Triazoles as inhibitors of fatty acid synthase

• US 8,450,350 B2
• Filed: 05/05/2011
• Issued: 05/28/2013
• Est. Priority Date: 05/05/2010
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Castro, Alfredo C., Chan, Lawrence K., Keaney, Gregg F., Nevalainen, Marta, Nevalainen, Vesa, Peluso, Stephane, Tibbitts, Thomas T., Bahadoor, Adilah
• Primary Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US13/101,970
• Publication Number:
  US 20110274654A1
• Time in Patent Office: 754 Days
• Field of Search: 514/359, 548/255
• US Class Current: 514/359
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/10 Anthelmintics
• CPC Class Codes: A61P 33/12 Schistosomicides
• CPC Class Codes: C07D 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 249/06 with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 249/18 Benzotriazoles
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Provided herein are triazole FASN inhibitors of the formula (I):

or a pharmaceutically acceptable form thereof; wherein the variables R^A, X, R^B, and R^C are defined herein.

Also provided herein are pharmaceutical compositions of the compounds provided herein as well as methods of their use for the treatment of various disorders such as hyperproliferative disorders, inflammatory disorders, obesity-related disorders and microbial infections.

Claims

1. A compound of the formula (I):

2. The compound of claim 1, wherein X is —

CN.

3. The compound of claim 1, wherein R^A is selected from C_6-14 aryl and 5-14 membered heteroaryl.

4. The compound of claim 3, wherein R^A is C_6-14 aryl.

5. The compound of claim 4, wherein R^A is a group of the formula (ii):

6. The compound of claim 5, wherein each of R¹, R², R³, R⁴ and R⁵ is independently selected from hydrogen, halogen, —

CN, —

OR^A1, —

N(R^A2)₂, —

CO₂H, —

CO₂R^A1, —

C(═

O)N(R^A2)₂, —

SO₂R^A1, C_1-10 alkyl, C_2-10 alkynyl, 3-14 membered heterocyclyl, and C_6-14 aryl;

or one or more of R¹ and R², R² and R³, R³ and R⁴ or R⁴ and R⁵ are joined to form a 5-14 membered heteroaryl ring.

7. The compound of claim 6, wherein each of R¹, R², R³, R⁴ and R⁵ is independently selected from hydrogen, halogen, —

OR^A1, C_1-10 alkyl, and —

C(═

O)N(R^A2)₂;

or R⁴ and R⁵ are joined to form a 5-14 membered heteroaryl ring.

8. The compound of claim 5, wherein R^A is a group of the formula (ii-d):

9. The compound of claim 8, wherein each of R¹ and R⁵ is independently halogen.

10. The compound of claim 9, wherein each of R¹ and R⁵ is independently selected from fluoro and chloro.

11. The compound of claim 1, wherein R^B and R^c together with the nitrogen (N) atom to which each is attached are joined to form a 5-14 membered carbocyclyl, heterocyclyl, aryl or heteroaryl ring.

12. The compound of claim 11, wherein R^B and R^c together with the nitrogen (N) atom to which each is attached are joined to form a 5-14 membered ring of the formula (xiv):

13. The compound of claim 12, wherein R⁴⁷ and R⁴⁹ are joined to form a C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl or 5-14 membered heteroaryl ring.

14. The compound of claim 13, wherein R⁴⁷ and R⁴⁹ are joined to form a C_3-10 carbocyclyl.

15. The compound of claim 14, wherein Q is CR⁴¹R⁴².

16. The compound of claim 15, wherein m is 1.

17. The compound of claim 16, wherein each R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁸, and R⁵⁰ is hydrogen;

and R⁴⁷ and R⁴⁹ are joined to form a C_3-10 carbocyclyl.

18. The compound of claim 17, wherein R^B and R^C together with the nitrogen (N) atom to which each is attached are joined to form a group of the formula (xiv-a):

19. The compound of claim 1, wherein R^B is C_6-14 aryl or 5-14 membered heteroaryl.

20. The compound of claim 19, wherein R^B is C_6-14 aryl.

21. The compound of claim 20, wherein R^B is phenyl.

22. The compound of claim 21, wherein R^B is unsubstituted phenyl.

23. The compound of claim 21, wherein R^B is phenyl that is substituted with L-R^D;

wherein;

L is a covalent bond or a divalent C_1-10 hydrocarbon chain, wherein one, two or three methylene units of L are optionally and independently replaced with one or more —

O—

, —

S—

, —

NR^B8—

, —

(C═

NR^B8)—

, —

C(═

O)—

, —

C(═

S)—

, —

S(═

O)—

, —

S(═

O)₂—

, divalent C_3-10 carbocyclyl, divalent 3-14 membered heterocyclyl, divalent C_6-14 aryl or divalent 5-14 membered heteroaryl group; and

R^D is selected from —

C(═

O)R^B7, —

CO₂H, —

CHO, and —

CO₂R^B7;

wherein R^B7 is selected from C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, 3-14 membered heteroaliphatic, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl.

24. The compound of claim 23, wherein L is a covalent bond, and R^D is —

CO₂H.

25. The compound of claim 1, wherein R^C is an acyclic group.

26. The compound of claim 25, wherein R^C is C_1-10 alkyl.

27. The compound of claim 26, wherein R^C is unsubstituted C_1-10 alkyl.

28. The compound of claim 27, wherein R^C is unsubstituted ethyl or unsubstituted isopropyl.

29. The compound of claim 1, wherein R^B is C_6-14 aryl or 5-14 membered heteroaryl;

and R^C is C_1-10 alkyl.

30. The compound of claim 29, wherein R^B is C_6-14 aryl;

and R^C is C_1-10 alkyl.

31. The compound of claim 1, wherein:

R^A is C_6-14 aryl;

R^B and R^C together with the nitrogen (N) atom to which each is attached are joined to form a 5-14 membered carbocyclyl, heterocyclyl, aryl or heteroaryl ring; and

X is selected from —

CN, —

C(═

O)N(R^X2)₂, and —

CO₂R^X1.

32. The compound of claim 31, wherein X is —

CN.

33. The compound of claim 1, wherein:

R^A is C_6-14 aryl;

R^B is C_6-14 aryl or 5-14 membered heteroaryl;

R^C is an acyclic group; and

X is selected from —

CN, —

C(═

O)N(R^X2)₂, and —

CO₂R^X1.

34. The compound of claim 33, wherein R^B is C_6-14 aryl and R^C is C_1-10 alkyl.

35. The compound according to claim 33, wherein X is —

CN.

36. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1, or a pharmaceutically acceptable form thereof;

and at least one pharmaceutically acceptable excipient.

37. The compound of claim 1, wherein the compound is: