Compounds and compositions as protein kinase inhibitors

1. A compound having Formula (2):

or pharmaceutically acceptable salts thereof;

wherein R 1 is halo or C 1-6 alkyl;

R 2 is H;

R 3 is (CR 2 ) 0-2 SO 2 R 12 ;

R 4 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; OR 12 , NR(R 12 ), halo, nitro, SO 2 R 12 , (CR 2 ) p R 13 or X; or R 4 is H;

R 6 is isopropoxy or methoxy;

one of R 8 and R 9 is (CR 2 ) q Y and the other is C 1-6 alkyl, cyano, C(O)O 0-1 R 12 , CONR(R 12 ) or CONR(CR 2 ) p NR(R 12 );

X is (CR 2 ) q Y, cyano, C(O)O 0-1 R 12 , CONR(R 12 ), CONR(CR 2 ) p NR(R 12 ), CONR(CR 2 ) p OR 12 , CONR(CR 2 ) p SR 12 , CONR(CR 2 ) p S(O) 1-2 R 12 or (CR 2 ) 1-6 NR(CR 2 ) p OR 12 ;

Y is pyrrolidinyl, piperidinyl or azetidinyl, each of which is attached to the phenyl ring via a carbon atom;

R 12 and R 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 12 is H or C 1-6 alkyl;

R is H or C 1-6 alkyl;

n is 0-1;

p is 0-4; and

q is 0.

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

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

4. The compound of claim 1 , wherein said compound is selected from the group consisting of

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-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.

6. A compound having Formula (1)

or pharmaceutically acceptable salts thereof; wherein

W is

A 1 and A 4 are independently C;

each A 2 and A 3 is C;

R 1 is halo or C 1-6 alkyl;

R 2 is H;

R 3 is (CR 2 ) 0-2 SO 2 R 12 ;

R 4 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; OR 12 , NR(R 12 ), halo, nitro, SO 2 R 12 , (CR 2 ) p R 13 or X;

R 5 , R 5′ , R 7 and R 10 are H;

R 6 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; OR 12 , NR(R 12 ), halo, nitro, SO 2 R 12 , (CR 2 ) p R 13 or X;

R 8 and R 9 are independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo or X; and provided one of R 8 and R 9 is X;

R is H or C 1-6 alkyl;

X is (CR 2 ) q Y;

Y is a 5-12 membered heterocyclic ring comprising N, O and/or S, and optionally substituted with C 1-6 alkyl, hydroxylC 1 -C 8 alkyl, C 1 -C 8 alkoxyC 1 -C 8 alkyl or a 5-12 membered heterocyclic ring comprising N, O and/or S; and wherein Y is attached to A 2 or A 3 or both via a carbon atom of said heterocyclic ring when q in (CR 2 ) q Y is 0;

R 12 and R 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 12 is H, C 1-6 alkyl;

p is 0-4; and

n and q are 0.

7. The compound of claim 6 , wherein R 3 is SO 2 R 12 and

R 12 is C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl.

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

9. The compound of claim 6 , wherein said compound is selected from the group consisting of

67

5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-[2-

(propane-2-sulfonyl)phenyl]-pyrimidine-2,4-diamine;

69

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

5-chloro-N2-(2-cyclobutoxy-5-methyl-4-

(piperidin-4-yl)phenyl)-N4-(2-

(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

72

2-[4-(4-{5-Chloro-4-[2-(propane-2-

sulfonyl)-phenylamino]-pyrimidin-2-

ylamino}-5-isopropoxy-2-methyl-phenyl)-

piperidin-1-yl]-ethanol;

73

5-chloro-N2-(2-isopropoxy-4-(1-(2-

methoxyethyl)piperidin-4-yl)-5-

methylphenyl)-N4-(2-(isopropylsulfonyl)

phenyl)pyrimidine-2,4-diamine;

74

N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-(2-

(isopropylsulfonyl)phenyl)-5-

methylpyrimidine-2,4-diamine;

75

5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-(2-

(propylsulfonyl)phenyl)pyrimidine-2,4-diamine;

77

5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-(2-

(pyrrolidin-1-ylsulfonyl)phenyl)

pyrimidine-2,4-diamine;

82

5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-(2-

(methylsulfonyl)phenyl)pyrimidine-2,4-diamine; and

84

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-(isopropylsulfonyl)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.