RU2007131102A - Pyrazole derivatives intended for the inhibition of cyclin-dependent kinases (CDK'S) and glycogen synthase kinase (GSK'S) - Google Patents

Claims (50)

1. The compound of formula (I):

or its salt, tautomer, N-oxide or MES, where R ¹ selected from the following substituents: (a) 2,6-dichlorophenyl; (b) 2,6-difluorophenyl; (c) a 2,3,6-trisubstituted phenyl group, wherein the substituents of the phenyl group are selected from fluoro, chloro, methyl and methoxy; (d) a group R ⁰ ; (e) a group R ^1a ; (e) a group R ^1b ; (g) a group R ^1c ; (h) a group R ^1d ; and (k) 2,6-difluorophenylamino; R ⁰ represents a carbocyclic or heterocyclic group containing from 3 to 12 members in the ring; or a C _1-8 hydrocarbon group optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano; C _1-4 oxy substituted hydrocarbon group, amino, mono- or di-C _1-4 amino substituted hydrocarbon group, and carbocyclic or heterocyclic groups containing from 3 to 12 members included in the ring, and where 1 or 2 carbon atoms of the hydrocarbon group optionally substituted with an atom or group selected from O, S, NH, SO, SO ₂ ; R ^{1a is} selected from cyclopropylcyanomethyl; furyl; benzoisoxazolyl; methylisoxazolyl; 2-monosubstituted phenyl and 2,6-disubstituted phenyl, where the substituents on the phenyl moiety are selected from methoxy, ethoxy, fluorine, chlorine and difluoromethoxy; with the proviso that R ^1a does not mean 2,6-difluorophenyl or 2,6-dichlorophenyl; R ^{1b is} selected from tetrahydrofuryl; and monosubstituted and disubstituted phenyl, where the substituents on said phenyl moiety are selected from fluorine, chlorine; methoxy; ethoxy and methylsulfonyl; R ^{1c is} selected from the following substituents: benzoisoxazolyl; five-membered heteroaryl ring systems containing one or two heteroatoms selected from O and N, and six-membered heteroaryl ring systems containing one or two heteroatoms - nitrogen atoms included in the ring system, said heteroaryl ring systems in each case are optionally substituted with methyl, fluorine chlorine or trifluoromethyl; and also phenyl substituted with one, two or three substituents selected from bromine, chlorine, fluorine, methyl, trifluoromethyl, ethoxy, methoxy, methoxyethoxy, methoxymethyl, dimethylaminomethyl and difluoromethoxy; with the proviso that R ^1a does not mean 2,6-difluorophenyl; R ^1d represents a group R ^1e —CH (CN) -, where R ^1e represents a carbocyclic or heterocyclic group containing from 3 to 12 members in the ring; R ^2a and R ^2b each represents hydrogen or methyl; and where A. in the case where R ¹ is (a) 2,6-dichlorophenyl, and R ^2a and R ^{2b are} both hydrogen; then R ³ can be selected from: (i) group

where R ⁹ selected from C (O) NR ⁵ R ⁶ ; C (O) -R ¹⁰ and 2-pyrimidinyl, where R ¹⁰ represents a C _1-4 alkyl group optionally substituted with one or more substituents selected from fluoro, chloro, cyano and methoxy; and R ¹¹ , where R ¹¹ represents a C _1-4 alkyl group substituted by one or more substituents selected from fluorine, chlorine and cyano; (ii) group

where R ¹² represents C _2-4 alkyl; (iii) group

where R ^{13 is} selected from methylsulfonyl, 4-morpholino, 4-thiomorpholino, 1-piperidino, 1-methyl-4-piperazino and 1-pyrrolidino; (iv) a substituted 3-pyridyl or 4-pyridyl group of the formula:

wherein said R ¹⁴ group is in the meta or para position with respect to the bond marked with an asterisk, and this group is selected from methyl, methylsulfonyl, 4-morpholino, 4-thiomorpholino, 1-piperidino, 1-methyl-4-piperazino, 1-pyrrolidino, 4-piperidinyloxy, 1-C _1-4 alkoxycarbonyl-piperidin-4-yloxy, 2-hydroxyethoxy and 2-methoxyethoxy; and (v) a group selected from 2-pyrazinyl, 5-pyrimidinyl, cyclohexyl, 1,4-dioxaspiro [4,5] decan-8-yl (ketal 4-cyclohexanone ethylene glycol), 4-methylsulfonylaminocyclohexyl, tetrahydrothiopyran-4-yl, 1 , 1-dioxo-tetrahydrothiopyran-4-yl, tetrahydropyran-4-yl, 4,4-difluorocyclohexyl and 3,5-dimethylisoxazol-4-yl; and B. in the case when R ¹ is (b) 2,6-difluorophenyl, and R ^2a and R ^{2b are} both hydrogen; then R ³ can be selected from: (vi) 1-methylpiperidin-3-yl; 4- (2-dimethylaminoethoxy) cyclohexyl; and an N-substituted 4-piperidinyl group, wherein said N-substituent is selected from cyanomethyl and cyanoethyl; and (vii) group

