(53) N- (4-chlorobenzyl) -1- [3- (methylsulfinyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(54) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(55) N- (4-chlorobenzyl) -1- [3- (methylsulfonyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(56) N- (4-chlorobenzyl) -1- [2- (ethylsulfinyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(57) N- (4-chlorobenzyl) -1- [2- (ethylsulfonyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(58) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfinyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(59) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfonyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(60) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- [2- (phenylsulfanyl) ethyl] -1,4-dihydro-3-quinoline Carboxamides;
(61) N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(62) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) -amino] methyl} -1-methyl-4-oxo- 1,4-dihydro-3-quinolinecarboxamide;
(63) N- (4-chlorobenzyl) -6-[(3-hydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(64) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(65) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl]-(methyl) amino] methyl} -1-methyl 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(66) N- (4-chlorobenzyl) -6-[(3,3-dihydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(67) N- (4-chlorobenzyl) -1-[(methylsulfinyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(68) N- (4-chlorobenzyl) -1-[(methylsulfonyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(69) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfinyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(70) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfonyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(71) N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
(72) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(73) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-6-[(4-oxo-1-piperidinyl) methyl] -1 , 4-dihydro-3-quinolinecarboxamide;
(74) N- (4-chlorobenzyl) -6-{[(cyanomethyl) (methyl) amino] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(75) N- (4-chlorobenzyl) -6-{[(3R) -3-hydroxypyrrolidinyl] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo -1,4-dihydro-3-quinolinecarboxamide;
(76) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6-[(methylsulfanyl) methyl] -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(77) N- (4-chlorobenzyl) -6-{[[(1R, 2S) -2-hydroxy-1-methyl-2-phenylethyl] (methyl) -amino] methyl} -1- [2 -(2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(78) N- (4-chlorobenzyl) -6-{[(2-hydroxy-2-phenylethyl) (methyl) amino] methyl} -1- [2- (2-methoxyethoxy) ethyl] 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(79) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) amino] -methyl} -1- [2- (2- Methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(80) 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6- (4-morpholinyl-methyl) -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(81) 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) Ethyl] (methyl) amino] methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(82) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide;
(83) N- (4-chlorobenzyl) -8- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(84) N- (4-chlorobenzyl) -8- (4-hydroxy-1-butynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(85) N- (4-chlorobenzyl) -6-{[3- (hydroxyimino) -1-azetidinyl] methyl} -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(86) N- (4-chlorobenzyl) -1- {2- [2- (4-morpholinyl) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1, 4-dihydro-3-quinolinecarboxamide;
(87) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(88) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfinyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(89) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfonyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(90) N- (4-chlorobenzyl) -1-[(4-chlorophenoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(91) N- (4-chlorobenzyl) -1-[(2-methoxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(92) 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] methoxy} Ethyl benzoate;
(93) N- (4-chlorobenzyl) -1-[(2-hydroxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(94) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinoline Carboxamides:
(95) N- (4-chlorobenzyl) -1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(96) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(97) N- (4-chlorobenzyl) -1- (1,1-dioxohexahydrothiopyran-4-yl) -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(98) N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(99) N- (4-chlorobenzyl) -1- (4-methyl-1-piperazinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(100) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(101) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-pyrrolidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(102) N- (4-chlorobenzyl) -1-[(2R) -2- (methoxymethyl) pyrrolidinyl] -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(103) N- (4-chlorobenzyl) -1- (dimethylamino) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(104) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(105) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(106) N- (4-chlorobenzyl) -1- (dimethylamino) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(107) N- (4-chlorobenzyl) -1- (dimethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(108) 1- (allyloxy) -N- (4-chlorobenzyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(109) N- (4-chlorobenzyl) -1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(110) N- (4-bromobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(111) N- (4-fluorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(112) N- (4-chlorobenzyl) -1-{[2- (4-morpholinyl) ethoxy] methyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(113) N- (4-chlorobenzyl) -1-{[2- (dimethylamino) ethoxy] methyl} -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(114) N- (4-chlorobenzyl) -1-{[2- (4-methyl-1-piperazinyl) ethoxy] methyl} -6- (4-morpholinylmethyl) -4-oxo- 1,4-dihydro-3-quinolinecarboxamide;
(115) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-{[2- (1-piperidinyl) ethoxy] methyl} -1,4- Dihydro-3-quinolinecarboxamide;
(116) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-{[2- (1-pyrrolidinyl) ethoxy] methyl} -1,4- A compound which is dihydro-3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof.
[63" claim-type="Currently amended] The method of claim 1,
(1) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(2) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -8-methoxy-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(3) N- (4-chlorobenzyl) -6- [3-hydroxy-1-propenyl] -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(4) N- (4-chlorobenzyl) -8-fluoro-6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecar Boxamide;
(5) N- (4-chlorobenzyl) -8-fluoro-6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(6) N- (4-chlorobenzyl) -1- [2- (diethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(7) N- (4-chlorobenzyl) -1- [2- (dimethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide hydrochloride;
(8) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-piperidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
(9) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [3- (1-piperidinyl) propyl] -1,4-di Hydro-3-quinolinecarboxamide;
(10) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (1-methyl-2-pyrrolidinyl) ethyl] -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(11) N- (4-chlorobenzyl) -1- [2- (diisopropylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro 3-quinolinecarboxamide;
(12) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-pyrrolidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
(13) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(14) N- (4-chlorobenzyl) -1- [3- (dimethylamino) propyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
(15) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(16) N- (4-chlorobenzyl) -6-[(E) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(17) N- (4-chlorobenzyl) -6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(18) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(19) tert-Butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinoli Nil] acetate;
(20) N- (4-chlorobenzyl) -1- (2-hydroxyethyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(21) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(22) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl dihydrogen phosphate;
(23) di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl) Propyl phosphate;
(24) sodium 2-[{8- [3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinoli Nil) propoxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate;
(25) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinoli Nil) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
(26) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy) -ethyl] -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(27) N- (4-cyanobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(28) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-propyl-1,4-dihydro-3-quinolinecarboxamide;
(29) N- (4-chlorobenzyl) -1-methyl-6- (1,4-oxazepan-4-ylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(30) N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (1,4-thiazepan-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide;
(31) 6- (azidomethyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(32) N- (4-chlorobenzyl) -6-[(4,4-difluoro-1-piperidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(33) N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarbothioamide;
(34) N- (4-chlorobenzyl) -6- (2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl) -1-methyl-4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(35) N- (4-chlorobenzyl) -1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(36) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(37) N- (4-chlorobenzyl) -1- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(38) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(39) N- (4-chlorobenzyl) -1- [2- (2-ethoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(40) N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(41) N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(42) N- (4-chlorobenzyl) -1- (4-hydroxy-2-butynyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(43) N- (4-chlorobenzyl) -6-{[(2-hydroxy-2-phenylethyl) (methyl) amino] methyl} -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(44) N- (4-chlorobenzyl) -1- [3- (methylsulfinyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(45) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(46) N- (4-chlorobenzyl) -1- [3- (methylsulfonyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(47) N- (4-chlorobenzyl) -1- [2- (ethylsulfinyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(48) N- (4-chlorobenzyl) -1- [2- (ethylsulfonyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(49) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfinyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(50) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfonyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(51) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- [2- (phenylsulfanyl) ethyl] -1,4-dihydro-3-quinoline Carboxamides:
(52) N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(53) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) -amino] methyl} -1-methyl-4-oxo- 1,4-dihydro-3-quinolinecarboxamide;
(54) N- (4-chlorobenzyl) -6-[(3-hydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(55) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(56) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl]-(methyl) amino] methyl} -1-methyl 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(57) N- (4-chlorobenzyl) -6-[(3,3-dihydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(58) N- (4-chlorobenzyl) -1-[(methylsulfinyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(59) N- (4-chlorobenzyl) -1-[(methylsulfonyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(60) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfinyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(61) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfonyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(62) N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
(63) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(64) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-6-[(4-oxo-1-piperidinyl) methyl] -1 , 4-dihydro-3-quinolinecarboxamide;
(65) N- (4-chlorobenzyl) -6-{[(3R) -3-hydroxypyrrolidinyl] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo -1,4-dihydro-3-quinolinecarboxamide;
(66) N- (4-chlorobenzyl) -6-{[[((1R, 2S) -2-hydroxy-1-methyl-2-phenylethyl] (methyl) -amino] methyl} -1- [2 -(2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(67) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) amino] -methyl} -1- [2- (2- Methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(68) 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6- (4-morpholinyl-methyl) -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(69) 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) Ethyl] (methyl) amino] methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(70) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide;
(71) N- (4-chlorobenzyl) -8- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(72) N- (4-chlorobenzyl) -8- (4-hydroxy-1-butynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(73) N- (4-chlorobenzyl) -6-{[3- (hydroxyimino) -1-azetidinyl] methyl} -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(74) N- (4-chlorobenzyl) -1- {2- [2- (4-morpholinyl) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1, 4-dihydro-3-quinolinecarboxamide;
(75) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(76) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfinyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(77) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfonyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(78) N- (4-chlorobenzyl) -1-[(4-chlorophenoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(79) N- (4-chlorobenzyl) -1-[(2-methoxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(80) 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] methoxy} Ethyl benzoate;
(81) N- (4-chlorobenzyl) -1-[(2-hydroxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(82) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinoline Carboxamides;
(83) N- (4-chlorobenzyl) -1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(84) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(85) N- (4-chlorobenzyl) -1- (1,1-dioxohexahydrothiopyran-4-yl) -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(86) N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(87) N- (4-chlorobenzyl) -1- (4-methyl-1-piperazinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(88) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(89) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-pyrrolidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(90) N- (4-chlorobenzyl) -1-[(2R) -2- (methoxymethyl) pyrrolidinyl] -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(91) N- (4-chlorobenzyl) -1- (dimethylamino) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(92) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(93) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(94) N- (4-chlorobenzyl) -1- (dimethylamino) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(95) A compound or a pharmaceutically acceptable salt thereof, which is 1- (allyloxy) -N- (4-chlorobenzyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide.
[64" claim-type="Currently amended] The method of claim 1,
(1) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(2) 1- (sec-butyl) -N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -8-methoxy-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(3) N- (4-chlorobenzyl) -6- [3-hydroxy-1-propenyl] -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(4) N- (4-chlorobenzyl) -8-fluoro-6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecar Boxamide;
(5) N- (4-chlorobenzyl) -8-fluoro-6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(6) N- (4-chlorobenzyl) -1- [2- (dimethylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide hydrochloride;
(7) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-piperidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
(8) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [3- (1-piperidinyl) propyl] -1,4-di Hydro-3-quinolinecarboxamide;
(9) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (1-methyl-2-pyrrolidinyl) ethyl] -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(10) N- (4-chlorobenzyl) -1- [2- (diisopropylamino) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro 3-quinolinecarboxamide;
(11) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1- [2- (1-pyrrolidinyl) ethyl] -1,4-di Hydro-3-quinolinecarboxamide;
(12) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(13) N- (4-chlorobenzyl) -1- [3- (dimethylamino) propyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
(14) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(15) N- (4-chlorobenzyl) -6-[(E) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(16) N- (4-chlorobenzyl) -6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(17) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(18) tert-butyl 2- [3-{[(4-chlorobenzyl) amino] carbonyl} -6- (3-hydroxy-1-propynyl) -4-oxo-1 (4H) -quinoli Nil] acetate;
(19) N- (4-chlorobenzyl) -1- (2-hydroxyethyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(20) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(21) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl dihydrogen phosphate;
(22) di (tert-butyl) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl) Propyl phosphate;
(23) sodium 2-[{8- [3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinoli Nil) propoxy] -8-oxooctanoyl} (methyl) amino] -1-ethanesulfonate;
(24) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinoli Nil) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
(25) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(26) N- (4-cyanobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(27) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-propyl-1,4-dihydro-3-quinolinecarboxamide;
