Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt or ester thereof:

wherein;

is selected from

X 1 , X 2 and X 3 are each independently selected from N or C(R 5 );

R 3 , R 4 and R 5 are each independently selected from the group consisting of:

1) Hydrogen;

2) Halogen;

3) —NO 2 ;

4) Cyano;

5) Optionally substituted —C 1 -C 8 alkyl;

6) Optionally substituted —C 3 -C 8 cycloalkyl;

7) Optionally substituted 3- to 8-membered heterocycloalkyl; and

8) Optionally substituted —C 1 -C 8 alkoxyl;

R is selected from the group consisting of

R 1 is

R 2 is selected from the group consisting of:

1) Hydrogen;

2) Halogen;

3) —NO 2 ;

4) Cyano;

5) Optionally substituted —C 1 -C 8 alkyl;

6) Optionally substituted —C 2 -C 8 alkenyl;

7) Optionally substituted —C 2 -C 8 alkynyl;

8) Optionally substituted —C 3 -C 8 cycloalkyl;

9) Optionally substituted aryl;

10) Optionally substituted arylalkyl;

11) Optionally substituted 3- to 8-membered heterocycloalkyl;

12) Optionally substituted heteroaryl;

13) Optionally substituted heteroarylalkyl;

14) —N(R 6 )(R 7 );

15) —S(O) 2 N(R 6 )(R 7 );

16) —N(R 6 )C(O)(R 7 ); and

17) —N(R 6 )S(O) 2 (R 7 );

wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 15 alkyl; cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl, alternatively, R 7 and R 6 are taken together with the nitrogen atom to which they are attached to form a heterocyclic.

2. The compound of claim 1 , wherein R 1 is

3. The compound of claim 1 , wherein R 2 is selected from the following:

4. The compound of claim 1 , wherein R 3 is selected from the following:

wherein each group is optionally substituted.

5. The compound of claim 1 , which is represented by Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or ester thereof:

wherein

R 1 , R 2 , R 3 and X 1 are as defined claim 1 .

6. The compound of claim 1 , which is represented by one of Formulae (IIa-1) to (IIa-4) or (IIb-1) to (IIb-4), or a pharmaceutically acceptable salt or ester thereof:

wherein R 1 , R 2 , R 3 , and X 1 are as defined claim 1 .

7. The compound of claim 1 , which is selected from compounds of Formula (IVa-1), (IVa-2), (IVa-3), or (IVa-4), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

8. The compound of claim 1 , which is selected from compounds of Formula (IVb-1), (IVb-2), (IVb-3), or (IVb-4), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

9. The compound of claim 1 , which is selected from compounds of Formula (Va-1), (Va-2), (Va-3), or (Va-4), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

10. The compound of claim 1 , which is selected from compounds of Formula (Vb-1), (Vb-2), (Vb-3), or (Vb-4), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

11. The compound of claim 1 , which is selected from compounds of Formula (VIa-1), (VIa-2), (VIa-3), or (VIa-4), or a pharmaceutically acceptable salt thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino.

12. The compound of claim 1 , which is selected from compounds of Formula (VIb-1), (VIb-2), (VIb-3), or (VIb-4), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

14. A method for treating an ASK-1 mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of Formula (I) according to claim 1 .

15. The method according to claim 14 , wherein the ASK-1 mediated disease or condition is selected from the group consisting of an autoimmune disorder, a neurodegenerative disorder, an inflammatory disease, chronic kidney disease, renal disease, cardiovascular disease, a metabolic disease, or an acute or chronic liver disease.

16. The method according to claim 15 , wherein the ASK-1 mediated disease or condition is a chronic liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or alpha 1-antitrypsin deficiency.

17. The method according to claim 15 , wherein the ASK-1 mediated disease or condition is a renal disease selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, kidney fibrosis and polycystic kidney disease.

18. The method according to claim 15 , wherein the ASK-1 mediated disease or condition is a cardiovascular disease selected from the group consisting of atherosclerosis, arteriosclerosis, reperfusion/ischemia in stroke, cardiac hypertrophy, respiratory diseases, heart attacks, and myocardial ischemia or a metabolic disease selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.

19. The method according to claim 15 , wherein the ASK-1 mediated disease or condition is a chronic kidney disease selected from the group consisting of polycystic kidney disease, pyelonephritis, kidney fibrosis and glomerulonephritis.

20. The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt or ester thereof:

Compound

Structure

 5a

 6a

 7a

24a

25a

28a

30a

32a

33a

49a

51a

53a

55a

58a

61a

21. The compound of claim 20 having the structure

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 20 having the structure

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 20 having the structure

or a pharmaceutically acceptable salt thereof.