Isoxazolines as inhibitors of fatty acid amide hydrolase

• US 8,927,551 B2
• Filed: 05/18/2010
• Issued: 01/06/2015
• Est. Priority Date: 05/18/2009
• Status: Expired due to Fees

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Behnke, Mark L., Castro, Alfredo C., Chan, Lawrence K., Evans, Catherine A., Grenier, Louis, Grogan, Michael J., Leblanc, Yves, Liu, Tao, Peluso, Stephane, Snyder, Daniel A., Tibbitts, Thomas T.
• Primary Examiner(s): Hui, San-Ming
• Assistant Examiner(s): CRUZ, KATHRIEN ANN
• Application Number:
  US12/782,655
• Publication Number:
  US 20110028482A1
• Time in Patent Office: 1,694 Days
• Field of Search: 514/249, 514/380, 514/342, 514/269, 514/365, 514/326, 514/254.04, 514/367, 514/314, 546/269.7, 546/209, 546/167, 548/246, 548/202, 548/163
• US Class Current: 514/249
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 261/04 having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention provides isoxazoline FAAH inhibitors of the formula (I):

• • or pharmaceutically acceptable forms thereof, wherein each of G, R^a, R^b, R^c, and R^d are as defined herein.

The present invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.

The present invention also provides methods for treating an FAAH-mediated condition comprising administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable form thereof, to a subject in need thereof.

Claims

1. A compound of the following formula:

2. The compound according to claim 1, wherein R^a, R^b, and R^c independently is selected from —

H, C_1-3 alkyl and C_1-3 perhaloalkyl.

3. The compound according to claim 2, wherein each R^a, R^b, and R^c is independently selected from —

H, —

CH₃ and —

CF₃.

4. The compound according to claim 3, wherein R^a and R^b are —

H and R^c is selected from —

CH₃ and —

CF₃.

5. The compound according to claim 3, wherein R^b and R^c are —

H and R^a is selected from —

CH₃ and —

CF₃.

6. The compound according to claim 3, wherein each of R^a, R^b, and R^c is —

H.

7. The compound according to claim 1, wherein R¹⁵ is selected from fluoro (—

F), bromo (—

Br), chloro (—

Cl), and iodo (—

I), —

OR¹⁶, —

C(═

O)N(R¹⁸)₂, —

SO₂N(R¹⁸)₂,

C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups.

8. The compound according to claim 1, wherein Y¹ is S, Y³ is N, and Y² and Y⁴ are independently CH or CR¹⁵.

9. The compound according to claim 8, wherein the compound is of the formula:

10. The compound according to claim 1, wherein Y¹ is S and each Y², Y³ and Y⁴ is independently CH or CR¹⁵.

11. The compound according to claim 10, wherein the compound is of the formulae:

12. The compound according to claim 1, wherein G is selected from —

Cl, —

Br, —

I, —

OR^e, —

ONR^fR^e, —

ONR^f(C═

O)R^e, —

ONR^fSO₂R^e, —

ONR^fPO₂R^e, —

ONR^fPO₂OR^e, —

SR^e, —

OSO₂R^e, —

NR^fSO₂R^e, —

OPO₂R^e, —

OPO₂OR^e, —

NR^fPO₂R^e, —

NR^fPO₂OR^e, —

OPO₂NR^fR^e, —

O(C═

O)R^e, —

O(C═

O)OR^e, —

NR^fR^e, —

NR^f(C═

O)R^e, —

NR^f(C═

O)OR^e, —

O(C═

O)NR^fR^e, —

NR^f(C═

NR^f)NR^fR^e, —

O(C═

NR^f)NR^fR^e, —

NR^f(C═

NR^f)OR^e, and —

[N(R^f)₂R^e]⁺X⁻

wherein X⁻

is a counterion.

13. The compound according to claim 12, wherein G is —

OR^e.

14. The compound according to claim 13, wherein R^e is C_6-14 aryl.

15. The compound according to claim 14, wherein R^e is phenyl.

16. The compound according to claim 15, wherein R^e is a monosubstituted phenyl.

17. The compound according to claim 15, wherein R^e is a phenyl group of the formula:

18. The compound according to claim 17, wherein R^h is selected from fluoro (—

F), bromo (—

Br), chloro (—

Cl), and iodo (—

I), —

CN, —

NO₂, —

OH, —

ORⁱ, —

SRⁱ, —

N(R^k)₂, —

N(R^k)₃⁺X⁻

, —

C(═

O)Rⁱ, —

CO₂Rⁱ, —

CO₂H, —

OC(═

O)Rⁱ, —

OCO₂Rⁱ, —

C(═

O)N(R^k)₂, —

OC(═

O)N(R^k)₂, —

NR^kC(═

O)Rⁱ, —

NR^kCO₂Rⁱ, —

NR^kC(═

O)N(R^k)₂, —

C(═

O)NR^kSO₂Rⁱ, —

NR^kSO₂Rⁱ, —

SO₂N(R^k)₂, —

SO₂Ri, C_1-10 alkyl, C₆ aryl, and 5-6 membered heteroaryl, wherein each alkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3 or 4 R^m groups; and

wherein X⁻

is a counterion.

19. The compound according to claim 18, wherein R^h is selected from —

C(═

O)Rⁱ, —

CO₂H, —

SO₂Rⁱ, and 5-membered heteroaryl independently substituted with 0 or 1 R^m groups.

20. The compound according to claim 19, wherein the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl.

21. The compound according to claim 15, wherein the phenyl group is a monosubstituted phenyl group of any one of the formulae:

22. The compound according to claim 15, wherein the phenyl group is a disubstituted phenyl group of any one of the formulae:

23. The compound according to claim 13, wherein G is —

OR^e is selected from;

24. The compound according to claim 13, wherein R^e is 5-14 membered heteroaryl.

25. The compound according to claim 24, wherein R^e is a 6-membered heteroaryl.

26. The compound according to claim 25, wherein R^e is a pyrindinyl group.

27. The compound according to claim 26, wherein R^e is a monosubstituted pyrindinyl group.

28. The compound according to claim 26, wherein R^e is a 3-pyridinyl group.

29. The compound according to claim 26, wherein R^e is a pyrindinyl group of the formula:

30. The compound according to claim 29, wherein R^h is selected from fluoro (—

F), bromo (—

Br), chloro (—

Cl), and iodo (—

I), —

CN, —

NO₂, —

OH, —

ORⁱ, —

SRⁱ, —

N(R^k)₂, —

N(R^k)₃⁺X⁻

, —

C(═

O)Rⁱ, —

CO₂Rⁱ, —

CO₂H, —

OC(═

O)Rⁱ, —

OCO₂Rⁱ, —

C(═

O)N(R^k)₂, —

OC(═

O)N(R^k)₂, —

NR^kC(═

O)Rⁱ, —

NR^kCO₂Rⁱ, —

NR^kC(═

O)N(R^k)₂, —

C(═

O)NR^kSO₂Rⁱ, —

NR^kSO₂Rⁱ, —

SO₂N(R^k)₂, —

SO₂Ri, C_1-10 alkyl, C₆ aryl, and 5-6 membered heteroaryl, wherein each alkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3 or 4 R^m groups; and

wherein X⁻

is a counterion.

31. The compound according to claim 30, wherein R^h is selected from —

C(═

O)Rⁱ, —

CO₂H, —

SO₂Rⁱ, and 5-membered heteroaryl independently substituted with 0 or 1 R^m groups.

32. The compound according to claim 31, wherein the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl.

33. The compound according to claim 29, wherein the pyridinyl group is a 3-pyridinyl group of the formulae:

34. The compound according to claim 13, wherein G is —

OR^e is selected from;

35. The compound according to claim 1, wherein the compound is substantially enantiomerically pure.

36. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.

37. The compound according to claim 34, wherein G is —

OR^e selected from the group consisting of;

38. The compound according to claim 1, wherein the compound is:

39. The compound according to claim 1, wherein the compound is:

40. The compound according to claim 1, wherein the compound is:

41. The compound according to claim 1, wherein the compound is:

42. The compound according to claim 1, wherein the compound is:

43. The pharmaceutical composition according to claim 36, wherein the compound is:

44. The pharmaceutical composition according to claim 36, wherein the compound is:

45. The pharmaceutical composition according to claim 36, wherein the compound is: