Patent EA-004460-B1 (EA)
Title: Indazole compounds and pharmaceutical compositions for inhibiting protein kinases and method for their use
Inventor: KANIA ROBERT STEVEN
IPC: A61P9/10
Filed: 2000-06-30
Abstract: 1. A compound of the Formula I: wherein: R<1> is a 6-12-membered aryl or 5-12-membered heteroaryl or a group of the formula CH=CH-R<3> or CH=N-R<3> where R<3> is an unsubstituted C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8, R<2> is a 6-12-membered aryl or 5-12-membered heteroaryl optionally substituted with alkyl C1-6, or Y-X, where Y is O, S, C=CH2, C=O, C2-8 alkylidene, NH, or N- (C1-8 alkyl), and X is a 6-12-membered aryl, 5-12-membered heteroaryl, NH-(C1-8 alkyl), NH-(C3-8 cycloalkyl), NH-(5-12-membered heterocycloalkyl), NH (5-12-membered aryl), NH-(5-12-menbered heteroaryl),NH-(C1-8 alkoxyl), or NH (di-C1-8 alkylamide), and X is optionally substituted with OH group, halo, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, or with a group of formula NH-C(OR<11>), or C(O)NH-R<11>, wherein R<11> is 5-12-membered heteroaryl or 6-12-membered aryl optionally substituted with alkyl C1-8, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkoxy group, NH-(5-12-membered heteroaryl), or R<11> is C1-8 cycloalkyl, optionally substituted with 6-12-membered aryl; or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 2. A compound of the Formula I (a): wherein: R<1> is a 6-12-membered aryl or 5-12-membered heteroaryl or a group of the formula CH=CH-R<3> or CH=N-R<3> where R<3> is C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8, and R<2> is a 6-12-membered aryl or Y-Ar, where Y is O, S, C=CH2, C=O, CH2, CHCH3 OR N-(C1-8 alkyl) and Ar is a 6-12-membered aryl optionally substituted with OH group with OH group, halo, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, or with a group of formula NH-C(OR<11>), or C(O)NH-R<11>, wherein R<11> is 5-12-membered heteroaryl or 6-12-membered aryl optionally substituted with C1-8 alkyl or C(O)(C1-8 alkyl, or R<11> is C3-8 cycloalkyl, optionally substituted with 6-12-membered aryl; or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 3. A compound of the Formula II: wherein: R<1> is a 6-12-membered aryl or 5-12-membered heteroaryl or a group of the formula CH=CH-R<3> or CH=N-R<3> where R<3> is C1-8 alkyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8; R<4> and R<7> are each independently hydrogen, OH, halo, C1-8 alkyl, C1-8 alkoxy, C1-8 alkenyl, aryloxy, thioaryl, CH2OH, CH2O-(C1-8 alkyl), CH2O-aryl,CH2-S-(C1-8 alkyl), or CH2-S-aryl; R<5> and R<6> are each independently hydrogen, OH, halo, Z-(C1-8 alkyl), Z-(C6-12 aryl), or Z-CH2CH=CH2, where Z is O, S, NH or CH2, and the alkyl and aryl moiety of Z-alkyl and Z-aryl are each optionally substituted with C1-8 alkyl; or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, wherein R<1> is a 7-12-membered bicyclic heteroaryl or a group of the formula CH=CH-R<3>, where R<3> is 5-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8; R<4> and R<7> are each independently hydrogen or C1-8 alkyl; and R<5> and R<6> are each independently halo, Z-(C1-8 alkyl) or Z-CH2CH=CH2, where Z is O or S, and alkyl is optionally substituted with C1-8 alkyl; or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 5. A compound of the Formula III: R<1> is a 6-12-membered aryl or 5-12-membered heteroaryl or a group of the formula CH=CH-R<3> or CH=N-R<3> where R<3> is C1-8 alkyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8; Y is O, S, C(CH2, C(O, S(O, SO2, CH2, CHCH3, NH or N-(C1-8 alkyl); R<8> is a C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl, 5-12-membered heteroaryl, C1-8 alkoxyl or C6-12 aryloxyl; R<10> is independently selected from hydrogen, halogen, and lower-alkyl; or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 6. A compound according to claim 5, R<1> is a 7-12-membered bicyclic heteroaryl or a group of the formula CH=CH-R<3>, where R<3> is 5-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8; Y is O, S, C(CH2, C(O, NH or N-(C1-8 alkyl); R<8> is 6-12-membered aryl, 5-12-membered heteroaryl, C1-8 alkyl, or C2-8 alkenyl, and R<10> is a hydrogen or halo atom, or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 7. A compound of the Formula III (a): wherein: R<1> is a 6-12-membered aryl or 5-12-membered heteroaryl or a group of the formula CH=CH-R<3> or CH=N-R<3> where R<3> is C1-8 alkyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8; Y is O, S, C(CH2, C(O, S(O, SO2, CH2, CHCH3, NH or N-(C1-8 alkyl); R<8> is a C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl, 5-12-membered heteroaryl, C1-8 alkoxyl or C6-12 aryloxyl; or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 8. A compound according to claim 7, wherein: R<1> is a 7-12-membered bicyclic heteroaryl or a group of the formula CH=CH-R<3>, where R<3> is 5-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8; Y is O, S, C(CH2, C(O, NH or N-(C1-8 alkyl); R<8> is 6-12-membered aryl, 5-12-membered heteroaryl, C1-8 alkyl, or C2-8 alkenyl, or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 9. A compound according to claim 7, wherein: R<1> is a group of the formula CH=CH-R<3>, where R<3> is 5-12-membered aryl and R<1> is optionally substituted with alkyl C1-8; Y is O or S, and R<8> is 6-12-membered aryl or 5-12-membered heteroaryl, or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 10. A compound of the Formula IV: wherein: R<1> is a 6-12-membered aryl or 5-12-membered heteroaryl or a group of the formula CH=CH-R<3> or CH=N-R<3> where R<3> is C1-8 alkyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl or 5-12-membered heteroaryl, and R<1> is optionally substituted with alkyl C1-8; Y is O, S, C(CH2, C(O, S(O, SO2, CH2, CHCH3, NH or N-(C1-8 alkyl); R<9> is a C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl, 5-12-membered heteroaryl, C1-8 alkoxyl or C6-12 aryloxyl; C3-12 cycloalkoxyl, NH-(C1-8 alkyl), NH-(6-12-membered aryl), NH-(5-12-membered heteroaryl), N(CH-(C1-8 alkyl), NH(C(O)R<11> or NH2, wherein R<11> is independently selected from a hydrogen atom, C1-8 alkyl, C3-8 cycloalkyl, 5-12-membered heterocycloalkyl, 6-12-membered aryl and 5-12-membered heteroaryl; and R<10> is a hydrogen or halo atom and lower alkyl; or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 11. A compound according to claim 7, wherein: R<1> is a group of the formula CH=CH-R<3>, where R<3> is 5-12-membered aryl and R<1> is optionally substituted with alkyl C1-8; Y is S or NH; and R<9> is C1-8 alkyl, C1-8 alkoxyl, or NH-(5-12-membered heteroaryl), or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof. 12. A compound, pharmaceutically acceptable prodrug or pharmaceutically acceptable salt, selected from: 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of claim 1; and a pharmaceutically acceptable carrier, diluent, or vehicle therefor. 14. A method of treating a mammalian disease condition mediated by protein kinase activity, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable prodrug or pharmaceutically acceptable salt as defined in claim 1. 15. A method according to claim 14, wherein the mammalian disease condition is associated with tumor growth, cell proliferation or angiogenesis. 16. A method of modulating the activity of a protein kinase receptor, comprising contacting the kinase receptor with an effective amount of a compound, pharmaceutically acceptable prodrug or pharmaceutically acceptable salt as defined in claim 1. 17. A method according to claim 16, wherein the protein kinase receptor is a VEGF receptor.