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.

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 (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  and R 2  together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring comprising 1-3 nitrogen atoms; 
         R 3  is (CR 2 ) 0-2 SO 2 R 12 , (CR 2 ) 0-2 SO 2 NRR 12 , (CR 2 ) 0-2 C(O)O 0-1 R 12 , (CR 2 ) 0-2 CONRR 12 , CO 2 NH 2 , or cyano; 
         R 4 , R 7  and R 10  are independently H; 
         R, R 5  and R 5′  are independently H or C 1-6  alkyl; 
         R 6  is halo or O(C 1-6  alkyl); 
         R 8  and R 9  are independently C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo or X, or one of R 8  and R 9  is H; and provided one of R 8  and R 9  is X; 
         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 an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A 2  or A 3  or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0; 
         R 12  is an optionally substituted 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; and 
         n is 0; and 
         p and q are independently 0-4; 
         and optionally in combination with a second therapeutic agent, wherein said condition is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder. 
       
     
     
         2 . The method of  claim 1 , wherein R 3  is SO 2 R 12 , SO 2 NH 2 , SO 2 NRR 12 , CO 2 NH 2 , CONRR 12 , C(O)O 0-1 R 12 , or cyano; and
 R 12  is C 1-6  alkyl, an optionally substituted C 3-7  cycloalkyl, C 3-7  cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl.   
     
     
         3 . The method of  claim 1 , wherein said compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The method of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         5 . The method of  claim 1 , wherein said compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         6 . The method of  claim 1 , wherein said condition is a cell proliferative disorder. 
     
     
         7 . The method of  claim 6 , 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. 
     
     
         8 . The method of  claim 7 , wherein said cell proliferative disorder is non-small cell lung cancer or neuroblastoma. 
     
     
         9 . The method of  claim 1 , wherein said second therapeutic agent is a chemotherapeutic agent. 
     
     
         10 . A method for treating a condition which responds to inhibition of 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 
       
       
         
           
           
               
               
           
         
         A 1  and A 4  are independently C or N; 
         each A 2  and A 3  is C, or one of A 2  and A 3  is N when R 6  and R 7  form a ring; 
         B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S; 
         Z 1 , Z 2  and Z 3  are independently NR 11 , C═O, CR—OR, (CR 2 ) 1-2  or ═C—R 12 ; 
         R 1  and R 2  are independently halo, OR 12 , NR(R 12 ), SR 12 , or an optionally substituted C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl; or one of R 1  and R 2  is H; 
         R 3  is (CR 2 ) 0-2 SO 2 R 12 , (CR 2 ) 0-2 SO 2 NRR 12 , (CR 2 ) 0-2 CO 1-2 R 12 , (CR 2 ) 0-2 CONRR 12  or cyano; 
         R 4 , R 6 , R 7  and R 10  are independently an optionally substituted 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 , R 7  and R 10  are independently H; 
         R, R 5  and R 5′  are independently H or C 1-6  alkyl; 
         R 8  and R 9  are independently C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo or X, or one of R 8  and R 9  is H when R 1  and R 2  form a ring; and provided one of R 8  and R 9  is X; 
         alternatively, R 1  and R 2 , or R 6  and R 7 , R 7  and R 8 , or R 9  and R 10 , when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R 7 , R 8 , R 9  and R 10  are absent when attached to N; 
         R 11  is H, C 1-6  alkyl, C 2-6  alkenyl, (CR 2 ) p CO 1-2 R, (CR 2 ) p OR, (CR 2 ) p R 13 , (CR 2 ) p NRR 12 , (CR 2 ) p CONRR 12  or (CR 2 ) p SO 1-2 R 12 ; 
         R 12  and R 13  are independently an optionally substituted 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; 
         X is (CR 2 ) q Y, cyano, CO 1-2 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 an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A 2  or A 3  or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0; and 
         n, p and q are independently 0-4; 
         and optionally in combination with a second therapeutic agent, wherein said condition is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder. 
       
     
     
         11 . The method of  claim 10 , wherein said condition is a cell proliferative disorder. 
     
     
         12 . The method of  claim 11 , 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. 
     
     
         13 . A method for inhibiting anaplastic lymphoma kinase, comprising administering a therapeutically effective amount of a compound of Formula (1), 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof; wherein 
         W is 
       
       
         
           
           
               
               
           
         
         A 1  and A 4  are independently C or N; 
         each A 2  and A 3  is C, or one of A 2  and A 3  is N when R 6  and R 7  form a ring; 
         B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S; 
         Z 1 , Z 2  and Z 3  are independently NR 11 , C═O, CR—OR, (CR 2 ) 1-2  or ═C—R 12 ; 
         R 1  and R 2  are independently halo, OR 12 , NR(R 12 ), SR 12 , or an optionally substituted C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl; or one of R 1  and R 2  is H; 
         R 3  is (CR 2 ) 0-2 SO 2 R 12 , (CR 2 ) 0-2 SO 2 NRR 12 , (CR 2 ) 0-2 CO 1-2 R 12 , (CR 2 ) 0-2 CONRR 12  or cyano; 
         R 4 , R 6 , R 7  and R 10  are independently an optionally substituted 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 , R 7  and R 10  are independently H; 
         R, R 5  and R 5′  are independently H or C 1-6  alkyl; 
         R 8  and R 9  are independently C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo or X, or one of R 8  and R 9  is H when R 1  and R 2  form a ring; and provided one of R 8  and R 9  is X; 
         alternatively, R 1  and R 2 , or R 6  and R 7 , R 7  and R 8 , or R 9  and R 10 , when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R 7 , R 8 , R 9  and R 10  are absent when attached to N; 
         R 11  is H, C 1-6  alkyl, C 2-6  alkenyl, (CR 2 ) p CO 1-2 R, (CR 2 ) p OR, (CR 2 ) p R 13 , (CR 2 ) p NRR 12 , (CR 2 ) p CONRR 12  or (CR 2 ) p SO 1-2 R 12 ; 
         R 12  and R 13  are independently an optionally substituted 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; 
         X is (CR 2 ) q Y, cyano, CO 1-2 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 an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A 2  or A 3  or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0; and 
         n, p and q are independently 0-4; 
         thereby inhibiting said kinase.