IP Library › Granted Patent US 8,153,644

Granted Patent B2

US 8,153,644 · App. 12/113,295 · Granted Apr 10, 2012

Diacylglycerol acyltransferase inhibitors

Assignee: Madrigal Pharmaceuticals, Inc.

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Quick Facts

Patent No.: US 8,153,644
App. No.: 12/113,295
Granted: Apr 10, 2012
Kind: B2

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Abstract

Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

Claims (402)

1. A compound of formula (I):

wherein:

R 1 is phenyl or 5- or 6-membered heteroaryl, said phenyl and heteroaryl being unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ;

R 2 is halogen, lower alkyl, haloloweralkyl or alkoxy;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl,

wherein both R3 and R4 are not absent;

R 5 is -lower alkyl,

-alkoxy,

-hydroxy,

-amine,

-lower alkyl amine,

-haloloweralkyl,

-lower alkoxy,

-lower alkenyloxy,

-cycloloweralkyl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-5- or 6-membered heterocycloalkyl, unsubstituted or substituted, with one to four substituents from lower alkyl, hydroxy, halogen, —SO 2 -loweralkyl, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-6-membered aryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-5- or 6-membered heteroaryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, C(O)O-lower alkyl or —C(O)O -lower alkyl-phenyl,

—(CH 2 ) n C(O)OH,

—CH 2 C(lower alkyl) 2 C(O)OH,

—CH 2 (cycloalkyl)C(O)OH,

-(cycloalkyl)C(O)OH,

—CH 2 C(CH 3 ) 3 ,

—(CH 2 ) n -cycloalkyl,

-cycloalkenyl,

-bicycloalkenyl-C(O)OH,

—(CH 2 ) n —O-alkyl,

—O—C(═C)-lower alkyl,

—O—(CH 2 ) n -phenyl,

—NSO 2 -loweralkyl,

—NSO 2 -cycloalkyl,

—NSO 2 -aryl,

—N-lower alkyl,

—N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH,

—N-heterocycloalkyl,

—N-aryl,

—N—(CH 2 ) n -aryl,

—N-heteroaryl, said heteroaryl being unsubstituted or substituted with alkyl,

—N—CH(lower alkyl)C(O)OH,

—N-(cycloalkyl)C(O)OH,

—N—CH(lower alkyl)C(O)O-lower alkyl, or

-phenyl-C(O)OH,

X is 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano;

Y is phenyl, heteroaryl, cycloloweralkyl, 5- or 6-membered heterocycloalkyl, or —N(CH 2 ) n )N—, said phenyl, cycloloweralkyl or heterocycloalkyl being unsubstituted or substituted with lower alkyl, halogen or cyano; and

n is 1, 2 or 3,

or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein:

R 1 is phenyl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ;

R 2 is halogen, lower alkyl, haloloweralkyl or alkoxy;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl;

wherein both R 3 and R 4 are not absent;

R 5 is -lower alkyl,

-alkoxy,

-hydroxy,

-amine,

-lower alkyl amine,

-haloloweralkyl,

-lower alkoxy,

-lower alkenyloxy,

-cycloloweralkyl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-6-membered aryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-5- or 6-membered heteroaryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

—(CH 2 ) n C(O)OH,

—CH 2 C(lower alkyl) 2 C(O)OH,

—CH 2 (cycloalkyl)C(O)OH,

-(cycloalkyl)C(O)OH,

—CH 2 C(CH 3 ) 3 ,

—(CH 2 ) n -cycloalkyl,

-cycloalkenyl,

-bicycloalkenyl-C(O)OH,

—(CH 2 ) n —O-alkyl,

—O—C(═C)-lower alkyl,

—O—(CH 2 ) n -phenyl,

—NSO 2 -loweralkyl,

—NSO 2 -cycloalkyl,

—NSO 2 -aryl,

—N-lower alkyl,

—N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH,

—N-heterocycloalkyl,

—N-aryl,

—N—(CH 2 )n-aryl,

—N-heteroaryl, said heteroaryl being unsubstituted or substituted with alkyl,

—N—CH(lower alkyl)C(O)OH,

—N-(cycloalkyl)C(O)OH,

—N—CH(lower alkyl)C(O)O-lower alkyl, or

-phenyl-C(O)OH,

X is 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano;

n is 1, 2 or 3.

3. The compound according to claim 1 , wherein:

R 1 is 5- or 6-membered heteroaryl unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ;

R 2 is halogen, lower alkyl, haloloweralkyl or alkoxy;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl;

wherein both R 3 and R 4 are not absent;

R 5 is -lower alkyl,

-alkoxy,

-hydroxy,

-amine,

-lower alkyl amine,

-haloloweralkyl,

-lower alkoxy,

-lower alkenyloxy,

-cycloloweralkyl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-6-membered aryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-5- or 6-membered heteroaryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

—(CH 2 ) n C(O)OH,

—CH 2 C(lower alkyl) 2 C(O)OH,

—CH 2 (cycloalkyl)C(O)OH,

-(cycloalkyl)C(O)OH,

—CH 2 C(CH 3 ) 3 ,

—(CH 2 ) n -cycloalkyl,

-cycloalkenyl,

-bicycloalkenyl-C(O)OH,

—(CH 2 ) n —O-alkyl,

—O—C(═C)-lower alkyl,

—O—(CH 2 ) n -phenyl,

—NSO 2 -loweralkyl,

—NSO 2 -cycloalkyl,

—NSO 2 -aryl,

—N-lower alkyl,

—N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH,

—N-heterocycloalkyl,

—N-aryl,

—N—(CH 2 ) n -aryl,

—N-heteroaryl, said heteroaryl being unsubstituted or substituted with alkyl,

—N—CH(lower alkyl)C(O)OH,

—N-(cycloalkyl)C(O)OH,

—N—CH(lower alkyl)C(O)O-lower alkyl, or

-phenyl-C(O)OH,

X is 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano;

n is 1, 2 or 3.

4. The compound according to claim 1 , wherein:

R 1 is phenyl or 5- or 6-membered heteroaryl, said phenyl and heteroaryl being unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ;

R 2 is halogen, lower alkyl, haloloweralkyl or alkoxy;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl;

wherein both R 3 and R 4 are not absent;

R 5 is -lower alkyl,

-alkoxy,

-hydroxy,

-amine,

-lower alkyl amine,

-haloloweralkyl,

-lower alkoxy,

-lower alkenyloxy,

-cycloloweralkyl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-6-membered aryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-5- or 6-membered heteroaryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

—(CH 2 ) n C(O)OH,

—CH 2 C(lower alkyl) 2 C(O)OH,

—CH 2 (cycloalkyl)C(O)OH,

-(cycloalkyl)C(O)OH,

—CH 2 C(CH 3 ) 3 ,

—(CH 2 ) n -cycloalkyl,

-cycloalkenyl,

-bicycloalkenyl-C(O)OH,

—(CH 2 ) n —O-alkyl,

—O—C(═C)-lower alkyl,

—O—(CH 2 ) n -phenyl,

—NSO 2 -loweralkyl,

—NSO 2 -cycloalkyl,

—NSO 2 -aryl,

—N-lower alkyl,

—N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH,

—N-heterocycloalkyl,

—N-aryl,

—N—(CH 2 ) n -aryl,

—N-heteroaryl, said heteroaryl being unsubstituted or substituted with alkyl,

—N—CH(lower alkyl)C(O)OH,

—N-(cycloalkyl)C(O)OH,

—N—CH(lower alkyl)C(O)O-lower alkyl, or

-phenyl-C(O)OH,

X is 6-membered aryl, unsubstituted or substituted with lower alkyl, halogen or cyano;

n is 1,2or 3.

5. The compound according to claim 1 , wherein:

R 1 is phenyl or 5- or 6-membered heteroaryl, said phenyl and heteroaryl being unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF3;

R 2 is halogen, lower alkyl, haloloweralkyl or alkoxy;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl;

wherein both R 3 and R 4 are not absent;

R5 is -lower alkyl,

-alkoxy,

-hydroxy,

-amine,

-lower alkyl amine,

-haloloweralkyl,

-lower alkoxy,

-lower alkenyloxy,

-cycloloweralkyl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-6-membered aryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-5- or 6-membered heteroaryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

—(CH 2 ) n C(O)OH,

—CH 2 C(lower alkyl) 2 C(O)OH,

—CH 2 (cycloalkyl)C(O)OH,

-(cycloalkyl)C(O)OH,

—CH 2 C(CH 3 ) 3 ,

—(CH 2 ) n -cycloalkyl,

-cycloalkenyl,

-bicycloalkenyl-C(O)OH,

—(CH 2 ) n —O-alkyl,

—O—C(═C)-lower alkyl,

—O—(CH 2 ) n -phenyl,

—NSO 2 -loweralkyl,

—NSO 2 -cycloalkyl,

—NSO 2 -aryl,

—N-lower alkyl,

—N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH,

—N-heterocycloalkyl,

—N-aryl,

—N—(CH 2 ) n -aryl,

—N-heteroaryl, said heteroaryl being unsubstituted or substituted with alkyl,

—N—CH(lower alkyl)C(O)OH,

—N-(cycloalkyl)C(O)OH,

—N—CH(lower alkyl)C(O)O-lower alkyl, or

-phenyl-C(O)OH,

X is 5- or 6-membered heteroaryl, unsubstituted or substituted with lower alkyl, halogen or cyano;

n is 1, 2 or 3.

