Claims for Patent: 8,377,921

Summary for Patent: 8,377,921

Title:	Compounds and compositions as protein kinase inhibitors
Abstract:	The invention provides novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine and pyridine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70), insulin-like growth factor (IGF-1R), or a combination thereof.
Inventor(s):	Pierre-Yves Michellys, Wei Pei, Thomas H. Marsilje, Bei Chen, Tetsuo Uno
Assignee:	Novartis AG
Application Number:	US13/172,572
Patent Claims:	1. A method for treating a condition mediated by anaplastic lymphoma kinase, comprising administering to a subject in need of treatment, a therapeutically effective amount of a compound of Formula (2), or pharmaceutically acceptable salts thereof; wherein R1 is halo or C1-6 alkyl; R2 is H; R3 is (CR2)0-2SO2R12; R4 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; or R4 is H; R6 is isopropoxy or methoxy; one of R8 and R9 is (CR2)qY and the other is C1-6 alkyl, cyano, C(O)O0-1R12, CONR(R12) or CONR(CR2)pNR(R12); X is (CR2)qY, cyano, C(O)O0-1R12, CONR(R12), CONR(CR2)pNR(R12), CONR(CR2)pOR12, CONR(CR2)pSR12, CONR(CR2)pS(O)1-2R12 or (CR2)1-6NR(CR2)pOR12; Y is pyrrolidinyl, piperidinyl or azetidinyl, each of which is attached to the phenyl ring via a carbon atom; R12 and R13 are independently 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H or C1-6 alkyl; R is H or C1-6 alkyl; n is 0-1; p is 0-4; and q is 0; and optionally in combination with a second therapeutic agent, wherein said condition is anaplastic large cell lymphoma, ALK+ non-Hodgkin's lymphoma, inflammatory myofibrolastic tumor, neuroblastoma or a neoplastic disease, wherein said neoplastic disease is non-small cell lung cancer. 2. The method of claim 1, wherein said condition is non-small cell lung cancer. 3. The method of claim 1, wherein said condition is neuroblastoma. 4. The method of claim 1, wherein said second therapeutic agent is a chemotherapeutic agent. 5. A method for treating a condition mediated by anaplastic lymphoma kinase, comprising administering to a subject in need of treatment, a therapeutically effective amount of a compound of Formula (1) or pharmaceutically acceptable salts thereof; wherein W is A1 and A4 are independently C; each A2 and A3 is C; R1 is halo or C1-6 alkyl; R2 is H; R3 is (CR2)0-2SO2R12; R4 is H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; R5, R5′, R7 and R10 are H; R6 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; R8 and R9 are independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo or X; and provided one of R8 and R9 is X; R is H or C1-6 alkyl; X is (CR2)qY; Y is a 5-12 membered heterocyclic ring comprising N, O and/or S, and optionally substituted with C1-6 alkyl, hydroxylC1-C8alkyl, C1-C8alkoxyC1-C8alkyl or a 5-12 membered heterocyclic ring comprising N, O and/or S; and wherein Y is attached to A2 or A3 or both via a carbon atom of said heterocyclic ring when q in (CR2)qY is 0; R12 and R13 are independently 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H, C1-6 alkyl; p is 0-4; and n and q are 0; and optionally in combination with a second therapeutic agent, wherein said condition is anaplastic large cell lymphoma, ALK+ non-Hodgkin's lymphoma, inflammatory myofibrolastic tumor, neuroblastoma or a neoplastic disease, wherein said neoplastic disease is non-small cell lung cancer. 6. The method of claim 1, wherein said compound is selected from the group consisting of: or pharmaceutically acceptable salts thereof. 7. The method of claim 1, wherein said compound is 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof. 8. The method of claim 5, wherein said compound is selected from the group consisting of or pharmaceutically acceptable salts thereof. 9. The method of claim 5, wherein said compound is N2-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine. 10. A method for treating a condition which responds to inhibition of anaplastic lymphoma kinase, comprising administering a therapeutically effective amount of a compound of Formula (2), wherein R1 is halo or C1-6 alkyl; R2 is H; R3 is (CR2)0-2SO2R12; R4 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; or R4 is H; R6 is isopropoxy or methoxy; one of R8 and R9 is (CR2)qY and the other is C1-6 alkyl, cyano, C(O)O0-1R12, CONR(R12) or CONR(CR2)pNR(R12); X is (CR2)qY, cyano, C(O)O0-1R12, CONR(R12), CONR(CR2)pNR(R12), CONR(CR2)pOR12, CONR(CR2)pSR12, CONR(CR2)pS(O)1-2R12 or (CR2)1-6NR(CR2)pOR12; Y is pyrrolidinyl, piperidinyl or azetidinyl, each of which is attached to the phenyl ring via a carbon atom; R12 and R13 are independently 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H or C1-6 alkyl; R is H or C1-6 alkyl; n is 0-1; p is 0-4; and q is 0; or a pharmaceutically acceptable salts thereof, and optionally in combination with a second therapeutic agent, to a subject in need of treatment; wherein said condition is anaplastic large cell lymphoma, ALK+ non-Hodgkin's lymphoma, inflammatory myofibrolastic tumor, neuroblastoma or a neoplastic disease, wherein said neoplastic disease is non-small cell lung cancer. 11. The method of claim 10, wherein said condition is non-small cell lung cancer. 12. The method of claim 10, wherein said condition is neuroblastoma. 13. The method of claim 10, wherein said second therapeutic agent is a chemotherapeutic agent. 14. The method of claim 10, wherein said compound is selected from the group consisting of: or pharmaceutically acceptable salts thereof. 15. The method of claim 10, wherein said compound is 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof. 16. A method for treating a condition which responds to inhibition of anaplastic lymphoma kinase, comprising administering a therapeutically effective amount of a compound of Formula (1), wherein W is A1 and A4 are independently C; each A2 and A3 is C; R1 is halo or C1-6 alkyl; R2 is H; R3 is (CR2)0-2SO2R12; R4 is H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; R5, R5′, R7 and R10 are H; R6 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; R8 and R9 are independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo or X; and provided one of R8 and R9 is X; R is H or C1-6 alkyl; X is (CR2)qY; Y is a 5-12 membered heterocyclic ring comprising N, O and/or S, and optionally substituted with C1-6 alkyl, hydroxylC1-C8alkyl, C1-C8alkoxyC1-C8alkyl or a 5-12 membered heterocyclic ring comprising N, O and/or S; and wherein Y is attached to A2 or A3 or both via a carbon atom of said heterocyclic ring when q in (CR2)qY is 0; R12 and R13 are independently 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H, C1-6 alkyl; p is 0-4; and n and q are 0; or a pharmaceutically acceptable salt thereof, and optionally in combination with a second therapeutic agent, to a subject in need of treatment; wherein said condition is anaplastic large cell lymphoma, ALK+ non-Hodgkin's lymphoma, inflammatory myofibrolastic tumor, non-small cell lung cancer or neuroblastoma. 17. The method of claim 16, wherein said condition is non-small cell lung cancer. 18. The method of claim 16, wherein said condition is neuroblastoma. 19. The method of claim 16, wherein said compound is selected from the group consisting of or pharmaceutically acceptable salts thereof. 20. The method of claim 16, wherein said compound is N2-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine.