Compounds and compositions as protein kinase inhibitors
View Patent ↗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 (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;
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
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;
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 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;
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
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;
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.