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Claims for Patent: 8,039,479

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Claims for Patent: 8,039,479

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): Michellys; Pierre-Yves (San Marcos, CA), Pei; Wei (San Diego, CA), Marsilje; Thomas H. (San Diego, CA), Chen; Bei (San Diego, CA), Uno; Tetsuo (San Diego, CA)
Assignee: IRM LLC (Hamilton, BM)
Application Number:11/943,436
Patent Claims: 1. A compound having Formula (2): ##STR00363## or pharmaceutically acceptable salts thereof; wherein R.sup.1 is halo or C.sub.1-6 alkyl; R.sup.2 is H; R.sup.3 is (CR.sub.2).sub.0-2SO.sub.2R.sup.12; R.sup.4 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; OR.sup.12, NR(R.sup.12), halo, nitro, SO.sub.2R.sup.12, (CR.sub.2).sub.pR.sup.13 or X; or R.sup.4 is H; R.sup.6 is isopropoxy or methoxy; one of R.sup.8 and R.sup.9 is (CR.sub.2).sub.qY and the other is C.sub.1-6 alkyl, cyano, C(O)O.sub.0-1R.sup.12, CONR(R.sup.12) or CONR(CR.sub.2).sub.pNR(R.sup.12); X is (CR.sub.2).sub.qY, cyano, C(O)O.sub.0-1R.sup.12, CONR(R.sup.12), CONR(CR.sub.2).sub.pNR(R.sup.12), CONR(CR.sub.2).sub.pOR.sup.12, CONR(CR.sub.2).sub.pSR.sup.12, CONR(CR.sub.2).sub.pS(O).sub.1-2R.sup.12 or (CR.sub.2).sub.1-6NR(CR.sub.2).sub.pOR.sup.12; Y is pyrrolidinyl, piperidinyl or azetidinyl, each of which is attached to the phenyl ring via a carbon atom; R.sup.12 and R.sup.13 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 R.sup.12 is H or C.sub.1-6 alkyl; R is H or C.sub.1-6 alkyl; n is 0-1; p is 0-4; and q is 0.

2. The compound of claim 1, wherein R.sup.3 is SO.sub.2R.sup.12; and R.sup.12 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl.

3. The compound of claim 1, wherein one of R.sup.8 and R.sup.9 is (CR.sub.2).sub.qY and the other is C.sub.1-6 alkyl; and n is 0.

4. The compound of claim 1, wherein said compound is selected from the group consisting of ##STR00364## ##STR00365## ##STR00366## or pharmaceutically acceptable salts thereof.

5. The compound of claim 1, wherein said compound is 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propa- ne-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.

6. A compound having Formula (1) ##STR00367## or pharmaceutically acceptable salts thereof; wherein W is ##STR00368## A.sup.1 and A.sup.4 are independently C; each A.sup.2 and A.sup.3 is C; R.sup.1 is halo or C.sub.1-6 alkyl; R.sup.2 is H; R.sup.3 is (CR.sub.2).sub.0-2SO.sub.2R.sup.12; R.sup.4 is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; OR.sup.12, NR(R.sup.12), halo, nitro, SO.sub.2R.sup.12, (CR.sub.2).sub.pR.sup.13 or X; R.sup.5, R.sup.5', R.sup.7 and R.sup.10 are H; R.sup.6 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; OR.sup.12, NR(R.sup.12), halo, nitro, SO.sub.2R.sup.12, (CR.sub.2).sub.pR.sup.13 or X; R.sup.8 and R.sup.9 are independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo or X; and provided one of R.sup.8 and R.sup.9 is X; R is H or C.sub.1-6 alkyl; X is (CR.sub.2).sub.qY; Y is a 5-12 membered heterocyclic ring comprising N, O and/or S, and optionally substituted with C.sub.1-6 alkyl, hydroxylC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxyC.sub.1-C.sub.8alkyl or a 5-12 membered heterocyclic ring comprising N, O and/or S; and wherein Y is attached to A.sup.2 or A.sup.3 or both via a carbon atom of said heterocyclic ring when q in (CR.sub.2).sub.qY is 0; R.sup.12 and R.sup.13 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 R.sup.12 is H, C.sub.1-6 alkyl; p is 0-4; and n and q are 0.

7. The compound of claim 6, wherein R.sup.3 is SO.sub.2R.sup.12 and R.sup.12 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl.

8. The compound of claim 6, wherein R.sup.6 is halo or OR.sup.12, wherein R.sup.12 is C.sub.1-6 alkyl.

9. The compound of claim 6, wherein said compound is selected from the group consisting of TABLE-US-00005 67 ##STR00369## 5-chloro-N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-[2- (propane-2-sulfonyl)phenyl]-pyrimidine-2,4-diamine; 69 ##STR00370## 5-chloro-N2-(2-isopropoxy-5-methyl-4-(1- (1-methylpiperidin-4-yl)piperidin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine; 71 ##STR00371## 5-chloro-N2-(2-cyclobutoxy-5-methyl-4- (piperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine; 72 ##STR00372## 2-[4-(4-{5-Chloro-4-[2-(propane-2- sulfonyl)-phenylamino]-pyrimidin-2- ylamino}-5-isopropoxy-2-methyl-phenyl)- piperidin-1-yl]-ethanol; 73 ##STR00373## 5-chloro-N2-(2-isopropoxy-4-(1-(2- methoxyethyl)piperidin-4-yl)-5- methylphenyl)-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine; 74 ##STR00374## N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-5- methylpyrimidine-2,4-diamine; 75 ##STR00375## 5-chloro-N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (propylsulfonyl)phenyl)pyrimidine-2,4-diamine; 77 ##STR00376## 5-chloro-N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (pyrrolidin-1-ylsulfonyl)phenyl) pyrimidine-2,4-diamine; 82 ##STR00377## 5-chloro-N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (methylsulfonyl)phenyl)pyrimidine-2,4-diamine; and 84 ##STR00378## 5-chloro-N4-(2-(cyclobutylsulfonyl)phenyl)-N2-(2- isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)pyrimidine-2,4-diamine;

or pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 9 and a pharmaceutically acceptable carrier.

14. A combination comprising a compound of claim 1, or pharmaceutically acceptable salts thereof, and a chemotherapeutic agent.

15. The combination of claim 14, for treating a cell proliferative disorder, wherein said cell proliferative disorder is lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor, non-small cell lung cancer or neuroblastoma.

16. The compound of claim 6, wherein said compound is N2-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopro- pylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 16 and a pharmaceutically acceptable carrier.
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