(28) 6- (azidomethyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(29) N- (4-chlorobenzyl) -6- (2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl) -1-methyl-4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(30) N- (4-chlorobenzyl) -1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(31) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(32) N- (4-chlorobenzyl) -1- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(33) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(34) N- (4-chlorobenzyl) -1- [2- (2-ethoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(35) N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(36) N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(37) N- (4-chlorobenzyl) -1- (4-hydroxy-2-butynyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(38) N- (4-chlorobenzyl) -1- [3- (methylsulfinyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(39) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(40) N- (4-chlorobenzyl) -1- [3- (methylsulfonyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(41) N- (4-chlorobenzyl) -1- [2- (ethylsulfinyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(42) N- (4-chlorobenzyl) -1- [2- (ethylsulfonyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(43) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfinyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(44) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfonyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(45) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- [2- (phenylsulfanyl) ethyl] -1,4-dihydro-3-quinoline Carboxamides :,
(46) N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(47) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) -amino] methyl} -1-methyl-4-oxo- 1,4-dihydro-3-quinolinecarboxamide;
(48) N- (4-chlorobenzyl) -6-[(3-hydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(49) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(50) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl]-(methyl) amino] methyl} -1-methyl 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(51) N- (4-chlorobenzyl) -6-[(3,3-dihydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(52) N- (4-chlorobenzyl) -1-[(methylsulfinyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(53) N- (4-chlorobenzyl) -1-[(methylsulfonyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(54) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfinyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(55) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfonyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(56) N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
(57) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(58) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-6-[(4-oxo-1-piperidinyl) methyl] -1 , 4-dihydro-3-quinolinecarboxamide;
(59) N- (4-chlorobenzyl) -6-{[(3R) -3-hydroxypyrrolidinyl] methyl} -1- [2- (2-methoxyethoxy) ethyl] -4-oxo -1,4-dihydro-3-quinolinecarboxamide;
(60) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) amino] -methyl} -1- [2- (2- Methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(61) 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6- (4-morpholinyl-methyl) -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(62) 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) Ethyl] (methyl) amino] methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(63) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide;
(64) N- (4-chlorobenzyl) -8- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(65) N- (4-chlorobenzyl) -8- (4-hydroxy-1-butynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(66) N- (4-chlorobenzyl) -6-{[3- (hydroxyimino) -1-azetidinyl] methyl} -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(67) N- (4-chlorobenzyl) -1-{(2- [2- (4-morpholinyl) ethoxy] ethyl} -6- (4-morpholinylmethyl) -4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(68) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(69) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfinyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(70) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfonyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(71) N- (4-chlorobenzyl) -1-[(2-methoxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(72) 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] methoxy} Ethyl benzoate;
(73) N- (4-chlorobenzyl) -1-[(2-hydroxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(74) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinoline Carboxamides;
(75) N- (4-chlorobenzyl) -1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(76) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(77) N- (4-chlorobenzyl) -1- (1,1-dioxohexahydrothiopyran-4-yl) -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(78) N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(79) N- (4-chlorobenzyl) -1- (4-methyl-1-piperazinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(80) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (1-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(81) N- (4-chlorobenzyl) -1- (dimethylamino) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(82) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(83) A compound which is 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide, or a pharmaceutically acceptable thereof Possible salts.
[65" claim-type="Currently amended] The method of claim 1,
(1) N- (4-chlorobenzyl) -8-fluoro-6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(2) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(3) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(4) N- (4-chlorobenzyl) -6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(5) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(6) N- (4-chlorobenzyl) -1- (2-hydroxyethyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(7) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(8) 3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinolinyl) propyl dihydrogen phosphate;
(9) sodium 2-[(8-{[3- (3-{[(4-chlorobenzyl) amino] carbonyl} -1-methyl-4-oxo-1,4-dihydro-6-quinoli Nil) -2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate;
(10) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy) -ethyl] -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(11) N- (4-chlorobenzyl) -1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinolinecarboxamide;
(12) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(13) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(14) N- (4-chlorobenzyl) -1- [2- (2-ethoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(15) N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(16) N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(17) N- (4-chlorobenzyl) -1- (4-hydroxy-2-butynyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(18) N- (4-chlorobenzyl) -1- [3- (methylsulfinyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(19) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(20) N- (4-chlorobenzyl) -1- [3- (methylsulfonyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(21) N- (4-chlorobenzyl) -1- [2- (ethylsulfinyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(22) N- (4-chlorobenzyl) -1- [2- (ethylsulfonyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(23) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfonyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(24) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- [2- (phenylsulfanyl) ethyl] -1,4-dihydro-3-quinoline Carboxamides;
(25) N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(26) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) -amino] methyl} -1-methyl-4-oxo- 1,4-dihydro-3-quinolinecarboxamide;
(27) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(28) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl]-(methyl) amino] methyl} -1-methyl 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(29) N- (4-chlorobenzyl) -6-[(3,3-dihydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(30) N- (4-chlorobenzyl) -1-[(methylsulfinyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(31) N- (4-chlorobenzyl) -1-[(methylsulfonyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(32) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfinyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(33) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfonyl) -methyl] -1,4-dihydro-3-quinolinecar Boxamide;
(34) N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4-dihydro-3 Quinolinecarboxamide;
(35) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(36) 1- {2- [2- (tert-butoxy) ethoxy] ethyl-N- (4-chlorobenzyl) -6- (4-morpholinyl-methyl) -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(37) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide;
(38) N- (4-chlorobenzyl) -8- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(39) N- (4-chlorobenzyl) -8- (4-hydroxy-1-butynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(40) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfanyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(41) N- (4-chlorobenzyl) -1-([(4-chlorophenyl) sulfinyl] methyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(42) N- (4-chlorobenzyl) -1-[(2-methoxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(43) 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] methoxy} Ethyl benzoate;
(44) N- (4-chlorobenzyl) -1-[(2-hydroxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(45) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinoline Carboxamides;
(46) N- (4-chlorobenzyl) -1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(47) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(48) N- (4-chlorobenzyl) -1- (1,1-dioxohexahydrothiopyran-4-yl) -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(49) N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(50) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(51) A compound which is 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide, or a pharmaceutically acceptable thereof Possible salts.
[66" claim-type="Currently amended] The method of claim 1,
(5) N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (tetrahydro-2H-pyran-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide;
(5) N- (4-chlorobenzyl) -1-methyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3quinolinecarbothioamide;
(5) N- (4-chlorobenzyl) -8- (2-hydroxyethoxy) -6- (3-hydroxypropyl) -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(5) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(5) 1- {2- [bis (2-hydroxyethyl) amino] ethyl} -N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1,4- A compound which is dihydro-3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof.
[67" claim-type="Currently amended] The method of claim 1,
(1) N- (4-chlorobenzyl) -8- [2-hydroxy-1- (hydroxymethyl) ethoxy] -6- (3-hydroxypropyl) -1-methyl-4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(2) N- (4-chlorobenzyl) -8-fluoro-6- (hydroxymethyl) -4-oxo-1- [3- (tetrahydro-2H-pyran-2-yloxy) propyl]- 1,4-dihydro-3-quinolinecarboxamide;
(3) N- (4-chlorobenzyl) -6- [ethyl (2-hydroxyethyl) amino] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(4) N- (4-chlorobenzyl) -1-cyclopropyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(5) 6-{[bis (2-hydroxyethyl) amino] methyl} -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(6) N- (4-chlorobenzyl) -6-{[(2-hydroxyethyl) (methyl) amino] methyl} -1-methyl-4-oxo-1,4-dihydro-3-quinolinecar Boxamide;
(7) 6-((benzyl (2-hydroxyethyl) amino) methyl) -N- (4-chlorobenzyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(8) N- (4-chlorobenzyl) -6-[(4,4-difluoro-1-piperidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(9) N- (4-chlorobenzyl) -6-{[4-fluoro-3,6-dihydro-1 (2H) -pyridinyl] methyl} -1-methyl-4-oxo-1,4 A compound that is dihydro-3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof.
[68" claim-type="Currently amended] The method of claim 1,
(1) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (3-hydroxy-1-propynyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(2) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] (methyl) amino] methyl} -1-methyl-4-oxo-1 , 4-dihydro-3-quinolinecarboxamide;
(3) N- (4-chlorobenzyl) -6-{[[2-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl] (methyl) amino] methyl} -1-methyl- 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(4) N- (4-chlorobenzyl) -6-[(3,3-dihydroxy-1-azetidinyl) methyl] -1-methyl-4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(5) N- (4-chlorobenzyl) -8-fluoro-6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(6) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (4-morpholinyl) ethyl] -4-oxo-1,4-di Hydro-3-quinolinecarboxamide;
(7) N- (4-chlorobenzyl) -6-[(Z) -3-hydroxy-1-propenyl] -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(8) N- (4-chlorobenzyl) -1-cyclopropyl-6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(9) N- (4-chlorobenzyl) -1- (2-hydroxyethyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(10) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(11) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1- [2- (2-methoxyethoxy) ethyl] -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(12) N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide;
(13) N- (4-chlorobenzyl) -8- (3-hydroxy-1-propynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(14) N- (4-chlorobenzyl) -8- (4-hydroxy-1-butynyl) -1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(15) N- (4-chlorobenzyl) -1-methyl-4-oxo-6- (tetrahydro-2H-pyran-4-ylmethyl) -1,4-dihydro-3-quinolinecarboxamide Compound or a pharmaceutically acceptable salt thereof.
[69" claim-type="Currently amended] The method of claim 1,
(1) N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(2) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxy-1-propynyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(3) 1-amino-N- (4-chlorobenzyl) -6- (3-hydroxypropyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(4) N- (4-bromobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(5) N- (4-fluorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox Compounds that are amides or pharmaceutically acceptable salts thereof.
[70" claim-type="Currently amended] The method of claim 1,
(1) N- (4-chlorobenzyl) -1-{[(4-chlorophenyl) sulfanyl] methyl} -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(2) N- (4-chlorobenzyl) -1-{[(4-chlorophenyl) sulfinyl] methyl} -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(3) N- (4-chlorobenzyl) -1-[(2-methoxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(4) 2-{[3-{[(4-chlorobenzyl) amino] carbonyl} -6- (4-morpholinylmethyl) -4-oxo-1 (4H) -quinolinyl] methoxy} Ethyl benzoate;
(5) N- (4-chlorobenzyl) -1-[(2-hydroxyethoxy) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(6) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinoline Carboxamides;
(7) N- (4-chlorobenzyl) -1- (1-methyl-4-piperidinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(8) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- (4-piperidinyl) -1,4-dihydro-3-quinolinecarboxamide ;
(9) N- (4-chlorobenzyl) -1- (1,1-dioxohexahydro-11 ambida ~ 6 ~ -thiopyran-4-yl) -6- (4-morpholinylmethyl)- 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
(10) N- (4-chlorobenzyl) -1- (4-morpholinyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide ;
(11) N- (4-chlorobenzyl) -1- [2- (2-hydroxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide;
(12) N- (4-chlorobenzyl) -1- [2- (2-ethoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide:
(13) N- (4-chlorobenzyl) -1- [2- (ethylsulfanyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(14) N- (4-chlorobenzyl) -1- [3- (methylsulfanyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(15) N- (4-chlorobenzyl) -1- (4-hydroxy-2-butynyl) -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3- Quinolinecarboxamide;
(16) 1- {2- [bis (2-hydroxyethyl) amino] ethyl} -N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(17) N- (4-chlorobenzyl) -1- [3- (methylsulfinyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(18) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfanyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(19) N- (4-chlorobenzyl) -1- [3- (methylsulfonyl) propyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(20) N- (4-chlorobenzyl) -1- [2- (ethylsulfinyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(21) N- (4-chlorobenzyl) -1- [2- (ethylsulfonyl) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinoline Carboxamides;
(22) N- (4-chlorobenzyl) -1- {3-[(3-hydroxypropyl) sulfonyl] propyl} -6- (4-morpholinylmethyl) -4-oxo-1,4- Dihydro-3-quinolinecarboxamide;
(23) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1- [2- (phenylsulfanyl) ethyl] -1,4-dihydro-3-quinoline Carboxamides;
(24) N- (4-chlorobenzyl) -1-[(methylsulfanyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(25) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfanyl) methyl] -1,4-dihydro-3-quinolinecarbox amides;
(26) N- (4-chlorobenzyl) -1-[(methylsulfinyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(27) N- (4-chlorobenzyl) -1-[(methylsulfonyl) methyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarbox amides;
(28) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfinyl) methyl] -1,4-dihydro-3-quinolinecarbox amides;
(29) N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1-[(phenylsulfonyl) methyl] -1,4-dihydro-3-quinolinecarbox amides;
(30) N- (4-chlorobenzyl) -1- [2- (2-methoxyethoxy) ethyl] -6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro- 3-quinolinecarboxamide:
(31) 1- {2- [2- (tert-butoxy) ethoxy] ethyl} -N- (4-chlorobenzyl) -6- (4-morpholinylmethyl) -4-oxo-1,4 -Dihydro-3-quinolinecarboxamide;
(32) A compound which is N- (4-chlorobenzyl) -1-cyclopropyl-6- (4-morpholinylmethyl) -4-oxo-1,4-dihydro-3-quinolinecarboxamide, or a pharmaceutical thereof Academically acceptable salts.
[71" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
[72" claim-type="Currently amended] A method of inhibiting viral DNA polymerase, comprising contacting the viral DNA polymerase with an inhibitory effective amount of the compound of claim 1.
[73" claim-type="Currently amended] 73. The method of claim 72, wherein the polymerase and the compound are contacted in vitro.
[74" claim-type="Currently amended] The method of claim 72, wherein the polymerase and the compound are contacted in vivo.
[75" claim-type="Currently amended] A method of treating herpesvirus infection comprising administering an effective amount of the compound of formula (I) as defined in claim 1 to a patient in need of treatment of the herpesvirus infection.
[76" claim-type="Currently amended] 76. The method of claim 75, wherein the herpesvirus is herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, human herpesvirus 7 or human herpesvirus How to be.
[77" claim-type="Currently amended] 76. The method of claim 75, wherein the herpesvirus is herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 7 or human herpesvirus.
[78" claim-type="Currently amended] 76. The method of claim 75, wherein said herpesvirus is human cytomegalovirus.
[79" claim-type="Currently amended] The method of claim 75, wherein the effective amount of the compound of claim 1 is administered orally, parenterally or topically.
[80" claim-type="Currently amended] 76. The method of claim 75, wherein the effective amount of the compound of claim 1 is from about 0.1 to about 300 mg / kg body weight.
[81" claim-type="Currently amended] 76. The method of claim 75, wherein the effective amount of the compound of claim 1 is from about 1 to about 30 mg / kg body weight.