where R ¹³ is as defined above in the text of this application; and B. in the case where R ¹ represents (c) a 2,3,6-trisubstituted phenyl group, where the substituents of the phenyl group are selected from fluoro, chloro, methyl and methoxy; and R ^2a and R ^{2b are} both hydrogen; then R ³ may be selected from groups (ii), (xi), (xii) and (xiii) as defined above; and (viii) 4-piperidinyl and 1-methyl-4-piperidinyl; (ix) tetrahydropyran-4-yl; and (x) group:

where R ⁴ represents C _1-4 alkyl; G. in the case when R ¹ represents (g) a group R ⁰ , where R ⁰ represents a carbocyclic or heterocyclic group containing from 3 to 12 members in the ring; or a C _1-8 hydrocarbon group optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano; C _1-4 oxy substituted hydrocarbon group, amino, mono- or di-C _1-4 amino substituted hydrocarbon group, and carbocyclic or heterocyclic groups containing from 3 to 12 members included in the ring, and where 1 or 2 carbon atoms of the hydrocarbon group optionally substituted with an atom or group selected from O, S, NH, SO, SO ₂ , then R ³ may be selected from the following: (xi) group:

where R ⁷ represents: an unsubstituted hydrocarbon group other than C _1-4 alkyl; a substituted C _1-4 hydrocarbon group having one or more substituents selected from fluorine, chlorine, hydroxy, methylsulfonyl, cyano, methoxy, NR ⁵ R ⁶ , and 4-7 membered saturated carbocyclic or heterocyclic ring systems containing up to two heteroatoms included in the ring system, which are selected from O, N and S; a group NR ⁵ R ⁶ , where R ⁵ and R ⁶ are selected from hydrogen and C _1-4 alkyl, C _1-2 alkoxy and C _1-2 alkoxy-C _1-4 alkyl, with the proviso that not more than one of R ⁵ and R ⁶ is C _1-2 alkoxy, or NR ⁵ R ⁶ forms a five- or six-membered saturated heterocyclic ring system containing one or two heteroatoms in the ring selected from O, N and S, wherein said heterocyclic ring system optionally substituted with one or more methyl groups; a five- or six-membered heteroaryl group containing one or two ring heteroatoms selected from N, S and O, said group optionally substituted with methyl, methoxy, fluorine, chlorine or an NR ⁵ R ⁶ group; a phenyl group optionally substituted with methyl, methoxy, fluorine, chlorine, cyano or an NR ⁵ R ⁶ group; C _3-6 cycloalkyl; and a five- or six-membered saturated heterocyclic ring system containing one or two heteroatoms in the ring selected from O, N and S, wherein said heterocyclic ring system is optionally substituted with one or more methyl groups; and (xii) group:

where R ^12a represents C _1-4 alkyl substituted with one or more substituents selected from fluorine, chlorine, C _3-6 cycloalkyl, oxa-C _4-6 cycloalkyl, cyano, methoxy and NR ⁵ R ⁶ , provided that at least two carbon atoms are present between the oxygen atom to which R ^{12 is} attached and the group NR ⁵ R ⁶ , if present; and D. in the case where R ¹ represents (e) a group R ^1a , and R ^2a and R ^2b both represent hydrogen, then R ³ may represent (xiii), a group

and E. in the case where R ¹ represents (e) a group R ^1b , and R ^2a and R ^2b both represent hydrogen, then R ³ may represent (xiv), a methyl group; and G. in the case when R ¹ represents (g) a group R ^1c , and R ^2a and R ^2b both represent hydrogen, then R ³ may represent (xv), a group:

and H. in the case where R ¹ represents (h) a group R ^1d , then R ³ represents a group —YR ^3a , where Y is a single bond or alkylene chain, the length of which is 1, 2, or 3 carbon atoms, and R ^{3a is} selected from hydrogen and carbocyclic and heterocyclic groups containing from 3 to 12 members in the ring; K. in the case where R ¹ is (k) 2,6-difluorophenylamino, and R ^2a and R ^{2b are} both hydrogen; then R ³ may be methyl; and L. in the case when R ¹ represents 2,6-dichlorophenyl and either (l) R ^2a represents methyl and R ^2b represents hydrogen, or (m) R ^2a represents hydrogen and R ^2b represents methyl; then R ³ may be a 4-piperidine group; or salts, tautomers, solvates and N-oxides of this compound. 2. The compound according to claim 1, where R ¹ represents 2,6-dichlorophenyl, R ^2a and R ^2b both represent hydrogen, and R ³ represents (i), a group:

where R ⁹ selected from C (O) NR ⁵ R ⁶ ; C (O) -R ¹⁰ where R ¹⁰ represents a C _1-4 alkyl group optionally substituted with one or more substituents selected from fluoro, chloro, cyano and methoxy; and R ¹¹ , where R ¹¹ represents a C _1-4 alkyl group substituted by one or more substituents selected from fluorine, chlorine and cyano. 3. The compound according to claim 2, where R ⁹ represents C (O) NR ⁵ R ⁶ , wherein NR ⁵ R ^{6 is} selected from dimethylamino groups and cyclic amino groups, such as the residue of morpholine, piperidine, piperazine, N-methylpiperazine, pyrrolidine and thiazolidine , a preferred example is a morpholine group. 4. The compound according to claim 2, where R ⁹ represents C (O) -R ¹⁰ and R ¹⁰ selected from methyl, trifluoromethyl and methoxymethyl. 5. The compound of claim 2, wherein R ⁹ is an R ¹¹ group and R ^{11 is} selected from a substituted methyl group and a 2-substituted ethyl group such as cyanomethyl, 2-cyanoethyl and 2-fluoroethyl. 6. The compound according to claim 1, where R ¹ represents 2,6-dichlorophenyl, R ^2a and R ^2b both represent hydrogen and R ³ represents (ii), a group:

where R ¹² represents C _2-4 alkyl, such as ethyl, isopropyl, n-butyl, isobutyl and tert-butyl. 7. The compound according to claim 1, where R ¹ represents 2,6-dichlorophenyl, R ^2a and R ^2b both represent hydrogen, and R ³ represents (iii), a group:

where R ^{13 is} selected from methylsulfonyl, 4-morpholino, 4-thiomorpholino, 1-piperidino, 1-methyl-4-piperazino and 1-pyrrolidino. 8. The compound according to claim 1, where R ¹ represents 2,6-dichlorophenyl, R ^2a and R ^2b both represent hydrogen, and R ³ represents (iv) a substituted 3-pyridyl or 4-pyridyl group of the formula

wherein said R ¹⁴ group is in the meta or para position with respect to the bond marked with an asterisk, and this group is selected from methyl, methylsulfonyl, 4-morpholino, 4-thiomorpholino, 1-piperidino, 1-methyl-4-piperazino, 1-pyrrolidino, 4-piperidinyloxy, 1-C _1-4 alkoxycarbonyl-piperidin-4-yloxy, 2-hydroxyethoxy and 2-methoxyethoxy. 9. The compound according to claim 1, where R ¹ represents 2,6-dichlorophenyl, R ^2a and R ^2b both represent hydrogen and R ³ represents (v), a group selected from 2-pyrazinyl, 5-pyrimidinyl, cyclohexyl, 1,4-dioxo-spiro [4,5] decan-8-yl (ketal of 4-cyclohexanoneethylene glycol), 4-methyl-sulfonylaminocyclohexyl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, tetrahydropyran-4-yl, 4,4-difluorocyclohexyl and 3,5-dimethylisoxazol-4-yl. 10. The compound according to claim 1, where R ¹ represents (b), 2,6-difluorophenyl, R ^2a and R ^{2b are} both hydrogen, and R ^{3 is} selected from the following: (vi) 1-methylpiperidin-3-yl; 4- (2-dimethylaminoethoxy) cyclohexyl; and an N-substituted 4-piperidinyl group, wherein said N-substituent is selected from cyanomethyl and cyanoethyl; and (vii) group:

where R ¹³ is as defined in claim 1. 11. The compound of claim 10, wherein R ¹ is 2,6-difluorophenyl, R ^2a and R ^{2b are} both hydrogen, and R ^{3 is} selected from 1-methylpiperidin-3-yl; 4- (2-dimethylaminoethoxy) cyclohexyl; and an N-substituted 4-piperidinyl group, wherein said N-substituent is selected from cyanomethyl and cyanoethyl. 12. The compound of claim 10, where R ¹ represents 2,6-difluorophenyl, R ^2a and R ^2b both represent hydrogen, and R ³ represents (vii), a group:

where R ^{13 is} selected from 4-morpholino, 4-thiomorpholino, 1-piperidino, 1-methyl-4-piperazino and 1-pyrrolidino. 13. The compound according to claim 1, where R ¹ represents a 2,3,6-trisubstituted phenyl group, where the substituents of the phenyl group are selected from fluorine, chlorine, methyl and methoxy; and R ^2a and R ^{2b are} both hydrogen; and R ^{3 is} selected from (viii), 4-piperidinyl and 1-methyl-4-piperidinyl, (ix) tetrahydropyran-4-yl and groups (ii), (x), (xi), (xii) and (xiii) as defined in claim 1. 14. The compound according to item 13, where the specified 2,3,6-trisubstituted phenyl group contains fluorine, chlorine, methyl or methoxy in the 2-position. 15. The compound of claim 14, wherein said 2,3,6-trisubstituted phenyl group contains at least two substituents selected from fluoro and chloro. 16. The compound of claim 13, wherein said 2,3,6-trisubstituted phenyl group is selected from 2,3,6-trichlorophenyl, 2,3,6-trifluorophenyl, 2,3, difluoro-6-chlorophenyl, 2,3 -difluoro-6-methylphenyl, 3-chloro-2,6-difluorophenyl, 2-chloro-3,6-difluorophenyl, 2-chloro-3-methoxy-6-fluorophenyl and 2-methoxy-3-fluoro-6-chlorophenyl . 17. The compound according to any one of paragraphs.13-16, where R ³ represents a group of 4-piperidinyl or 1-methyl-4-piperidinyl. 18. The compound according to any one of paragraphs.13-16, where R ³ represents (x), a group:

where R ⁴ is as defined in claim 1. 19. The compound according to any one of paragraphs.13-16, where R ³ represents (ii), a group:

where R ¹² is as defined in claim 1. 20. The compound according to any one of paragraphs.13-16, where R ³ represents (xi), a group:

where R ⁷ is as defined in claim 1. 21. The compound according to any one of paragraphs.13-16, where R ³ represents (xii), a group:

where R ^12a is as defined in claim 1. 22. The compound according to claim 1, where R ¹ represents a group R ^1a , R ^2a and R ^2b both represent hydrogen, and R ³ represents (xiii), a group

23. The compound according to claim 1, where R ¹ represents a group R ^1b , R ^2a and R ^2b both represent hydrogen, and R ³ represents (xiv) a methyl group. 24. The compound according to claim 1, where R ¹ represents a group R ^1c , R ^2a and R ^2b both represent hydrogen, and R ³ represents (xv) a group

25. The compound according to claim 1, where R ¹ represents (k), a 2,6-difluorophenylamino group, R ^2a and R ^{2b are} both hydrogen; and R ³ is methyl. 26. The compound according to claim 1, where R ¹ represents 2,6-dichlorophenyl, R ³ represents a 4-piperidine group and either (l) R ^2a represents methyl and R ^2b represents hydrogen, or (m) R ^2a represents hydrogen and R ^2b represents methyl. 27. The compound according to claim 1, where R ¹ represents (g), a group R ⁰ , where R ⁰ means a carbocyclic or heterocyclic group containing from 3 to 12 members in the ring; or a C _1-8 hydrocarbon group optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano; C _1-4 hydroxy substituted hydrocarbon groups, amino, mono- or di-C _1-4 amino substituted hydrocarbon groups, and carbocyclic or heterocyclic groups containing from 3 to 12 members included in the ring, and where 1 or 2 carbon atoms of the hydrocarbon group optionally substituted with an atom or group selected from O, S, NH, SO, SO ₂ ; wherein R ^{3 is} selected from the following: (xi) group:

(xii) group:

where R ⁷ , R ^7a and R ^12a are as defined in the text of this application. 28. The compound according to claim 1, selected from the following compounds: 4- (2,6-Dichlorobenzoylamino) -1H-pyrazole-3-carboxylic acid (4-methoxymethoxycyclohexyl) amide; 4- (2,3-difluoro-6-methoxybenzoylamino) -1H-pyrazole-3-carboxylic acid (1-methanesulfonylpiperidin-4-yl) amide; 4- (3-chloro-2,6-difluorobenzoylamino) -1H-pyrazole-3-carboxylic acid (1-methanesulfonylpiperidin-4-yl) amide; and 4- (2-chloro-3,6-difluorobenzoylamino) -1H-pyrazole-3-carboxylic acid (1-methanesulfonylpiperidin-4-yl) amide; and their salts, solvates, tautomers and N-oxides. 29. The compound according to any one of claims 1 to 28 in the form of a salt, solvate or N-oxide. 30. The compound according to any one of claims 1 to 29 for use in the prevention or treatment of a disease or disease condition mediated by a cyclin-dependent kinase or glycogen synthase kinase-3. 31. A method for the prevention or treatment of a disease or disease condition mediated by a cyclin-dependent kinase or glycogen synthase-3 kinase, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 29. 32. A method of alleviating or reducing the manifestations of a disease or disease state mediated by a cyclin-dependent kinase or glycogen synthase kinase 3, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 29. 33. A method of treating a disease or condition including abnormal cell growth or resulting from abnormal cell growth in a mammal, comprising administering to the mammal a compound according to any one of claims 1 to 29 in an amount effective to inhibit abnormal cell growth. 34. A method of alleviating or reducing the manifestations of a disease or condition involving abnormal cell growth or resulting from abnormal cell growth in a mammal, comprising administering to the mammal a compound according to any one of claims 1 to 29 in an amount effective to inhibit abnormal cell growth. 35. A method of treating a disease or condition involving abnormal cell growth or resulting in abnormal cell growth in a mammal, comprising administering to the mammal a compound according to any one of claims 1 to 29 in an amount effective to inhibit cyclin-dependent kinase cdk activity (such as cdk1 or cdk2) or glycogen synthase-3 kinase activity. 36. A method of alleviating or reducing the manifestations of a disease or condition involving abnormal cell growth or resulting from abnormal cell growth in a mammal, comprising administering to the mammal a compound according to any one of claims 1 to 29 in an amount effective to inhibit cdk activity (such as cdk1 or cdk2) or glycogen synthase-3 kinase activity. 37. A method of inhibiting a cyclin-dependent kinase or glycogen synthase-3 kinase, comprising contacting the kinase with a kinase-inhibiting compound according to any one of claims 1 to 29. 38. A method of modulating cellular processes (eg, cell division) by inhibiting the activity of a cyclin-dependent kinase or glycogen synthase-3 kinase using a compound according to any one of claims 1 to 29. 39. The compound according to any one of claims 1 to 29 for use in the prevention or treatment of a disease state in the manner described above. 40. The use of a compound according to any one of claims 1 to 29 for the manufacture of a medicament, wherein the medicament is intended for any one or more of the uses indicated above. 41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 and a pharmaceutically acceptable carrier. 42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 and a pharmaceutically acceptable carrier in a form suitable for oral administration. 43. The compound according to any one of claims 1 to 29 for use in medicine. 44. The compound according to any one of claims 1 to 29 for any application and method described above, in the manner described above. 45. A method for diagnosing and treating a disease or disease condition mediated by a cyclin-dependent kinase, comprising (i) screening a patient to determine whether the condition or disease to which the patient is or may be susceptible is one that is treatable using a compound having activity against cyclin-dependent kinase; and (ii) when it is shown that the patient’s disease or condition is susceptible to said treatment, administering to the patient a compound according to any one of claims 1 to 29. 46. The use of a compound according to any one of claims 1 to 29 for the manufacture of a medicament for the treatment or prophylaxis of diseases and painful conditions in which, as a result of a patient’s screening, the patient is found to be at or at risk for a disease or condition that is susceptible to treatment using a compound having cyclin-dependent kinase activity. 47. The compound according to any one of claims 1 to 29 for use in inhibiting tumor growth in a mammal. 48. The compound according to any one of claims 1 to 29 for use in inhibiting tumor cell growth (eg, in a mammal). 49. A method of inhibiting tumor growth in a mammal (eg, human), comprising administering to the mammal (eg, human) an effective tumor growth inhibiting amount of a compound according to any one of claims 1 to 29. 50. A method of inhibiting the growth of tumor cells (for example, tumor cells present in a mammal, such as a human), comprising contacting the tumor cells with an effective tumor cell growth inhibiting amount of a compound according to any one of claims 1 to 29.