• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Formula (1) A pharmaceutical composition comprising a compound of formula (1) and a pharmacologically acceptable salt thereof. The meanings of the symbols used in the general formula (1) throughout this specification are as follows: R 1 and R 2 are independently hydrogen, fluorine or alkyl; R 3 is aryl or heteroaryl. Compositions comprising the compounds of formula (1) are compositions for the inhibition of protein kinases and are useful for the treatment and inhibition of proliferative diseases such as cancer, inflammation and arthritis.
    公开号:KR20030036862A
    申请号:KR10-2003-7004561
    申请日:1998-11-02
    公开日:2003-05-09
    发明作者:김경에스.；킴볼에스.데이비드；포스마이클에이.；미스라라지엔.；카이첸-웨이；롤린스데이비드비.；웹스터케빈；헌트존티.；한웬-칭
    申请人:브리스톨-마이어즈 스퀴브 컴페니；
    IPC主号:
    专利说明:

    Composition for inhibiting cyclin dependent kinase {COMPOSITION FOR INHIBITING CYCLIN DEPENDENT KINASES}
    [1] The present invention relates to a composition for inhibiting cyclin dependent kinase (cdks).
    [2] In general, because the role of cdks in the regulation of cell proliferation is important, by inhibiting it, any disease characterized by abnormal cell proliferation, such as benign prostatic hyperplasia, familial adenosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis , Reversible arthritis, psoriasis, glomerulonephritis, restenosis following vasodilation or vascular surgery, proliferative scar formation, inflammatory bowel disease, transplant rejection, endotoxin shock and fungal infection May inhibit cell proliferation.
    [3] For the treatment of diseases characterized by abnormal cell proliferation by inhibiting cyclin dependent kinases as described above, the present invention is directed to the inhibition of protein kinases such as cyclin dependent kinases (cdks), such as cdc2 (cdk1), cdk2 and cdk4. It is an object to provide a composition. The composition for inhibiting protein kinase of the present invention is useful for the treatment and prevention of proliferative diseases such as cancer, inflammation and arthritis. The composition of the present invention is also useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
    [4] The present invention provides a pharmacological composition comprising the compound of formula (1).
    [5] More specifically, the present invention provides a compound of formula (1)
    [6]
    [7] And pharmacologically acceptable salts thereof as an active ingredient. Throughout this specification, the meanings of the symbols used in Formula 1 are as follows:
    [8] R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    [9] R 3 is aryl or heteroaryl
    [10] R 4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    [11] CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    [12] CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    [13] COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocyclo Alkyl; or
    [14] SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo Alkyl, SO 2 -alkyl-heterocycloalkyl; or
    [15] C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCN) NH-alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) NH-heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    [16] C (NNO 2 ) NH-alkyl, C (NNO 2 ) NH-cycloalkyl, C (NNO 2 ) NH-aryl, C (NNO 2 ) NH-alkyl-cycloalkyl, C (NNO 2 ) NH-alkyl-aryl , C (NNO 2 ) NH-heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH-heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    [17] C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH-heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    [18] C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHCO-alkyl-aryl, C (NH) NHCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    [19] C (NOR 6 ) NH-alkyl, C (NOR 6 ) NH-cycloalkyl, C (NOR 6 ) NH-aryl, C (NOR 6 ) NH-alkyl-cycloalkyl, C (NOR 6 ) NH-alkyl-aryl , C (NOR 6 ) NH-heteroaryl, C (NOR 6 ) NH-alkyl-heteroaryl, C (NOR 6 ) NH-heterocycloalkyl, C (NOR 6 ) NH-alkyl-heterocycloalkyl;
    [20] R 5 is hydrogen or alkyl;
    [21] R 6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    [22] m is an integer from 0 to 2; And
    [23] n is an integer from 1 to 3.
    [24] Described below are definitions of various terms used to describe the compounds of the present invention. This definition applies to the terms used throughout this specification, whether individually or as part of a larger group, unless they are otherwise limited in certain instances.
    [25] Any heteroatom that does not satisfy the valence should be assumed to have a hydrogen atom to satisfy that valency.
    [26] Carboxylate anions represent negatively charged -COO - groups.
    [27] "Alkyl" or "alk" is a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12 carbon atoms unless otherwise defined. Optionally the alkyl group is a substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, the alkyl group may substitute up to four substituents defined by R at its possible attachment position. When an alkyl group is substituted by an alkyl group, this may be referred to interchangeably as a "branched alkyl group". Typical examples of such unsubstituted groups are methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2 , 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Typical substituents include, but are not limited to, one or more of the following groups: halo (F, Cl, Br, I), haloalkyl (CCl 3 or CF 3 ), alkoxy, alkylthio, hydroxy, carboxy (-COOH) , Alkyloxycarbonyl (-C (O) R), alkylcarbonyloxy (-OCOR), amino (-NH 2 ), carbamoyl (-NHCOOR- or OCONHR-), urea (-NHCONHR-) or thiol (-SH). The defined alkyl group may also consist of one or more carbon and carbon double bonds or one or more carbon and carbon triple bonds.
    [28] "Alkenyl" is a straight, branched or cyclic hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon and carbon double bond.
    [29] "Alkynyl" is a straight, branched or cyclic hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon and triple bond of carbon.
    [30] Cycloalkyl is an alkyl species containing from 3 to 15 carbon atoms and there is no cross or resonance double bond between the carbon atoms. It may comprise 1 to 4 rings. Typical examples of such unsubstituted groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like. Typical substituents are one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and / or alkylthio.
    [31] As used herein, "alkoxy" or "alkylthio" means an alkyl group as described above bonded via an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.
    [32] "Alkoxyoxycarbonyl" refers to an alkoxy group bonded through a carbonyl group. Representative chemical formulas of alkoxycarbonyl radicals are as follows: —C (O) OR, wherein the R group is a straight or branched C 1-6 alkyl group.
    [33] "Alkylcarbonyl" refers to an alkali group bonded through a carbonyl group.
    [34] As used herein, "alkylcarbonyloxy" refers to an alkylcarbonyl group bonded through an oxygen linkage.
    [35] "Arylalkyl" is an aromatic ring bonded to an alkyl group as described above.
    [36] “Aryl” includes, for example, fused groups such as naphthyl, phenandrenyl, and the like, as well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl, and the like. The aryl group therefore contains at least one ring having at least six atoms, and such rings may be up to five and contain 22 atoms therein. It may have a cross (resonance) double bond between adjacent carbon atoms or suitable heteroatoms. The aryl group is optionally at least one group, ie halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S (O) m (m = 0,1,2) or thiol, but is not limited thereto.
    [37] "Heteroaryl" is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms containing one or more heteroatoms O, S or N or a bicyclic aromatic group having 8 to 10 atoms, with carbon or nitrogen atoms attached thereto Location. One or two additional carbon atoms are then optionally replaced by a hetero atom selected from O or S, and one to three additional carbon atoms are optionally replaced by a hetero atom nitrogen. The heteroaryl group is optionally substituted as described herein. Typical heteroaryl groups are: thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxyzolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl , Pyrazinyl, pyridazinyl, pyrimidinal, triazinylazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, benzooxadia Zolyl, benzofurazanyl and tetrahydropyranyl. Typical substituents are one or more of the following groups: halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkyl S (O m (m = 0,1,2) or thiol.
    [38] "Heteroarylium" means a heteroaryl group having a nitrogen atom of the fourth group and thus is positively charged.
    [39] "Heterocycloalkyl" is a cycloalkyl group (non-aromatic) in which one carbon atom present in the ring is replaced by a heteroatom selected from O, S or N and in addition up to three carbon atoms can be replaced with said heteroatom. .
    [40] "Neutral of a fourth group" means a nitrogen atom charged in a quaternary amount, such as positively charged nitrogen (e.g., tetramethylammonium, N-methylpyridinium), protonated in a tetraalkylalmonium group Positively charged nitrogen in ammonium species (eg trimethylhydroammonium, N-hydropyridinium), positively charged nitrogen in amine N-oxides (eg N-methyl-morpholine-N-oxide, pyridine-N- Oxides) and nitrogen (eg, N-aminopyridinium) positively charged in the N-amino-ammonium group.
    [41] "Heteroatom" means O, S or N selected on an independent basis.
    [42] "Halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.
    [43] When a functional group is referred to as "protected", this means that the functional group is present in a modified form to prevent undesirable side effects at the site of protection. Suitable protecting groups for the compounds of the present invention will be known from applications considering the state of the art in the art and reference may be made to the following standard text: Green, T.W. et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).
    [44] Specific examples of suitable compound salts according to the invention, including inorganic or organic acids, include hydrochloride, hydrobromide, sulfates, phosphates. Also suitable for pharmacological use include, but are not limited to, salts or pharmacologically acceptable salts thereof which can be used, for example, for the separation or purification of free compound 1.
    [45] All stereoisomers of the compounds according to the invention are assumed to be in mixture or in pure or substantially pure form. The definition of a compound of the present invention includes all possible stereoisomers and mixtures thereof. More specifically, separate optical isomers having racemic morphology and specific activity. Racemic forms can be degraded by physical compositions such as partial crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates, for example, by conventional compositions for optically crystallizing the active acid to form salts.
    [46] It is to be understood that solvates (eg hydrates) of the compound of formula 1 are also within the scope of the present invention. The solvation method uses a general method known in the art. Thus, the compounds of the present invention will exist in free or hydrated form and can be obtained by methods that illustrate the following schemes.
    [47]
    [48] As described in Scheme 1, a compound of Formula 1 is prepared, wherein X is S. 2-aminothiazole (2) is reacted with bromine in the presence of sodium or potassium thiocyanate to obtain thiocyanated aminothiazole, more specifically 5-thiocyanatoaminothiazole (3). Compound 3 is then reacted with R 4 -L (where L is a leaving group such as halogen) in the presence of a base such as triethylamine to produce 5-thiocyanatothiazole intermediate (4) (R 4 is As defined herein). The intermediate product (4) is reduced to thiol (5) using dithiothreitol (DTT), sodium borohydride, zinc or other known reducing agent. Compound (5) is reacted with an alkyl, aryl, or heteroaryl halide such as R 3 (CR 1 R 2 ) nL (where L is a leaving group such as halogen) in the presence of a base such as potassium carbonate Obtain the compound of 1. The step of reducing the thiocyanothiazole intermediate (4) with thiol (5) and reacting the reduced thiol (5) to produce the compound of formula 1 (X is S) proceeds continuously without purification.
    [49]
    [50] In Scheme 2, the 2,5-thioacetyl-2-acetylaminothiazole of structure 6 is reacted with an alkoxide such as potassium t-butoxide in alcohol or THF solvent and the resulting thiol is represented by the formula R 3 (CR 1 R 2 ) reacting with a group of nL (where L is a leaving group such as halogen) such as 2-halomethyloxazole (7) to give a compound of formula (8) wherein R 1 and R 2 are hydrogen and R 6 is acetyl To produce). 2-halomethyloxazole compounds of formula 7 can be prepared via several synthetic routes known in the art. Chem. Pharm. Bull. 30, 1865 (1982); Bull. Chem. Soc. Japan (52, 3597 (1979); JCS Chem. Comm . 322 (1981); Comprehensive Heterocyclic Chemstry , vol . 6, 177, published by A. Katritzky and CW Rees, Pergamon Press (1984).
    [51] Compounds of formula 8 (wherein R 4 is acetyl and X is S) are hydrogenated in the presence of a base such as sodium hydroxide to produce compounds of formula 9. The compound of formula 9 is then reacted with R 4 -L (where L is a leaving group such as halogen) in the presence of a base such as triethylamine to produce a compound of formula 1 wherein X is S. As such, the compound of formula 9 (R 4 is hydrogen in the compound of formula 1) is treated with a drug such as isothiocyanate, halide, acyl halide, chloroformate, isocyanate or sulfonyl chloride to give thiourea, Amine, amide, carbamate, urea or sulfonamides can be produced. The method of Scheme 2 more specifically describes methyloxazole groups, but is generally for R 3 (CR 1 R 2 ) n-groups as specified by Formula 1.
    [52] Alternatively, the compound of formula (7), wherein L is bromine, can be prepared by halogenating 2-methyloxazole with N-bromosuccinimide in the presence of dibenzoylperoxide.
    [53]
    [54] Scheme 3 describes a method for the selective preparation of compound 7, i.e., formula R 3 (CR 1 R 2 ) n L, wherein L is chlorine and n is integer 1. Compound 7 in the scheme is prepared as follows. The compounds of formula 10 and 11 are reacted in the presence of a base such as triethylamine to produce the compound of formula 12. Compound 12 is oxidized by an oxidizing agent such as oxalylchloride / DMSO in the presence of a base such as triethylamine to produce the compound of formula 13. This is cyclized by a drug such as phosphorus oxychloride to provide a compound of formula 7 wherein L is chlorine. Alternatively, the compound of formula 13 may be prepared by reacting an amino ketone corresponding to 10 with an acid chloride such as 11.
    [55]
    [56] In addition, the diazoketone represented by Formula 14 in Scheme 4 and the chloronitrile represented by Formula 15 may be reacted in the presence of BF 3 etherate to obtain a compound of Formula 7 wherein L is chlorine.
    [57]
    [58]
    [59] In Scheme 5, starting compound 16 The resin-bonded benzyl alcohol support and 2-methoxy-4-hydroxybenzaldehyde used in the solid phase synthesis obtained from Merrifield resin, denoted by, is reduced using a reducing agent such as NaBH 4 . In step 1, starting material 16 is treated with triphosphene and triphenylphosphine (PPh 3 ) in dichloromethane to give chlorobenzyl resin of formula 17. In step 2, thiocyanato trifluoroacetamide (18) is alkylated with resin-bound benzyl chloride (17) in the presence of diisopropylethylamine (DIPEA). The obtained product is resin-bonded thiocyanate (19). The thiocyanato trifluoroacetamide compound represented by Formula 17 may be reacted with trifluoroacetic anhydride using 5-thiocyanatoaminothiazole of Formula 3 (Scheme 1) using a base such as 2,6-lutidine. It can manufacture by making it react.
    [60] The resin-bound thiocyanate 19 in step 3 is then reduced to a resin-bound thiol 20 using a reducing agent such as dithiothritol under tetrahydrofuran (THF) and methanol. The resulting resin-bonded thiols (20) were converted to R 3 (in the presence of a base such as 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) at 80 ° C. in dimethyl formamide (DMF). CR 1 R 2 ) nL (where L is a leaving group) to form a compound of formula (21) (step 4). In step 5 the protection of the trifluoroacetyl group of compound 21 with sodium borohydride is produced to produce the compound of formula 22. In step 6, protected compound 22 is reacted with R 6 X (where X is a leaving group) in the presence of a base such as diisopropylethylamine to give a compound of formula 23. The product is then separated from the solid phase resin using trifluoroacetic acid (TFA) in step 7 to produce a compound of formula 1 wherein X is S. Compounds of Formula 1 (where X is S (O) m and m is 1 or 2) are compounds of Formula 1 (wherein m is 0), and oxidants such as sodium periodate, metachloroperbenzoic acid or oxone It can manufacture by using and oxidizing.
    [61] Starting materials of Schemes 1-5 are commercially available or may be prepared by conventional manufacturing methods known in the art.
    [62] All compounds of formula 1 can be prepared by modifying the methods described herein.
    [63] Preferred compounds of formula 1 are as follows:
    [64] R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    [65] R 3 is
    [66] Wherein Y is oxygen, sulfur or NR 9 ;
    [67] R 4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    [68] CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    [69] CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    [70] COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocyclo Alkyl; or
    [71] SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo Alkyl, SO 2 -alkyl-heterocycloalkyl; or
    [72] C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCN) NH-alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) NH-heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    [73] C (NNO 2 ) NH-alkyl, C (NNO 2 ) NH-cycloalkyl, C (NNO 2 ) NH-aryl, C (NNO 2 ) NH-alkyl-cycloalkyl, C (NNO 2 ) NH-alkyl-aryl , C (NNO 2 ) NH-heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH-heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    [74] C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH-heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    [75] C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHCO-alkyl-aryl, C (NH) NHCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    [76] C (NOR 6 ) NH-alkyl, C (NOR 6 ) NH-cycloalkyl, C (NOR 6 ) NH-aryl, C (NOR 6 ) NH-alkyl-cycloalkyl, C (NOR 6 ) NH-alkyl-aryl , C (NOR 6 ) NH-heteroaryl, C (NOR 6 ) NH-alkyl-heteroaryl, C (NOR 6 ) NH-heterocycloalkyl, C (NOR 6 ) NH-alkyl-heterocycloalkyl;
    [77] R 5 is hydrogen; And
    [78] R 6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    [79] R 7 and R 8 are independently hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkylheterocycloalkyl or halogen;
    [80] R 9 is H or alkyl;
    [81] m is an integer of 0; And
    [82] n is an integer of 1;
    [83] Most preferred compounds of formula 1 are as follows:
    [84] R 1 is hydrogen;
    [85] R 2 is hydrogen, fluorine or alkyl;
    [86] R 3 is substituted oxazole having the following arrangement:
    [87]
    [88] R 4 is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    [89] R 5 is hydrogen;
    [90] R 7 is hydrogen;
    [91] R 8 is an alkyl group such as tert-butyl;
    [92] m is an integer of 0; And
    [93] n is an integer 1.
    [94] Compounds of the invention have pharmacological properties; More specifically, compounds of formula 1 are inhibitors of cyclin dependent kinases (cdks), such as protein kinases such as cdc2 (cdk1), cdk2 and cdk4. The novel compounds of formula (1) are expected to have utility in the treatment of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative diseases and cardiovascular diseases, for example.