6. The compound according to claim 1 , wherein:

R 1 is phenyl or 5- or 6-membered heteroaryl, said phenyl and heteroaryl being unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ;

R 2 is halogen, lower alkyl, haloloweralkyl or alkoxy;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl;

wherein both R3 and R 4 are not absent;

R 5 is -lower alkyl,

-alkoxy,

-hydroxy,

-amine,

-lower alkyl amine,

-haloloweralkyl,

-lower alkoxy,

-lower alkenyloxy,

-cycloloweralkyl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-6-membered aryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O -lower alkyl-phenyl,

-5- or 6-membered heteroaryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

—(CH 2 ) n C(O)OH,

—CH 2 C(lower alkyl) 2 C(O)OH,

—CH 2 (cycloalkyl)C(O)OH,

-(cycloalkyl)C(O)OH,

—CH 2 C(CH 3 ) 3 ,

—(CH 2 ) n -cycloalkyl,

-cycloalkenyl,

-bicycloalkenyl-C(O)OH,

—(CH 2 ) n —O-alkyl,

—O—C(═C)-lower alkyl,

—O—(CH 2 ) n -phenyl,

—NSO 2 -loweralkyl,

—NSO 2 -cycloalkyl,

—NSO 2 -aryl,

—N-lower alkyl,

—N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH,

—N-heterocycloalkyl,

—N-aryl,

—N—(CH 2 ) n -aryl,

—N-heteroaryl, said heteroaryl being unsubstituted or substituted with alkyl,

—N—CH(lower alkyl)C(O)OH,

—N-(cycloalkyl)C(O)OH,

—N—CH(lower alkyl)C(O)O-lower alkyl, or

-phenyl-C(O)OH,

X is 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano;

Y is phenyl, unsubstituted or substituted with lower alkyl, halogen or cyano; and

n is 1, 2 or 3.

7. The compound according to claim 1 , wherein:

R 1 is phenyl or 5- or 6-membered heteroaryl, said phenyl and heteroaryl being unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; is halogen, lower alkyl, haloloweralkyl or alkoxy;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl;

wherein both R 3 and R 4 are not absent;

R 5 is -lower alkyl,

-alkoxy,

-hydroxy,

-amine,

-lower alkyl amine,

-haloloweralkyl,

-lower alkoxy,

-lower alkenyloxy,

-cycloloweralkyl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-6-membered aryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

-5- or 6-membered heteroaryl, unsubstituted or substituted with one to four substituents from lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl,

—(CH 2 ) n C(O)OH,

—CH 2 C(lower alkyl) 2 C(O)OH,

—CH 2 (cycloalkyl)C(O)OH,

-(cycloalkyl)C(O)OH,

—CH 2 C(CH 3 ) 3 ,

—(CH 2 ) n -cycloalkyl,

-cycloalkenyl,

-bicycloalkenyl-C(O)OH,

—(CH 2 ) n —O-alkyl,

—O—C(═C)-lower alkyl,

—O—(CH 2 ) n -phenyl,

—NSO 2 -loweralkyl,

—NSO 2 -cycloalkyl,

—NSO 2 -aryl,

—N-lower alkyl,

—N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH,

—N-heterocycloalkyl,

—N-aryl,

—N—(CH 2 ) n -aryl,

—N-heteroaryl, said heteroaryl being unsubstituted or substituted with alkyl,

—N—CH(lower alkyl)C(O)OH,

—N-(cycloalkyl)C(O)OH,

—N—CH(lower alkyl)C(O)O-lower alkyl, or

-phenyl-C(O)OH,

X is 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano;

Y is cycloloweralkyl or 5- or 6-membered heterocycloalkyl, said cycloloweralkyl or heterocycloalkyl being unsubstituted or substituted with lower alkyl, halogen or cyano; and

n is 1, 2 or 3.

8. The compound according to claim 1 , wherein:

R 1 is phenyl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; and

X is 6-membered aryl, unsubstituted or substituted with lower alkyl, halogen or cyano.

9. The compound according to claim 1 , wherein:

R 1 is phenyl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; and

X is 5- or 6-membered heteroaryl, unsubstituted or substituted with lower alkyl, halogen or cyano.

10. The compound according to claim 1 , wherein:

R 1 is 5- or 6-membered heteroaryl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; and

X is 6-membered aryl, unsubstituted or substituted with lower alkyl, halogen or cyano.

11. The compound according to claim 1 , wherein:

R 1 is 5- or 6-membered heteroaryl, unsubstituted or substituted with halogen, lower alkyl, —O-lower alkyl or O—CF 3 ; and

X is 5- or 6-membered heteroaryl, unsubstituted or substituted with lower alkyl, halogen or cyano.

12. The compound according to claim 1 , wherein:

R 1 is phenyl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; and

Y is phenyl, unsubstituted or substituted with lower alkyl, halogen or cyano.

13. The compound according to claim 1 , wherein:

R 1 is 5- or 6-membered heteroaryl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; and

Y is phenyl, unsubstituted or substituted with lower alkyl, halogen or cyano.

14. The compound according to claim 1 , wherein:

R 1 is phenyl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; and

Y is cycloloweralkyl or 5- or 6-membered heterocycloalkyl, said cycloloweralkyl or heterocycloalkyl being unsubstituted or substituted with lower alkyl, halogen or cyano.

15. The compound according to claim 1 , wherein:

R 1 is 5- or 6-membered heteroaryl, unsubstituted or substituted with halogen, lower alkyl, alkoxy or O—CF 3 ; and

Y is cycloloweralkyl or 5- or 6-membered heterocycloalkyl, said cycloloweralkyl or heterocycloalkyl being unsubstituted or substituted with lower alkyl, halogen or cyano.

16. The compound according to claim 1 , wherein:

X is 6-membered aryl, unsubstituted or substituted with lower alkyl, halogen or cyano; and

Y is phenyl, heteroaryl, cycloloweralkyl, 5- or 6-membered heterocycloalkyl, or —N(CH 2 ) n N—, said phenyl, cycloloweralkyl or heterocycloalkyl being unsubstituted or substituted with lower alkyl, halogen or cyano.

17. The compound according to claim 1 , wherein:

X is 5- or 6-membered heteroaryl, unsubstituted or substituted with lower alkyl, halogen or cyano; and

18. The compound according to claim 1 , wherein:

X is 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano; and

Y is phenyl, unsubstituted or substituted with lower alkyl, halogen or cyano.

19. The compound according to claim 1 , wherein:

X is 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano; and

Y is cycloloweralkyl or 5- or 6-membered heterocycloalkyl, said cycloloweralkyl or heterocycloalkyl being unsubstituted or substituted with lower alkyl, halogen or cyano.

20. The compound according to claim 1 , wherein R 1 is phenyl, unsubstituted or substituted with halogen.

21. The compound according to claim 1 , wherein R 1 is pyridine, unsubstituted or substituted with halogen.

22. The compound according to claim 1 , wherein R 2 is halogen, trifluoromethyl, trifluoroethyl, methyl, ethyl, propyl, methoxymethyl or methoxyethyl.

23. The compound according to claim 1 , wherein R 5 is lower alkyl, alkoxy, hydroxy, lower alkyl amine; cycloloweralkyl, unsubstituted or substituted with one to four substituents from loweralkyl, hydroxy, halogen, —C(O)OH, —C(O)O -lower alkyl or —C(O)O-lower alkyl-phenyl; 5- or 6-membered heterocycloalkyl, unsubstituted or substituted, with one to four substituents from lower alkyl, hydroxy, halogen, —SO 2 -loweralkyl, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl; (CH 2 ) n C(O)OH; CH 2 C(lower alkyl) 2 C(O)OH; CH 2 (cycloalkyl)C(O)OH; (cycloalkyl)C(O)OH; NSO 2 -loweralkyl; N-lower alkyl; N-cycloalkyl, said cycloalkyl being unsubstituted or substituted with —C(O)OH; N—CH(lower alkyl)C(O)OH; or N-(cycloalkyl)C(O)OH.

24. The compound according to claim 1 , wherein X is phenyl, pyridine or pyrimidine.

25. The compound according to claim 1 , wherein Y is phenyl, pyridine, piperazine, piperidine, pyrrolidine or cyclopentane.

26. The compound according to claim 1 , wherein R 3 is nitrogen, unsubstituted or substituted with lower alkyl.

27. The compound according to claim 1 , wherein R 4 is NH.

28. The compound according to claim 1 , wherein n is 1.

29. The compound according to claim 1 , selected from the group consisting of:

(1R,2R)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl-amino]-biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid,

(1S,2S)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl-amino]-biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid,

(S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid ethyl ester,

(S)-3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid ethyl ester,

(S)-3-(4-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester,

2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6((S)-1-isobutyryl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide,

2,2-dimethyl-3-{5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl}-propionic acid,

(S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester,

(S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic acid ethyl ester, and

(S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyrimidin-2-ylarnino)-pyrrolidine-1-carboxylic acid ethyl ester.

30. The compound of claim 1 wherein:

R 1 is unsubstituted phenyl or phenyl substituted with halogen, lower alkyl, alkoxy or O—CF 3 ;

R 2 is halogen, lower alkyl, haloloweralkyl or alkoxy;

X is a 6-membered aryl or 5- or 6-membered heteroaryl, said aryl or heteroaryl being unsubstituted or substituted with lower alkyl, halogen or cyano;

R 3 is nitrogen, oxygen or absent, said nitrogen being unsubstituted or substituted with lower alkyl;

R 4 is carbon, NH, oxygen or absent, said carbon being unsubstituted or substituted with lower alkyl;

wherein both R 3 and R 4 are not absent;

R 5 is lower alkyl, lower alkoxy, -hydroxy, -cycloloweralkyl, which is unsubstituted or substituted with one to four substituents selected from the group consisting of lower alkyl, hydroxy, halogen, —C(O)OH, —C(O)O-lower alkyl or —C(O)O-lower alkyl-phenyl, or 5 or 6-membered heterocycloalkyl, unsubstituted or substituted, with one substituent selected from the group consisting of lower alkyl, —C(O)OH, or —C(O)O-lower alkyl

or pharmaceutically acceptable salts thereof.

31. The compound of claim 30 wherein R 3 is absent.

32. The compound of claim 31 wherein X is phenyl.

33. The compound of claim 30 wherein R 5 is a 5 or 6-membered heterocycloalkyl ring, said ring being unsubstituted or substituted in one position with C(O)OH or —C(O)O-lower alkyl.

34. The compound of claim 30 wherein R 3 is nitrogen or lower alkyl substituted nitrogen.

35. The compound of claim 34 wherein X is phenyl.

36. The compound of claim 35 wherein said compound is 3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic acid ethyl ester or its pharmaceutically acceptable salts.

37. The compound of claim 34 wherein X is 5 or 6-membered heteroaryl ring containing from 1 to 2 heteroatoms.

38. The compound of claim 37 wherein said heteroatoms are nitrogen atoms.

39. The compound of claim 38 wherein said compound is 3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyrimidin-2-ylamino)-pyrrolidine-1 -carboxylic acid ethyl ester or its pharmaceutically acceptable salts.

40. The compound of claim 38 wherein said compound is 3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester or its pharmaceutically acceptable salts.

41. The compound of claim 38 wherein said compound is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-isobutyryl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide ethyl ester.

42. The compound of claim 30 wherein R 3 is oxygen.

43. The compound of claim 42 wherein X is 5 or 6-membered heteroaryl ring containing from 1 to 2 heteroatoms.

44. The compound of claim 43 wherein said compound is 3-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbony)amino}-pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid ethyl ester or its pharmaceutically acceptable salts.

45. The compound of claim 38 wherein said compound is 3-(5-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid ethyl ester or its pharmaceutically acceptable salts.

46. The compound of claim 33 wherein Y is 5- or 6-membered heterocycloalkyl being unsubstituted or substituted with lower alkyl, halogen or cyano.

47. The compound of claim 46 wherein said compound is 2,2-dimethyl-3-{5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl}-propionic acid or its pharmaceutically acceptable salts.

48. The compound of claim 32 wherein R 5 is cycloloweralkyl unsubstituted or substituted in one position with C(O)OH or —C(O)O-lower alkyl.

49. The compound of claim 33 wherein said compound is 3-(4-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester or its pharmaceutically acceptable salts.

50. The compound of claim 48 wherein said compound is 2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid, its lower alkyl esters or their pharmaceutically acceptable salts.

51. The compound of claim 50 wherein said compound is (1S,2S)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-ylcarbamoyl}-cyclopentanecarboxylic acid ethyl ester or its pharmaceutically acceptable salts.

Assignments (5)

CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE'S ADDRESS PREVISOUSLY RECORDED ON REEL 027216 FRAME 0440.ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNORS INTEREST Recorded Jun 12, 2012

From: VIA, LLC

To: MADRIGAL PHARMACEUTICALS, INC.

Reel/Frame 028390/0021 →

COLLATERAL ASSIGNMENT OF PATENTS Recorded Nov 16, 2011

From: MADRIGAL PHARMACEUTICALS, INC.

To: BAY CITY CAPITAL FUND IV, L.P.

Reel/Frame 027241/0166 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 11, 2011

From: VIA PHARMACEUTICALS, INC.

To: VIA, LLC

Reel/Frame 027216/0375 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 11, 2011