Patent EA-003527-B1 (EA)
Title: Substituted 4-aminothiazoles as inhibitors of cyclin-dependent kinases
Inventor: CHONG WESLEY K
IPC: C07D277/20
Filed: 1998-10-27
Abstract: 1. A compound of the Formula I: wherein: R<1> is 1 is a substituted or unsubstituted group selected from: C1-6-alkyl ; phenyl, 5-9-membered heterocycle, containing as heteroatoms N, O, S; cycloalkyl; (C1-6-alkyl)-carbonyl; (C1-6-alkyl)-aryl; and when R<1> is substituted, each substituent independently is a halogen; haloalkyl; C1-6-alkyl; C1-6-alkoxyl; amino; nitro; thioether; cyano; amido; carboxyl; sulfonamide; ketone; aldehyde; ester; oxygen; phenyl; 5-9-membered heterocycle, containing as heteroatoms N, O, S; phenyl, substituted 5-7-heterocycle, containing as heteroatoms N, O or (C1-6-alkyl)-amino, optionally having substituents such as indicated for R<1>; and R<2> is phenyl, or 5-9-membered heterocyclic ring, containing as heteroatoms S and N, having substituent in adjacent position in relation to joining point, the ring being optionally substituted; wherein each substituent R<2> is independently halogen, haloalkyl, C1-6-alkyl; hydroxyl, C1-6-alkoxyl; amino; nitro; cyano; C1-6-alkylcarbomoyl, benzoyloxy, benzoyloxycarbonyl, aryl; or pharmaceutically acceptable salt a compound of the Formula I; or prodrug of compound of the Formula I or pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein when R<1> is substituted, each substituent independently is a halogen, haloalkyl, C1-6-alkyl, oxygen, C1-6-alkoxyl, amino, nitro, imine, cyano, amido, carboxyl, sulfonamide, ketone, or ester; and each substituent of R<2> independently is a halogen, haloalkyl, C1-6-alkyl, hydroxyl, C1-6-alkoxyl, amino, nitro, C1-6alkylcarbamoyl, benzoyloxy, benzoyloxycarbonyl, or pharmaceutically acceptable salt or prodrug thereof. 3. A compound according to claim 1, wherein R<1> is substituted phenyl group, or a pharmaceutically acceptable salt, prodrug. 4. A compound according to claim 1, wherein R<1> is phenyl, substituted by alkylamino or pyridine group, or pharmaceutically acceptable salt, prodrug thereof. 5. A compound according to claim 1, wherein R<1> is selected from the group consisting of: or pharmaceutically acceptable salt, prodrug thereof. 6. A compound according to claim 1, wherein R<1> is phenyl substituted by optionally substituted sulfonamide group and pharmaceutically acceptable salt, prodrug thereof. 7. A compound according to claim 1, wherein R<1> is selected from the group consisting of: where R<3> is selected from the group consisting of C1-6alkyl, C1-6alkoxy, aryl, aryloxy, and amine or a pharmaceutically acceptable salt, prodrug thereof. 8. A compound according to claim 1, wherein R<2> is ortho-substituted phenyl or thienyl, or a pharmaceutically acceptable salt, prodrug thereof. 9. A compound according to claim 8, wherein R<2> is o-halophenyl or o-dihalophenyl or a pharmaceutically acceptable salt, prodrug thereof. 10. A compound according to claim 9, wherein R<2> is o-difluorophenyl or a pharmaceutically acceptable salt, prodrug thereof. 11. A compound according to claim 1 selected from the group consisting of: and pharmaceutically acceptable salt, prodrug thereof. 12. A compound according to claim 1 selected from the group consisting of: and pharmaceutically acceptable salt, prodrug thereof. 13. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, prodrug of said compound. 14. A pharmaceutical composition comprising: (a) an amount of a cell-cycle control agent effective to inhibit CDK4 or a CDK4/cyclin complex, said cell-cycle control agent being selected from the group consisting of: (i) a compound of the Formula I: wherein: R<1> is 1 is a substituted or unsubstituted group selected from: C1-6-alkyl ; phenyl, 5-9-membered heterocycle, containing as heteroatoms N, O, S; cycloalkyl; (C1-6-alkyl)-carbonyl; (C1-6-alkyl)-aryl; and when R<1> is substituted, each substituent independently is a halogen; haloalkyl; C1-6-alkyl; C1-6-alkoxyl; amino; nitro; thioether; cyano; amido; carboxyl; sulfonamide; ketone; aldehyde; ester; oxygen; phenyl; 5-9-membered heterocycle, containing as heteroatoms N, O, S; phenyl, substituted 5-7-heterocycle, containing as heteroatoms N, O or (C1-6-alkyl)-amino, optionally having substituents such as indicated for R<1>; and R<2> is phenyl, or 5-9-membered heterocyclic ring, containing as heteroatoms S and N, having substituent in adjacent position in relation to joining point, the ring being optionally substituted; wherein each substituent R<2> is independently halogen, haloalkyl, C1-6-alkyl; hydroxyl, C1-6- alkoxyl; amino; nitro; cyano; C1-6-alkylcarbomoyl, benzoyloxy, benzoyloxycarbonyl, aryl; (ii) a pharmaceutically acceptable salt of a compound of the Formula I; and (iii) a prodrug or pharmaceutically active metabolite of a compound of the Formula I or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier. 15. A method of treating a disease or disorder mediated by inhibition of CDK4 or a CDK4/cyclin complex, comprising administering to a subject in need of such treatment a cell cycle control agent selected from the group consisting of compounds of the Formula I: wherein: R<1> is 1 is a substituted or unsubstituted group selected from: C1-6-alkyl ; phenyl, 5-9-membered heterocycle, containing as heteroatoms N, O, S; cycloalkyl; (C1-6-alkyl)-carbonyl; (C1-6-alkyl)-aryl; and when R<1> is substituted, each substituent independently is a halogen; haloalkyl; C1-6-alkyl; C1-6-alkoxyl; amino; nitro; thioether; cyano; amido; carboxyl; sulfonamide; ketone; aldehyde; ester; oxygen; phenyl; 5-9-membered heterocycle, containing as heteroatoms N, O, S; phenyl, substituted 5-7-heterocycle, containing as heteroatoms N, O or (C1-6-alkyl)-amino, optionally having substituents such as indicated for R<1>; and R<2> is phenyl, or 5-9-membered heterocyclic ring, containing as heteroatoms S and N, having substituent in adjacent position in relation to joining point, the ring being optionally substituted; wherein each substituent R<2> is independently halogen, haloalkyl, C1-6-alkyl; hydroxyl, C1-6- alkoxyl; amino; nitro; cyano; C1-6-alkylcarbomoyl, benzoyloxy, benzoyloxycarbonyl, aryl; or pharmaceutically acceptable salt a compound of the Formula I; or prodrug of compound of the Formula I or pharmaceutically acceptable salt thereof.