    [95] More specifically, compounds of Formula 1 are useful for the treatment of various cancers, including but not limited to:
    [96] Lung, esophagus, gallbladder, ovary, pancreas, stomach, uterus, thyroid, prostate and skin carcinoma, including squamous cell carcinoma, including bladder, breast, colon, kidney, liver, small cell lung cancer;
    [97] Lymphoid hematopoietic tumors, such as leukemia, acute lymphocytic leukemia, acute lymphangiogenic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, live blastoma lymphoma and Burkett's lymphoma;
    [98] Myeloid hematopoietic tumors, including acute and chronic spinal cord leukemia, spinal cord dysplasia and promyelocytic lymphoma
    [99] -Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma
    [100] Tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, gliomas and schwannomas
    [101] Other tumors including melanoma, carcinoma, teratocarcinoma, osteosarcoma, parasites, pigmentosum, keratinous carcinoma, thyroid hair follicle cancer and Kaposi's sarcoma.
    [102] In general, because the role of cdks in the regulation of cell proliferation is important, inhibitors can be used for any disease characterized by abnormal cell proliferation, such as benign prostatic hyperplasia, familial adenosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis , Reversible cell proliferation useful for treating psoriasis, glomerulonephritis, restenosis following vasodilation or vascular surgery, proliferative scar formation, inflammatory bowel disease, transplant rejection, endotoxin shock and fungal infection Can act as an inhibitor.
    [103] The compounds of formula 1 are also useful for the treatment of Alzheimer's disease, as recent studies suggest that cdk5 is involved in the phosphorylation of tau protein ( J. Biochem , 117,741-749 (1995)).
    [104] The compound of formula 1 may induce or inhibit apoptosis. Various human diseases make apoptosis abnormal. As modulators of apoptosis responses, compounds of formula (I) include cancer (including but not limited to the above-mentioned types), viral infections (herpesviruses, poxviruses, Epstein-Barr virus, sinds) Bisvirus and adenovirus), prevention of AIDS outbreaks in HIV-infected individuals, autoimmune diseases (autophages mediating systemic lupus, erythematosis, glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus Disorders including, but not limited to, neurodegenerative disorders (Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration) Spinal cord dysplasia, aplastic anemia, ischemia associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, Including but not limited to, atherosclerosis, toxic-induced or alcohol-related liver disease, diseases of the blood (including but not limited to chronic and aplastic anemia), degenerative diseases of musculoskeletal tissues (osteoporosis and arthritis) Not), aspirin-sensitive nonarrhythmic sinusitis, bladder fibrosis, multiple sclerosis, renal disease and cancer.
    [105] As an inhibitor of cdks, the compound of formula 1 can modulate the level of RNA and DNA synthesis in the cell. Therefore, these drugs are useful for the treatment of viral infections (HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbisvirus and adenovirus).
    [106] Compounds of formula 1 are also useful for the chemical prevention of cancer. The definition of chemoprevention is to inhibit the development of invasive cancer or to prevent the recurrence of culture by preventing the initiation of mutagenesis or by preventing the progression of already damaged pre-malignant cells.
    [107] The compounds of formula 1 are also useful for inhibiting angiogenesis and metastasis of tumors.
    [108] Compounds of formula 1 can act as inhibitors of other protein kinases such as protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abl, and other proteins It may have an effect in the treatment of diseases associated with kinases.
    [109] The compounds of the present invention may also contain known anti-cancer therapies such as radiation therapy or cytostatic agents or cytotoxic agents such as DNA interactions such as cisplatin or doxorubicin; Topoisomerase II inhibitors such as etoposide; Topoisomerase I inhibitors such as CPT-11 or topotecan; Tubulin interaction agents, such as pasilataxel, docetaxel or epothilones; Hormonal agents such as tamoxifen; Thymidylate synthase inhibitors such as 5-fluorouracil; And anti-metabolites such as, but not limited to, methoxresate, which are useful in combination (administered together or continuously).
    [110] When formulated in fixed double baths, such mixed products include the compounds of the invention within the dosage ranges described below and other pharmacologically active agents or therapeutic agents within the approved dosage ranges. For example, the cdc2 inhibitor olomusin is known to act synergistically with known cytotoxic agents in inducing apoptosis ( J. Cell Sci ., 108, 2897 (1995)). It is also possible to administer the compound of formula 1 continuously when it is inadequate to combine with a known anticancer or cytotoxic agent. The order of administration in the present invention is not limited; The compound of formula 1 can be used regardless of whether it is before or after the administration of a known anticancer or cytotoxic agent. For example, the inhibitor of cyclin-dependent kinase flavopyridol has its cytotoxic activity influenced by the sequence of anticancer drug administration. Cancer Research , 57, 3375 (1997).
    [111] The pharmacological properties of the compounds according to the invention can be confirmed by numerous drug assays. Good examples of drug analysis performed on the compounds according to the invention and their salts are described below. The compounds of Examples 1-8 exhibited cdc2 / cyclin B1 kinase activity with IC 50 values of 50 μM or less. The compounds of Examples 1-8 exhibited cdk2 / cycline E kinase activity with IC 50 values of 50 μM or less. The compounds of Examples 1-8 exhibited cdk4 / cyclin D1 kinase activity with IC 50 values of 50 μM or less.
    [112] cdc2 / cyclin B1 kinase assay
    [113] cdc2 / cyclin B1 kinase activity was measured by monitoring the binding of 32 P with histone H1. The reaction was performed with 50ng baculovirus of GST-cdc2 expression, 75ng baculovirus of GST-cyclin B1 expression, 1ug histone HI in kinase buffer (50mM Tris, pH 8.0, 10mM MgCl 2 , 1mM EGTA, 0.5mM DTT). (Boehringer Mannheim), consisting of 0.2mCi and 25mM ATP of 32 P g-ATP. The reaction was incubated at 30 ° C. for 30 minutes and culture was stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15%. Then incubate for 20 minutes on ice. Reactions were harvested on GF / C unifilter plates using a Packard Filtermate Universal harvester. And filters were counted on a Packard topcount 96-well liquid scintillation counter (Marshak, DR, Vanderberg, MT, Bae, YS, Yu, IJ, J. , 45, 391-400 (1991), Cellular Biochemistry , herein Included in references).
    [114] c dk2 / cycline E kinase assay
    [115] cdk2 / cyclin E kinase activity was measured by monitoring the binding of 32 P and retinoblastoma protein. This reaction was performed with a 500 ng GST-retinal cell tumor protein produced by 2.5 ng baculovirus, bacteria of GST-cdk2 / cyclin E expression in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl 2 , 5 mM EGTA, 2 mM DTT). aa 776-928), 0.2mCi of 32 P g-ATP and 25mM ATP. The reaction was incubated at 30 ° C. for 30 minutes and culture was stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15%. Then incubate for 20 minutes on ice. Reactions were harvested on GF / C unifilter plates using a Packard Filtermate Universal harvester. The filters were then counted on a Packard top count 96-well liquid scintillation counter.
    [116] cdk4 / cyclin D1 kinase activity
    [117] cdk4 / cyclin D1 kinase activity was measured by monitoring the binding of 32 P and retinoblastoma protein. The reaction was produced in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl 2 , 5 mM EGTA, 2 mM DTT), 165 ng baculovirus of GST-cdk4 expression, 282 ng bacterially expressed with S-tag cyclin D1, bacteria 500 ng GST-retinoblastoma protein (aa 776-928), 0.2 μCi of 32 P γ-ATP and 25 μM ATP. The reaction was incubated at 30 ° C. for 1 hour and culture was stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15%. Then incubate for 20 minutes on ice. Reactions were harvested on GF / C unifilter plates using a Packard Filtermate Universal harvester. And the filters were counted on a Packard top count 96-well liquid scintillation counter (Coleman, KG, Wautlet, BS, Morissey, D, Mulheron, JG, Sedman, S., Brinkley, P., Price, S., Wedster, KR (1997) Identification of CDK4 sequence and p16 binding included in Cyclin D. J. Biol . Chem . 272 , 30: 18869-18874, incorporated herein by reference).
    [118] The present invention further relates to the use of a medicament as described above, which has the function of controlling cancer, inflammation and arthritis and comprises at least one compound of formula 1 as defined above or at least one pharmaceutically acceptable acid added salt thereof. And the present invention relates to the use of a compound of formula 1 as defined above for the preparation of a medicament having activity against proliferative diseases as described above that acts against cancer, inflammation and / or arthritis.
    [119] The following examples and methods of preparation describe means and methods for carrying out and using the invention and are intended to show specific examples rather than limitation thereof. It is to be understood that other embodiments are possible within the spirit and scope of the invention as defined in the claims herein.
