Granted Patent B2

US 8,410,088 · App. 13/447,007 · Granted Apr 2, 2013

Abstract

Claims (35)

1. A compound of Formula (Ig) or a pharmaceutically acceptable salt thereof:

wherein R 2 , R 4 and R 12 are each, independently C 1-6 alkyl;

R 6 is C 6 -C 10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q 2 -T 2 , wherein Q 2 is a bond or C 1 -C 3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 2 is H, halo, cyano, —OR a , —NR a R b , —(NR a R b R c ) + A − , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR b C(O)R a , —NR b C(O)OR a , —S(O) 2 R a , —S(O) 2 NR a R b , or R S2 , in which each of R a , R b and R c , independently is H or R S3 , A − is a pharmaceutically acceptable anion, each of R S2 and R S3 , independently, is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R a and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S2 , R S3 , and the 4 to 12-membered heterocycloalkyl ring formed by R a and R b , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 3 is selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR d , COOR d , —S(O) 2 R d , —NR d R e , and —C(O)NR d R e , each of R d and R e independently being H or C 1 -C 6 alkyl, or -Q 3 -T 3 is oxo; or any two neighboring -Q 2 -T 2 , together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

R 7 is -Q 4 -T 4 , in which Q 4 is a bond, C 1 -C 4 alkyl linker, or C 2 -C 4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 4 is H, halo, cyano, NR f R g , —OR f , —C(O)R f , —C(O)OR f , —C(O)NR f R g , —C(O)NR f OR g , —NR f C(O)R g , —S(O) 2 R f , or R S4 , in which each of R f and R g , independently is H or R S5 , each of R S4 and R S5 , independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R S4 and R S5 is optionally substituted with one or more -Q 5 -T 5 , wherein Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo; and

R 8 is H, halo, hydroxyl, COOH, cyano, R S6 , OR S6 , or COOR S6 , in which R S6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C 1 -C 6 alkylamino, or di-C 1 -C 6 alkylamino, and R S6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, and di-C 1 -C 6 alkylamino; or R 7 and R 8 , together with the N atom to which the are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, and the 4 to 11-membered heterocycloalkyl ring formed by R 7 and R 8 is optionally substituted with one or more -Q 6 -T 6 , wherein Q 6 is a bond, C(O), C(O)NR m , NR m C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R m being H or C 1 -C 6 alkyl, and T 6 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) p R p in which p is 0, 1, or 2 and R p is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 6 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 6 is H, halo, hydroxyl, or cyano; or -Q 6 -T 6 is oxo.

2. The compound of claim 1 , wherein R 6 is C 6 -C 10 aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q 2 -T 2 , wherein Q 2 is a bond or C 1 -C 3 alkyl linker, and T 2 is H, halo, cyano, —OR a , —NR a R b , —(NR a R b R c ) + A − , C(O)NR a R b , —NR b C(O)R a , —S(O) 2 R a , or R S2 , in which each of R a and R b , independently is H or R S3 , each of R S2 and R S3 , independently, is C 1 -C 6 alkyl, or R a and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S2 , R S3 , and the 4 to 7-membered heterocycloalkyl ring formed by R a and R b , is optionally, independently substituted with one or more -Q 3 -T 3 , wherein Q 3 is a bond or C 1 -C 3 alkyl linker and T 3 is selected from the group consisting of halo, C 1 -C 6 alkyl, 4 to 7-membered heterocycloalkyl, OR d , —S(O) 2 R d , and —NR d R e , each of R d and R e independently being H or C 1 -C 6 alkyl, or -Q 3 -T 3 is oxo; or any two neighboring -Q 2 -T 2 , together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S.

3. The compound of claim 1 , wherein the compound is of Formula (II) or a pharmaceutically acceptable salt thereof:

wherein Q 2 is a bond or methyl linker, T 2 is H, halo, —OR a , —NR a R b , —(NR a R b R c ) + A − , or —S(O) 2 NR a R b , R 7 is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q 5 -T 5 and R 8 is ethyl.

4. A compound of Formula (IIa) or a pharmaceutically acceptable salt thereof:

wherein

each of R a and R b , independently is H or R S3 , R S3 being C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R a and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S3 and the 4 to 12-membered heterocycloalkyl ring formed by R a and R b , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 3 is selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR d , COOR d , —S(O) 2 R d , —NR d R e , and —C(O)NR d R e , each of R d and R e independently being H or C 1 -C 6 alkyl, or -Q 3 -T 3 is oxo;

R 7 is -Q 4 -T 4 , in which Q 4 is a bond, C 1 -C 4 alkyl linker, or C 2 -C 4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 4 is H, halo, cyano, NR f R g , —OR f , —C(O)R f , —C(O)OR f , —C(O)NR f R g , —C(O)NR f OR g , —NR f C(O)R g , —S(O) 2 R f , or R S4 , in which each of R f and R g , independently is H or R S5 , each of R S4 and R S5 , independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R S4 and R S5 is optionally substituted with one or more -Q 5 -T 5 , wherein Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo; provided that R 7 is not H; and

R 8 is H, halo, hydroxyl, COOH, cyano, R S6 , OR S6 , or COOR S6 , in which R S6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, amino, mono-C 1 -C 6 alkylamino, or di-C 1 -C 6 alkylamino, and R S6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, and di-C 1 -C 6 alkylamino; or R 7 and R 8 , together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring which has 0 to 2 additional heteroatoms and is optionally substituted with one or more -Q 6 -T 6 , wherein Q 6 is a bond, C(O), C(O)NR m , NR m C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R m being H or C 1 -C 6 alkyl, and T 6 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) p R p in which p is 0, 1, or 2 and R p is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 6 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 6 is H, halo, hydroxyl, or cyano; or -Q 6 -T 6 is oxo.

5. The compound of claim 4 , wherein R a and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom and the ring is optionally substituted with one or more -Q 3 -T 3 , wherein the heterocycloalkyl is azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl.

6. The compound of claim 5 , wherein R 7 is C 3 -C 8 cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 .

7. The compound of claim 6 , wherein R 7 is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q 5 -T 5 .

8. The compound of claim 7 , R 8 is H or C 1 -C 6 alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, and di-C 1 -C 6 alkylamino.

9. The compound of claim 1 , wherein the compound is selected from

and pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a compound of Formula (Ig) of claim 1 and a pharmaceutically acceptable carrier.

11. A compound, which is

12. A pharmaceutically acceptable salt of

13. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 12 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (Ig) of claim 1 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising a compound of Formula (IIa) of claim 4 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (IIa) of claim 4 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a compound of Formula (II) of claim 3 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (II) of claim 3 and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier.

Assignments (6)