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同族专利:

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公开号 | 公开日

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CN1333753A|2002-01-30|

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AU760207B2|2003-05-08|

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HU0200308A3|2003-03-28|

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CZ20012454A3|2002-03-13|

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BR9916772A|2004-06-15|

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NO20013383D0|2001-07-06|

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EA003945B1|2003-10-30|

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CN1161336C|2004-08-11|

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EA200100757A1|2001-12-24|

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IL144171D0|2002-05-23|

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WO2000040561A1|2000-07-13|

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EP1140850A1|2001-10-10|

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ID29550A|2001-09-06|

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US6248739B1|2001-06-19|

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JP2002534416A|2002-10-15|

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HU0200308A2|2002-06-29|

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NZ512824A|2003-09-26|

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NO20013383L|2001-09-07|

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AU2348600A|2000-07-24|

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SK8302001A3|2002-04-04|

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TR200101906T2|2001-12-21|

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CA2353636A1|2000-07-13|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-01-08|Priority to US11530199P

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1999-01-08|Priority to US60/115,301

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1999-06-23|Priority to US14061099P

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1999-06-23|Priority to US60/140,610

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1999-12-22|Application filed by 로렌스 티. 마이젠헬더, 파마시아 앤드 업존 캄파니

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1999-12-22|Priority to PCT/US1999/027960

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2001-11-14|Publication of KR20010101421A

优先权:

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申请号 | 申请日 | 专利标题

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US11530199P| true| 1999-01-08|1999-01-08|

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US60/115,301|1999-01-08|

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US14061099P| true| 1999-06-23|1999-06-23|

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US60/140,610|1999-06-23|

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PCT/US1999/027960|WO2000040561A1|1999-01-08|1999-12-22|Quinolinecarboxamides as antiviral agents|