    [120] EXAMPLE
    [121] Example 1
    [122] N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [123]
    [124] A. Preparation of 1-benzyloxycarbonylamino-2-butanol
    [125] 1-amino-2-butanol (5.5 g, 61.8 mmol), benzyl chloroformate (11.5 g, 676.6 mmol) and sodium carbonate (7.16 g, 67.7 mmol) in water (50 mL) at 0 ° C. for 3 hours. Stirred. Water (50 mL) was added to the reaction mixture and the product was extracted with methylene chloride (3 × 20 mL). Methylene chloride extract was dried under Na 2 S0 4 and concentrated. The residue was passed through a short column (SiO 2, hexanes: ethyl acetate / 10: 1, and ethyl acetate) to give 1-benzyloxycarbonylamino-2-butanol (13.9 g, 100%) as a liquid.
    [126] 1 H NMR (CDCl 3 ) δ 7.30 (m, 5H), 5.45 (s, 1H), 5.06 (s, 2H), 3.57 (s, 1H), 3.31 (m, 1H), 3.04 (m, 1H), 2.91 (m, 1 H), 1.43 (m, 2 H), 0.91 (t, J = 7.6 Hz, 3H).
    [127] B. Preparation of 1-benzyloxycarbonylamino-2-butanone
    [128] Oxalyl chloride (37 mL 2M solution in methylene chloride, 74 mmol) was added to methylene chloride (60 mL) under argon at −78 ° C. followed by DMSO (7.8 g, 100 mmol). The mixture was stirred at −78 ° C. for 20 minutes and thereto was added a solution of 1-benzyloxycarbonylamino-2-butanol (13.9 g, 61.8 mmol) in methylene chloride (40 mL). The mixture was stirred at -78 ° C for 1 hour and triethylamine (21 mL) was added thereto. Warm to room temperature (rt) and wash sequentially with 1N hydrochloric acid and aqueous sodium bicarbonate solution. The methylene chloride solution was dried under Na 2 S0 4 and concentrated to give 1-benzyloxycarbonylamino-2-butanone (11.2 g, 82%) as a solid, which was pure enough to be used for the next reaction.
    [129] 1 H NMR (CDCl 3 ) δ 7.32 (m, 5H), 5.50 (s, 1H), 5.06 (s, 2H), 4.07 (s, 2H), 2.43 (q, J = 7.6 Hz, 2H), 1.06 ( q, J = 7.6 Hz, 3H).
    [130] C. Preparation of 1-amino-2-butanone
    [131] A solution of 1-benzyloxycarbonylamino-2-butanone (9.30 mg, 42 mmol) in ethanol (50 mL) and 1N hydrochloric acid (46 mL) were present with Pd / C (1.5 g, 10%) in a hydrogen atmosphere and at room temperature. Stir for hours. The mixture was filtered through a celite bed and the filtrate solution was concentrated. The residue was triturated with ethyl ether to give 1-amino-2-butanone (5.3 g, 102%) as a hydrochloride salt.
    [132] 1 H NMR (CD 3 OD) δ 3.97 (s, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H).
    [133] D. Preparation of 2-amino-5-thiocyanatothiazole
    [134] 2-aminothiazole (41 g, 410 mM) and sodium thiocyanate (60 g, 740 mM, dried in vacuo overnight at 130 ° C. oven) were dissolved in 450 mL anhydrous methanol and the solution was cooled in a cold water bath. To this was added dropwise bromine (23 mL, 445 mM) dropwise. Stir at room temperature for 4 hours after addition. 500 mL of water was added to the mixture and stirred for 5 minutes, then filtered through a layer of celite and the layers washed with water. The pH of the filtrate solution was about 1. The pH of the solution was adjusted to about 7 by removing most of the methanol under reduced pressure and adding aqueous sodium carbonate with slow stirring. The precipitated solid was filtered off, washed with water and dried to give 37 g (57%) of the desired product as a dark brown color. Melting point was 140-143 degreeC.
    [135] 1 H NMR (CD 3 OD) δ 7.33 (s, 1H); MS (CI / NH 3 ) m / e 179 (M + Na) + , 158 (M + H) + .
    [136] E. Preparation of 2-acetylamino-5-thiocyanatothiazole
    [137] Acetic anhydride (1.2 g, 0.12 mol) was added to a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) at room temperature. Added. The mixture was stirred at rt for 6 h. The mixture was concentrated and dried and methanol (50 mL) was added to the residue. The precipitate was recovered and washed with water. The solid was dried and recrystallized from methanol to give 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) at a melting point of 212 ° C. as a solid.
    [138] 1 H NMR (CD 3 OD) δ 7.79 (s, 1 H), 2.23 (s, 3 H).
    [139] F. Preparation of [[2- (acetylamino) -5-thiazolyl] -thio] acetic acid-1,1-dimethylethyl ester
    [140] To a mixture of 2-acetamino-5-thiocyanatothiazole (5.97 g, 30 mmol) in methanol (360 mL) was added dithiothritol (9.26 g, 60 mmol) at room temperature under argon. The mixture was stirred at rt for 2 h and then concentrated to give a reduced solid product. This solid product was dissolved in DMF (30 mL) and tert-butyl bromoacetate (5.85 g, 30 mmol) and potassium carbonate (5.0 g, 36 mmol) were added to the resulting solution. The mixture was stirred at rt for 2 h and water (200 mL) was added. The precipitate was recovered, washed with water and dried. The solid was dissolved in methylene chloride (100 mL) and methanol (10 mL) and filtered through a pad of silica gel. The filtrate solution was concentrated to afford the desired product (7.5 g, 87%) having a melting point of 162-163 ° C.
    [141] 1 H NMR (CDCl 3 ) δ 12.2 (s, 1H), 7.48 (s, 1H), 3.37 (s, 2H), 2.32 (s, 3H), 1.45 (s, 9H); MS m / e 289 (M + H) + , 287 (MH) − .
    [142] HPLC (Column: YMC S3 ODS 4.6x150 mm; Flow: 2.5 mL / min; Solvent System: 0-100% in 8 min. B. Solvent A: 10% Methanol-90% Water-0.2% H 3 PO 4 ; Solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 220 nm): retention time 6.44 minutes.
    [143] G. Preparation of [[2- (acetylamino) -5-thiazolyl] thio] acetic acid
    [144] A solution of [[2- (acetylamino) -5-thiazolyl] thio] acetic acid 1,1-dimethylethyl ester (4.32 g, 15 mmol) in methylene chloride (30 mL) and trifluoroacetic acid (20 mL) overnight at room temperature Stirred and concentrated in vacuo. Ethyl ether (50 mL) was added to the residue. The precipitated solid was recovered, washed with ethyl ether and dried to give the desired product (3.38 g, 97%) having a melting point of 210 ° C. as a solid.
    [145] 1 H NMR (CD 3 OD) δ 7.48 (s, 1H), 3.47 (s, 2H), 2.20 (s, 3H) ppm; MS m / e 231 (MH) - ; HPLC (column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL / min; solvent system: 0-100% at 8 min B. solvent A: 10% methanol-90% water-0.2% H 3 PO 4 ; solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 4.32 min.
    [146] H. Preparation of [[2- (acetylamino) -5-thizolyl] thio] -N- (2-oxobutyl) acetamide
    [147] [[2- (acetylamino) -5-thizolyl] thio] acetic acid (9.0 g, 38.8 mmol), HOBT (5.94 g, 38.3 mmol) and ethyldimethylaminopropylcarbodiimide hydrochloride salt in DMF (50 mL) 11.16 g, 58.2 mmol) were stirred at 0 ° C. for 0.5 h. To this mixture was added 1-amino-2-butanone hydrochloride (5.27 g, 42.7 mmol) followed by triethylamine (15 mL, 107.5 mmol). The mixture was stirred at 0 ° C. for 0.5 h and at rt for 1 h. Water (200 mL) was added and the product extracted with methylene chloride (5 × 100 mL) containing 10% methanol. Methylene chloride extract was dried under Na 2 S0 4 and concentrated. The residue was triturated with water and the precipitated solid product was recovered by filtration. This was dried to give the desired product (10.5 g, 90%) having a melting point of 195-196 ° C.
    [148] 1 H NMR (CDCl 3 ) δ 7.53 (s, 1H), 4.14 (s, 2H), 3.46 (s, 2H), 2.50 (q, J = 7.6Hz, 2H), 2.25 (s, 3H), 1.12 ( t, J = 7.6 Hz, 3H); MS m / e 302 (M + H) + .
    [149] HPLC (column: zorbox rapid resolution C-18; flow rate: 2.5 mL / min; solvent system: 0-100% at 8 min. B. solvent A: 10% methanol-90% water-0.2% H 3 PO 4 ; solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 4.36 min.
    [150] I. Preparation of N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [151] Concentrated sulfonic acid (10 mL) in a solution of [[2- (acetylamino) -5-thiazolyl] thio] -N- (2-oxobutyl) acetamide (10.5 g, 34.8 mmol) in acetic anhydride (100 mL) ) Was added. The mixture was stirred at 55-60 ° C. for 2 hours and concentrated in vacuo after addition of sodium acetate (15 g, 0.18 mmol). To the residue was added cold water (100 mL). The precipitated solid was recovered, washed with water and dried. This was purified by flash column chromatography (SiO 2 ; methylene chloride: methanol / 100: 5) to give N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio having a melting point of 147-148 ° C. ] -2-thiazolyl] acetamide (4.2 g, 43%) was obtained as a solid.
    [152] 1 H NMR (CDCl 3 ) δ 12.47 (s, 1H), 7.29 (s, 1H), 6.61 (s, 1H), 3.91 (s, 2H), 2.64 (q, J = 7.6Hz, 2H), 2.25 ( s, 3H), 1.21 (t, J = 7.6 Hz, 3H) ppm; MS m / e 284 (M + H) + .
    [153] HPLC (column: zorbox rapid resolution C-18; flow rate: 2.5 mL / min; solvent system: 0-100% at 8 min. B. solvent A: 10% methanol-90% water-0.2% H 3 PO 4 ; solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 6.50 minutes.
    [154] Example 2
    [155] N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzamide
    [156]
    [157] A. Preparation of 2-amino-5-[[(5-ethyl-2-oxazolyl) methyl] thio] -thiazole
    [158] A solution of N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide (1.3 g, 4.6 mmol) in 1N hydrochloric acid (15 mL) at 80-90 ° C. Stir for 3 hours. It was cooled to room temperature and the pH of the solution was adjusted to 7 with sodium carbonate. The product was extracted with methylene chloride (3x10 mL). The combined extracts were dried under Na 2 S0 4 and concentrated. The residue was triturated with ethyl ether and the precipitated solid was recovered to give 2-amino-5-[[(5-ethyl-2-oxazolyl) methyl] thio] -thiazole (610 mg) having a melting point of 119-120 ° C. , 55%) was obtained as a solid.
    [159] 1 H NMR (CDCl 3 ) δ 6.93 (s, 1H), 6.61 (s, 1H), 5.41 (s, 2H), 3.82 (s, 3H), 2.62 (q, J = 7.6Hz, 2H), 1.18 ( t, J = 7.6 Hz, 3H); MS m / e 242 (M + H) + ;
    [160] HPLC (column: zorbox rapid resolution C-18; flow rate: 2.5 mL / min; solvent system: 0-100% at 8 min. B. solvent A: 10% methanol-90% water-0.2% H 3 PO 4 ; solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 3.96 min.
    [161] B. Preparation of N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzamide
    [162] 2-amino-5-[[(5-ethyl-2-oxazolyl) -methyl] thio] -thiazole (48.2 mg, 0.2 mmol) in methylene chloride (0.5 mL), benzoyl chloride (24.4 mg, 0.21 mmol) And a mixture of triethylamine (35 mg, 0.35 mmol) was stirred for 10 minutes at room temperature. The organic solution was washed with water and concentrated. The residue was purified by flash column (SiO 2 ; hexane: ethyl acetate / 2: 1) to give N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio] having a melting point of 122-123 ° C. -2-thiazolyl] benzamide (41 mg, 59%) was obtained as a solid.
    [163] 1 H NMR (CDCl 3 ) δ 12.65 (s, 1H), 7.96 (m, 2H), 7.61 (m, 1H), 7.49 (m, 2H), 6.88 (s, 1H), 6.56 (s, 1H), 3.93 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); MS m / e 346 (M + H) + ;
    [164] HPLC (column: zorbox rapid resolution C-18; flow rate: 2.5 mL / min; solvent system: 0-100% at 8 min. B. solvent A: 10% methanol-90% water-0.2% H 3 PO 4 ; solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 7.94 min.
    [165] Example 3
    [166] N- [5-[[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzsulfonamide
    [167]
    [168] 2-amino-5-[[(5-ethyl-2-oxazolyl) methyl] thio] -thiazole (24.1 mg, 0.1 mmol), benzenesulfonyl chloride (19.4 mg, 0.11 mmol in methylene chloride (0.3 mL) ) And triethylamine (22 mg, 0.21 mmol) were stirred at rt for 10 h. The resulting reaction mixture was prepared for preparative HPLC (Column: YMC Pack ODSA S3 20 × 100 mm; Method: 0% B to 100% B gradient and flow rate 20 mL / min in 20 min; UV: 254 nm; Solvent A: 10% Methanol-90% Water- 0.1% TFA; solvent B: 90% methanol-10% water-0.1% TFA) and dried via freeze drying followed by N- [5-[[(5-ethyl-2-oxazolyl) methyl] Thio] -2-thiazolyl] benzsulfonamide (2.5 mg) was obtained as a solid.
    [169] 1 H NMR (CDCl 3 ) δ 7.88 (d, J = 8.0 Hz, 1H), (s, 2H), 7.49 (m, 3H), 6.89 (s, 1H), 6.64 (s, 1H), 4.01 (s , 2H), 2.68 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H); MS m / e 382 (M + H) + .
    [170] HPLC (column: zorbox rapid resolution C-18; flow rate: 2.5 mL / min; solvent system: 0-100% at 8 min. B. solvent A: 10% methanol-90% water-0.2% H 3 PO 4 ; solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 6.84 minutes.
    [171] Example 4
    [172] N- [5-[[(4,5-dimethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [173]
    [174] A. Preparation of 2- (bromomethyl) -4,5-dimethyloxazole
    [175] Of 2,4,5-trimethyloxazole (0.50 mL, 4.3 mmol), N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g, 0.86 mmol) in carbon tetrachloride (4 mL) The mixture was heated at 76 ° C. for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the solids were removed by filtration. The filtrate solution was washed with saturated aqueous NaHCO 3 (20 mL) and concentrated. The residue was purified by flash column chromatography (SiO 2 ; hexanes: ethyl acetate / 4: 1) to give 2- (bromomethyl) -4,5-dimethyloxazole (64 mg) as a yellow oil.
    [176] 1 H NMR (CDCl 3 ) δ 4.4 (s, 2H), 2.25 (s, 3H), 2.05 (s, 3H).
    [177] B. Preparation of N- [5-[[(4,5-dimethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [178] N- [5- (acetylthio) -2-thiazolyl] acetamide (0.050 g, 0.23 mmol) was dissolved in dry THF (10 mL) and potassium tert-butoxide (1.0 M solution in THF, 0.25 mL, 0.25 mmol) was added. The reaction mixture was stirred for 15 minutes at room temperature and 2- (bromomethyl) -4,5-dimethyloxazole (0.064 g, 0.34 mmol) was added to this mixture. The reaction mixture was stirred at rt for 3 h and saturated aqueous NaHCO 3 solution (20 mL) was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3x20 mL). The concentrated organic layer was concentrated and the residue was purified by flash column chromatography (SiO 2 ; methanol: dichloromethane / 1: 20) to give N- [5-[[(4,5-dimethyl-2-oxazolyl) as a yellow oil. ) Methyl] thio] -2-thiazolyl] acetamide (15 mg, 23%) was obtained.
    [179] 1 H NMR (CDCl 3 ) δ 11.78 (s, 1H), 7.38 (s, 1H), 3.90 (s, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.05 (s, 3H); MS m / e 284 (M + H) + .
    [180] HPLC (Column: Zorbox Rapid Resolution C-18; Flow Rate: 2.5 mL / min; Solvent System: 0-100% at 8 min. B. Solvent A: 10% CH 3 OH-90% H 2 O-0.2% H 3 PO 4 ; Solvent B: 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 254 nm): Retention time 5.87 minutes.
    [181] Example 5
    [182] N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [183]
    [184] A. Preparation of Diazomethane
    [185] To a mixture of 15 mL of 40% aqueous KOH solution and 50 mL of diethyl ether was added 5 g (68 mmol) of N-methyl-N'-nitro-N-nitrosoguanidine with partial stirring at 0 ° C. The resulting mixture was stirred at 0 ° C. for 0.5 h. The organic phase was separated supernatant into a dry flask and the solid KOH pellets were dried to give 50 mL of diazomethane solution (ca 0.5M, by acetic acid titration).
    [186] B. Preparation of 1-diazo-3,3-dimethyl-2-butanone
    [187] To diazomethane solution at 0 ° C. 1.23 mL (1.21 g, 10 mmol, Aldrich) trimethylacetyl chloride in 1 mL diethyl ether was added dropwise with stirring. The resulting mixture was kept at 0 ° C. for 16 hours. The solution was sparged with argon to remove excess diazomethane and diethyl ether was removed under reduced pressure. As a result, 1.33 g (10 mmol, 100%) of crude 1-diazo-3,3-dimethyl-2-butanone was obtained as a yellow liquid.
    [188] C. Preparation of 2-Chloromethyl-5-t-butyloxazole
    [189] A solution of 1.33 g (10 mmol) 1-diazo-3,3-dimethyl-2-butanone in 5 mL chloroacetonitrile in a solution of 2 mL (2.3 g, 16 mmol) boron trifluoride etherate in 20 mL chloroacetonitrile at 0 ° C. Was added. The resulting solution was stirred at 0 ° C. for 0.5 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution to neutralize the acid and the product was extracted three times with dichloromethane. The combined extracts were dried (sodium sulfate), concentrated and purified by flash column chromatography (Merck silica, 25x200 mm, dichloromethane) to give 1.1 g 2- (chloromethyl) -5-t- as a yellow liquid. Butyloxazole (6.4 mmol, 64% total from hydrochloric acid) was obtained.
    [190] 1 H NMRδ (CDCl 3 ): 1.30 (s, 9H), 4.58 (s, 2H), 6.68 (s, 1H); MS 174 (M + H) + ; TLC: R f (silica gel, dichloromethane) = 0.33; HPLC: t R (YMC S-3 ODS 4.6x50 mm rapid resolution; 2.5 mL / min, 0-100% B gradient at 8 min, solvent A: 10% CH 3 OH-90% H 2 O-0.2% H 3 PO 4, solvent B: 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 254 nm) = 6.5 min.
    [191] D. Preparation of N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [192] In a 50 mg (0.23 mmol, used in a chemistry lab) N- [5- (acetylthio) -2-thiazolyl] acetamide in 50 mL (10 M THF at room temperature) was added 0.25 mL of potassium tert-butoxide solution (1 M solution, 0.25 mmol). Added under argon. The resulting suspension was stirred at room temperature for 15 minutes and then a solution of 59 mg 2- (chloromethyl) -5-t-butyloxazole (0.34 mmol) in 1 mL THF was added. The resulting mixture was stirred at rt for 16 h, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 25 × 200 mm, 1: 1 EtOAc / hexanes, then 100% EtOAc) to give 44 mg (0.14) as a white solid. mmol, 61%) N- [5-[[5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide.
    [193] 1 H NMRδ (CDCl 3 ) 1.27 (s, 9H), 2.27 (s, 3H), 3.95 (s, 2H), 6.59 (s, 1H), 7.31 (s, 1H), 11.03 (wide s, 1H); MS 312 (M + H) + ;
    [194] TLC: R f (silica gel, ethyl acetate) = 0.53, UV;
    [195] HPLC: retention time (YMC S-3 ODS 4.6x50 mm rapid resolution; 2.5 mL / min, 0-100% B gradient over 8 min, solvent A: 10% CH 3 OH-90% H 2 O-0.2% H 3 PO 4 ; Solvent B: 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 254 nm) = 6.8 min.
    [196] Example 6
    [197] N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamide
    [198]
    [199] A. Preparation of N-[(5-thiocyanato) -2-thiazolyl] trifluoroacetamide (18)
    [200] Trifluoroaceti in a mixture of 5-thiocyano-2-aminothiazole (30 mmol), 2,6-lutidine (35 mmol), and dichloromethane (50 mL) in tetrahydrofuran (25 ml) at -78 ° C. Canhydride (33 mmol) was added slowly under argon. After addition the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with dichloromethane (100 mL) and the organic solution was washed with 5% aqueous citric acid followed by brine. Dried under magnesium sulfate and passed through a pad of silica gel. The product containing the eluate was concentrated to give 5.3 g pale brown solid.
    [201] 1 H NMR (CHCl 3 ) δ 12.4 (br, 1H), 7.83 (s, 1H).
    [202] B. Preparation of 4-hydroxymethyl-3-methoxyphenyloxy Merrifield Resin (16)
    [203] 4-hydroxy-3-methoxybenzyldihydride (44.5 g) in dimethylformamide (100 mL) in a suspension of sodium hydride (11.7 g, 60% in mineral oil, 293 mmol) in dimethylformamide (30 mL) at 0 ° C. , 292.5 mmol) was added slowly under argon. To the resulting mixture was added a catalyst amount of Merifield resin (1% DVB, Advanced Chemtech, Loading 1.24 mmol / g, 50 g, 62 mmol) and tetra-n-butylammonium iodide. And it was heated at 65 ° C. for one day. The resin was filtered off, washed with water (2x), 50% dimethylformamide in water (3x), dimethylformamide (2x) and methanol (5x) and dried in vacuo. The dried resin (15 g) was treated overnight with sodium borohydride (3.4 g, 90 mmol) and ethanol (50 mL) in tetrahydrofuran (50 mL). The resin was filtered off, washed with 50% dimethylformamide (3x), dimethylformamide (2x), methanol (2x) and dichloromethane (5x) in water and dried in vacuo.
    [204] C. Preparation of 4-Chloromethyl-3-methoxyphenyloxy Merrifield Resin (17)
    [205] Triphosphene (9.2 g, 31 mmol) was added slowly and partially over 30 minutes to a solution of triphenylphosphine (17 g, 65 mmol) in dichloromethane (200 mL) at 0 ° C. After addition the reaction mixture was stirred at 0 ° C. for 10 minutes. The solvent was removed in vacuo and the residue was redissolved in dichloromethane (200 mL). 4-hydroxymethyl-3-methoxyphenyloxy Merrifield resin (12 g) was added to this mixture. The resulting mixture was stirred for 4 hours. The resin was washed with dry dichloromethane (6 ×) and dried in vacuo.
    [206] D. Preparation of 4- [N-[(5-thiocyanato) -2-thiazolyltrifluoroacetamido] methyl] -3-methoxyphenyloxy merifield resin (19)
    [207] 4-Chloromethyl-3-methoxyphenyloxy Merifield Resin (15g), N-[(5-thiocyanato) -2-thiazolyl] trifluoroacetamide (14g, 55.3) in dimethylformamide (50mL) mmol) and a mixture of diisopropylethylamine (7.8 mL, 45 mmol) and dichloromethane (100 mL) were stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x) and dried in vacuo.
    [208] E. Preparation of 4-[[N-[(5-mercapto) -2-thiazolyl] trifluoroacetamido] methyl] -3-methoxyphenyloxy merifield resin (20)
    [209] 4- [N-[(5-thiocyanato) -2-thiazolyltrifluoroacetamido] methyl] -3-methoxyphenyloxy merifield resin in tetrahydrofuran (100 mL) (19, 18.5 g) And a mixture of dithiothreitol (12 g, 78 mmol) and methanol (100 mL) were stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x), dried in vacuo and stored at -20 ° C under argon.
    [210] F. 4-N- [5-[[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trifluoroacetamido] methyl-3-methoxyphenyloxymary Preparation of Field Resin 21
    [211] Argon stream to 4-[[N-[(5-mercapto) -2-thiazolyl] trifluoroacetamido] methyl] -3-methoxyphenyloxy merifield resin in dimethylformamide (3 mL) (20 , 500 mg), foamed for 5 minutes by a mixture of halides (2.0 mmol) and 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU, 1.5 mmol) and the mixture was bubbled. Heated at 80 ° C. for 2 hours. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x) and dried in vacuo.
    [212] G. Preparation of 4-N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] methyl-3-methoxyphenyloxy merifield resin (22)
    [213] 4-N- [5-[[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trifluoroacetamido] methyl-3- in tetrahydrofuran (2 mL) A mixture of methoxyphenyloxy merrifield resin (21, 500 mg), sodium borohydride (4 mmol), and ethanol (2 mL) was stirred overnight. The resin was washed with 50% dimethylformamide (2x), dimethylformamide (2x), methanol (2x) and dichloromethane (4x) in water and dried in vacuo.
    [214] H. 4-N- [5-[[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamido] methyl-3-methoxyphenyloxy merifield resin Manufacture of 23
    [215] 4-N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl in dichloromethane (2 mL) in a polypropylene tube consisting of a polyethylene glass stock and a Lewis cock stopper] A mixture of methyl-3-methoxyphenyloxy merrifield resin (22, 100 mg), diisopropylethylamine (1.2 mmol) and trimethylacetyl chloride (1 mmol) was stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x) and used in the next step without drying.
    [216] I. Preparation of N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamide
    [217] 4-N- [5-[[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamido] methyl-3-methoxyphenyloxy merifield resin (23 ) Was treated for 4 hours with 60% trifluoroacetic acid in dichloromethane (2 mL) in a polypropylene tube consisting of polyethylene glass stock and a Lewiscock stopper. The solution was separated supernatant into tubes and the resin washed with dichloromethane. The mixed organic solution was concentrated in Speed Vac. The residue was purified by prep-HPLC to give 11.3 mg of the desired product.
    [218] MS m / e 354 (M + H) + .
    [219] Example 7
    [220] N- [5-[[(4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [221]
    [222] A. Preparation of 2- (2-chloroacetamido) -1-butanol
    [223] Chloroacetyl chloride (4.6 mL, 58 mmol) was added dropwise to a mixture of 2-amino-1-butanol (5.0 mL, 53 mmol) and triethylamine (15.0 mL, 111 mmol) in dichloromethane (20 mL) at -70 ° C. The reaction mixture was stirred at −70 ° C. for 15 minutes and then warmed to room temperature. It was diluted with EtOAc (50 mL) and water (50 mL) was added to cool the reaction. The organic layer was separated and the aqueous layer extracted with EtOAc (3 × 30 mL). The mixed organic layer was concentrated to give 2- (2-chloroacetamido) -1-butanol (8.6 g, 98%) as a brown solid.
    [224] 1 H NMR (CDCl 3 ) δ 6.75 (bs, 1H), 4.10 (s, 2H), 4.08 (dd, 1H), 3.90 (m, 1H), 3.68 (m, 2H), 2.98 (bs, 1H), 1.60 (m, 2 H), 0.97 (t, 3 H).
    [225] B. Preparation of 2- (2-chloroacetamido) -1-butyraldehyde
    [226] To a solution of oxalyl chloride (14.5 mL, 29.0 mmol) in dichloromethane (30 mL) at −78 ° C. was added dropwise DMSO (2.75 mL, 38.8 mmol) over 5 minutes. After stirring at −78 ° C. for 10 minutes, a solution of 2- (2-chloroacetamido) -1-butanol (4.0 g, 24 mmol) in 20 mL dichloromethane was added dropwise over 15 minutes. The reaction mixture was stirred at -78 ° C for 40 minutes. Triethyl amine (9.4 mL, 68 mmol) was added dropwise over 5 minutes, and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solid was removed by filtration and washed with EtOAc. The organic phase was washed with 1N HCl (2 × 100 mL) and saturated aqueous NaHCO 3 (1 × 10 mL) and concentrated to give 2- (2-chloroacetamido) -1-butyraldehyde (3.7 g, 95%) as a brown oil. .
    [227] 1 H NMR (CDCl 3 ) δ 9.60 (s, 1H), 4.52 (q, 1H), 4.12 (s, 2H), 2.05 (m, 1H), 1.80 (m, 1H), 0.97 (t, 3H).
    [228] C. Preparation of 2-Chloromethyl-4-ethyloxazole
    [229] POCl 3 (6.3 mL, 68 mmol) was added to a solution of 2- (2-chloroacetamido) -1-butyraldehyde (3.7 g, 23 mmol) in toluene (10 mL). The reaction mixture was heated at 90 ° C. for 1 h under nitrogen. After cooling the reaction mixture to room temperature, it was poured into ice water (10 mL) and the pH of the solution was adjusted to 7 with 5N NaOH. The toluene layer was separated and the aqueous layer was washed with dichloromethane (3x20 mL). The mixed organic solution was concentrated and distilled to give 2-chloromethyl-4-ethyloxazole (1.1 g, 31%) as a colorless liquid.
    [230] 1 H NMR (CDCl 3 ) δ 7.30 (s, 1H), 4.22 (s, 2H), 2.50 (q, 2H), 1.22 (t, 3H).
    [231] D. Preparation of N- [5-[[(4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    [232] To a solution of 2-acetylamino-5-thiazolylthiol (0.010 g, 0.050 mmol) in dry THF (5 mL) was added potassium tert-butoxide (1.0 M solution in THF, 0.060 mL, 0.060 mmol). The reaction mixture was stirred at rt for 15 min and thereto was added 2-chloromethyl-4-ethyloxazole (0.015 g, 0.10 mmol). After 3 hours, saturated aqueous NaHCO 3 solution (5 mL) was added to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (3x10 mL) and the mixed organic layers were concentrated. The residue was purified by flash chromatography (SiO 2 ; methanol: dichloromethane / 1: 20) to give N- [5-[[(4-ethyl-2-oxazolyl) methyl] thio] -2- as a white solid. Thiazolyl] acetamide (5 mg, 36%) was obtained.
    [233] 1 H NMR (CDCl 3 ) δ 11.25 (s, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 3.95 (s, 2H), 2.50 (q, 2H), 2.27 (s, 3H), 1.19 (t, 3 H); MS m / e 284 (M + H) + ; HPLC (Column: Zorbox Rapid Resolution C-18; Flow Rate: 2.5 mL / min; Solvent System: 0-100% at 8 min. B. Solvent A: 10% CH 3 OH-90% H 2 O-0.2% H 3 PO 4 : solvent B: 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 254 nm): retention time 6.14 minutes.
    [234] Additional compounds were prepared and described below in Table 1 using the methods described herein or modified methods known to those of ordinary skill in the art.
    [235] TABLE 1
    [236]
    [237]
    [238]
    [239]
    [240]
    [241]
    [242]
    [243]
    [244]
    [245]
    [246]
    [247]
    [248]
    [249]
    [250]
    [251]
    [252]
    [253]
    [254]
    [255]
    [256]
    [257]
    [258]
    [259]
    [260]
    [261]
    [262]
    [263]
    [264]
    [265]
    [266]
    [267]
    [268]
    [269]
    [270]
    [271]
    [272]
    [273]
    [274]
    [275]
    [276]
    [277]
    [278]
    [279]
    [280]
    [281]
    [282]
    [283]
    [284]
    [285]
    [286]
    [287]
    [288]
    [289]
    [290]
    [291]
    [292]
    [293]
    [294]
    [295]
    [296]
    [297]
    [298]
    [299]
    [300]
    [301]
    [302]
    [303]
    [304]
    [305]
    [306]
    [307]
    [308]
    [309]
    [310] Example 636
    [311] N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] -N'-cyano-N "-(2,6-difluorophenyl) guanidine Manufacture
    [312]
    [313] A solution of 100 mg of N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-aminothiazole and 68 mg of 2,6-difluorophenyl isothiocyanate was prepared under argon. Heat at 16 ° C. The solution was distilled for drying and the residue was purified by flash chromatography to yield 91 mg of thiourea intermediate.
    [314] 30 mg N- [5-[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] -N "-(2,6-difluorophenyl) in 0.5 mL methylene chloride To a solution of thiourea, 52 mg of ethyl-3 (3-dimethylamino) propyl carbodiimide hydrochloride and 48 μl of diisopropylethylamine was added 29 mg of cyanamide solution in 0.1 mL tetrahydrofuran for 1 hour. After stirring, the solvent was removed and the crude was purified by HPLC to yield 8 mg of Example 636 compound.
    [315] MS: (M + H) + 449 +
    [316] 1 H NMR (400 MHz, CDCl 3 ): d 1.27 (9H, s), 4.19 (2H, s), 6.69 (1H, s), 7.03 (2H, m), 7.35 (1H, m), 8.74 (1H, s).
    [317] Example 637
    [318] Preparation of N- [5-[[(5-isopropyl-2-oxazolyl) fluoro] methyl] thio] -2-thiazolyl acetamide
    [319]
    [320] To a stirred mixture of 2-acetamido-5-thiazole thiol acetate (141 mg) in 3 mL dry THF was added 1N t-BuOK (0.72 mL) in THF under argon. The mixture was stirred for 25 minutes at room temperature and a solution of 5-isopropyl- (2- (chlorofluoromethyl) oxazole (116 mg) in 2 mL dry THF was added The reaction mixture was stirred at 60 ° C. for 18 h and 150 mL Diluted with EtOAc and washed with saturated NH 4 Cl solution (2 × 25 mL), saturated NaHCO 3 solution (1 × 25 mL) and brine (1 × 25 mL) The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. 637 compound was obtained.
    [321] MS: (M + H) + 316
    [322] HPLC retention time 3.52 min (Column: YMC ODS S05 4.6x50 mm Column, 0-100% B gradient over 4 min, Solvent A: 10% CH 3 OH-90% H 2 O-0.2% H 3 PO 4 ; Solvent B : 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 220 nm).
    [323] Compositions for inhibiting protein kinases comprising the compound of formula 1 of the present invention are useful for the treatment and prevention of proliferative diseases such as cancer, inflammation and arthritis. The compositions of the present invention are also useful for the treatment of neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
    权利要求:
    Claims (29)
    [1" claim-type="Currently amended] An anticancer composition comprising a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof combined with a pharmaceutically acceptable carrier and an anticancer agent in a fixed dose:
    Formula (1)

    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is aryl or heteroaryl
    R 4 is alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocyclo Alkyl; or
    SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocycloalkyl, SO 2- Alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCN) NH-alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) NH-heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2 ) NH-alkyl, C (NNO 2 ) NH-cycloalkyl, C (NNO 2 ) NH-aryl, C (NNO 2 ) NH-alkyl-cycloalkyl, C (NNO 2 ) NH-alkyl-aryl , C (NNO 2 ) NH-heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH-heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH-heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHCO-alkyl-aryl, C (NH) NHCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6 ) NH-alkyl, C (NOR 6 ) NH-cycloalkyl, C (NOR 6 ) NH-aryl, C (NOR 6 ) NH-alkyl-cycloalkyl, C (NOR 6 ) NH-alkyl-aryl , C (NOR 6 ) NH-heteroaryl, C (NOR 6 ) NH-alkyl-heteroaryl, C (NOR 6 ) NH-heterocycloalkyl, C (NOR 6 ) NH-alkyl-heterocycloalkyl;
    R 5 is hydrogen or alkyl;
    R 6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    m is an integer from 0 to 2;
    n is an integer of 1 to 3;
    "Alkyl" in the above means alkyl containing 1 to 12 carbon atoms;
    "Aryl" means a monocyclic or bicyclic aromatic ring comprising 1 to 5 rings having 6 or more atoms;
    "Heteroaryl" means a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms comprising one or more heteroatoms O, S, or N or a bicyclic aromatic group having 8 to 10 atoms;
    "Cycloalkyl" is cycloalkyl containing 3 to 15 carbon atoms;
    "Heterocycloalkyl" means a non-aromatic cycloalkyl group in which one carbon atom present in the ring can be replaced by a heteroatom selected from O, S, or N and additionally up to three carbon atoms.
    [2" claim-type="Currently amended] An anticancer composition comprising a pharmacologically acceptable carrier and a compound represented by the formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof, which is administered in turn with an anticancer treatment or an anticancer agent.
    [3" claim-type="Currently amended] The anticancer composition according to claim 2, which is administered prior to the chemotherapy or anticancer agent.
    [4" claim-type="Currently amended] The anticancer composition according to claim 2, which is administered after the anticancer treatment or the anticancer agent.
    [5" claim-type="Currently amended] A composition for inhibiting protein kinase containing an effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient in an amount effective to inhibit protein kinase.
    [6" claim-type="Currently amended] A composition for inhibiting cyclin-dependent kinase containing an effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient in an amount effective to inhibit cyclin-dependent kinase.
    [7" claim-type="Currently amended] A composition for inhibiting cdc2 (cdk1) containing an effective amount of a compound represented by the formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient in an amount effective to inhibit cdc2.
    [8" claim-type="Currently amended] A composition for inhibiting cdk2 containing an effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an effective ingredient in an amount effective to inhibit cdk2.
    [9" claim-type="Currently amended] A composition for inhibiting cdk3, comprising, as an active ingredient, a compound represented by the formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof in an amount effective to inhibit cdk3.
    [10" claim-type="Currently amended] A composition for inhibiting cdk4 containing an effective amount of a compound represented by the formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an effective ingredient in an amount effective to inhibit cdk4.
    [11" claim-type="Currently amended] A composition for inhibiting cdk5 containing an effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an effective ingredient in an amount effective to inhibit cdk5.
    [12" claim-type="Currently amended] A composition for inhibiting cdk6 containing an effective amount of a compound represented by the formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an effective ingredient in an amount effective to inhibit cdk6.
    [13" claim-type="Currently amended] A composition for inhibiting cdk7, which contains, as an active ingredient, a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof in an amount effective to inhibit cdk7.
    [14" claim-type="Currently amended] A composition for inhibiting cdk8 containing an effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an effective ingredient in an amount effective to inhibit cdk8.
    [15" claim-type="Currently amended] A composition for treating proliferative disease, comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [16" claim-type="Currently amended] A composition for treating cancer, comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [17" claim-type="Currently amended] A composition for treating inflammation, inflammatory bowel disease or transplant rejection, comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [18" claim-type="Currently amended] A composition for treating arthritis, comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [19" claim-type="Currently amended] A composition for the treatment of infection by HIV or the treatment and inhibition of development of AIDS, comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [20" claim-type="Currently amended] A composition for the treatment of a viral infection comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [21" claim-type="Currently amended] A composition for treating fungal infections comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [22" claim-type="Currently amended] A composition for inhibiting cancer or tumor recurrence, comprising a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [23" claim-type="Currently amended] A composition for treating neurodegenerative disease containing a therapeutically effective amount of a compound represented by formula (1) as defined in claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
    [24" claim-type="Currently amended] The composition of claim 1 used in the treatment of proliferative diseases.
    [25" claim-type="Currently amended] The composition of claim 1 used for the treatment of cancer.
    [26" claim-type="Currently amended] The composition of claim 1, which is used to inhibit the occurrence of cancer or tumor recurrence.
    [27" claim-type="Currently amended] The composition of claim 2 used for the treatment of proliferative diseases.
    [28" claim-type="Currently amended] The composition of claim 2 used for the treatment of cancer.
    [29" claim-type="Currently amended] The composition of claim 2 used to inhibit the occurrence of cancer or tumor recurrence.
    类似技术:
    公开号 | 公开日 | 专利标题
    JP6105008B2|2017-03-29|Substituted pyrazolo [1,5-a] pyrimidine compounds as TRK kinase inhibitors
    US20190330202A1|2019-10-31|Novel compounds
    CN105452226B|2017-09-12|Tetrahydrochysene and dihydro-isoquinoline PRMT5 inhibitor and application thereof
    JP6321045B2|2018-05-09|Heterocyclic amides as kinase inhibitors
    KR102148678B1|2020-08-27|Dihydropyrimidine compounds and their application in pharmaceuticals
    AU2015244698B2|2019-05-16|Cyclopropanamine compound and use thereof
    JP6524081B2|2019-06-05|Dihydropyrimidine compounds and their application in medicine
    US9555035B2|2017-01-31|Heterocyclyl compounds as MEK inhibitors
    US8569307B2|2013-10-29|Indole compounds as an inhibitor of cellular necrosis
    KR20180095625A|2018-08-27|Novel compounds
    AU2007310064B2|2013-03-28|Indole compound
    AU2004263353B2|2009-11-26|Novel gamma-secretase inhibitors
    EP1600442B1|2018-01-17|Heteroarylcarbamoylbenzene derivative
    AU766193B2|2003-10-09|2-amino-thiazole derivatives, process for their preparation, and their use as antitumor agents
    EP2078003B1|2017-03-08|Anilinopiperazine derivatives and methods of use thereof
    AU747427B2|2002-05-16|Novel angiogenesis inhibitors
    DE60004685T2|2004-07-29|Pyrazolopyrimidine as a medicinal product
    ES2234628T3|2005-07-01|Diaminotiazoles and its use to inhibit protein-kinases.
    ES2629414T3|2017-08-09|Thiazole derivatives
    AU2005251990B2|2008-11-20|Hetroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes
    JP4968860B2|2012-07-04|Anilinopiperazine derivatives and methods using anilinopiperazine derivatives
    JP5210172B2|2013-06-12|Pyridiazinone derivatives for tumor therapy
    US6921763B2|2005-07-26|Pyrazolopyrimidines as therapeutic agents
    AU2005245386B2|2008-11-27|Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer
    ES2275500T3|2007-06-16|Compounds of 5-piridil-1,3-azol, procedure for its production and use of the same.
    同族专利:
    公开号 | 公开日
    AT374771T|2007-10-15|
    CZ20001744A3|2001-05-16|
    KR100454426B1|2004-10-26|
    EP1042307A4|2003-01-29|
    IL135589D0|2001-05-20|
    TW593292B|2004-06-21|
    NO316773B1|2004-05-03|
    US6040321A|2000-03-21|
    AU1295599A|1999-05-31|
    CO4990957A1|2000-12-26|
    PL204642B1|2010-01-29|
    NO20002153D0|2000-04-27|
    CZ297907B6|2007-04-25|
    JP4344084B2|2009-10-14|
    JP2001522842A|2001-11-20|
    CA2309551C|2006-03-28|
    ZA9810332B|2000-05-11|
    RU2211839C2|2003-09-10|
    AR017182A1|2001-08-22|
    CY1107509T1|2013-03-13|
    DK1042307T3|2008-01-28|
    HU0004559A2|2002-04-29|
    EP1042307B1|2007-10-03|
    CA2309551A1|1999-05-20|
    EP1042307A1|2000-10-11|
    DE69838515D1|2007-11-15|
    TR200001344T2|2000-09-21|
    AU730607B2|2001-03-08|
    CN1278806A|2001-01-03|
    NO20002153L|2000-05-11|
    IL135589A|2004-06-20|
    NZ503828A|2003-03-28|
    MY120779A|2005-11-30|
    KR20010031896A|2001-04-16|
    UY25239A1|2000-12-29|
    DE69838515T2|2008-07-03|
    BR9814124A|2000-10-03|
    ES2296347T3|2008-04-16|
    WO1999024416A1|1999-05-20|
    EG24028A|2008-03-26|
    HU0004559A3|2002-05-28|
    ID23983A|2000-06-14|
    CN1160343C|2004-08-04|
    PT1042307E|2007-11-15|
    PE131699A1|2000-03-08|
    PL340540A1|2001-02-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-11-12|Priority to US6519597P
    1997-11-12|Priority to US60/065,195
    1998-11-02|Application filed by 브리스톨-마이어즈 스퀴브 컴페니
    1998-11-02|Priority to PCT/US1998/023197
    2003-05-09|Publication of KR20030036862A
    优先权:
    申请号 | 申请日 | 专利标题
    US6519597P| true| 1997-11-12|1997-11-12|
    US60/065,195|1997-11-12|
    PCT/US1998/023197|WO1999024416A1|1997-11-12|1998-11-02|Aminothiazole inhibitors of cyclin dependent kinases|
    [返回顶部]