Granted Patent B2

US 9,604,922 · App. 14/630,248 · Granted Mar 28, 2017

Abstract

Claims (72)

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

wherein:

R 1 is methyl;

L a is C 1 -C 6 alkyl, C 3 -C 10 carbocycle, C 6 -C 10 aryl, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, carbocycle, aryl, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with halogen;

R 2 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, C 6 -C 10 aryl, C 3 -C 10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;

R 3 is H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, SO 2 R 4 , or S(O)R 4 , wherein the alkyl, alkenyl, or alkynyl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;

R 4 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, C 6 -C 10 aryl, C 3 -C 10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;

or alternatively, R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo; and

n is 1 or 2.

2. The compound of claim 1 , wherein R 2 is C 1 -C 10 alkyl, or phenyl optionally substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl).

3. The compound of claim 1 , wherein R 3 is H or C 1 -C 10 alkyl.

4. The compound of claim 1 , wherein R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo.

5. The compound of claim 1 , wherein R 4 is C 1 -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl.

6. The compound of claim 1 , wherein L a is a C 1 -C 6 alkyl.

7. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is methyl;

L a is a C 1 -C 6 alkyl;

R 2 is C 1 -C 10 alkyl or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl;

R 3 is H, C 1 -C 10 alkyl, SO 2 R 4 , or S(O)R 4 ;

R 4 is C 1 -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl;

or alternatively, R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo; and

n is 1 or 2.

8. A method of treating a neurological disease selected from multiple sclerosis and psoriasis by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is C 1 -C 6 alkyl;

L a is C 1 -C 6 alkyl, C 3 -C 10 carbocycle, C 6 -C 10 aryl, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, carbocycle, aryl, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with halogen;

R 2 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, C 6 -C 10 aryl, C 3 -C 10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;

R 3 is H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, SO 2 R 4 , or S(O)R 4 , wherein the alkyl, alkenyl, or alkynyl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;

R 4 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, C 6 -C 10 aryl, C 3 -C 10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;

or alternatively, R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo; and

n is 1 or 2.

9. The method of claim 8 , wherein the neurological disease is multiple sclerosis.

10. The method of claim 8 , wherein the disease is relapsing-remitting multiple sclerosis.

11. The method of claim 8 , wherein the compound of Formula (I) is in the form of a pharmaceutically acceptable salt.

12. The compound of claim 7 , wherein R 2 is C 1 -C 10 alkyl and R 3 is H or C 1 -C 10 alkyl.

13. The compound of claim 1 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 8 , wherein:

R 1 is C 1 -C 6 alkyl;

L a is a C 1 -C 6 alkyl;

R 2 is C 1 -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl, OH, O(C 1 -C 6 alkyl), or halo;

R 3 is H, C 1 C 10 alkyl, SO 2 R 4 , or S(O)R 4 ;

R 4 is C 1 -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl;

or alternatively, R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo; and

n is 1 or 2.

19. The method of claim 18 , wherein R 1 is methyl.

20. The method of claim 19 , wherein R 2 is C 1 -C 10 alkyl and R 3 is H or C 1 -C 10 alkyl.

21. The method of claim 8 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

22. The method of claim 8 , wherein the compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

23. The method of claim 8 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

24. The method of claim 8 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

25. The method of claim 8 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

26. The method of claim 8 , wherein R 1 is methyl.

27. The method of claim 8 , wherein R 2 is C 1 -C 10 alkyl, or phenyl optionally substituted one or more times with C 1 -C 6 alkyl, OH, or O(C 1 -C 6 alkyl).

28. The method of claim 8 , wherein R 3 is H or C 1 -C 10 alkyl.

29. The method of claim 8 , wherein R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo.

30. The method of claim 8 , wherein R 4 is C l -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl.

31. The method of claim 8 , wherein L a is a C 1 -C 6 alkyl.

Assignments (6)