Apoptosis signal-regulating kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9943521-B2
Application number	US-201615357878-A
Country	US
Kind code	B2
Filing date	Nov 21, 2016
Priority date	Dec 21, 2012
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The present invention relates to compounds of Formula (I):

Wherein variables are as defined above. The compounds have apoptosis signal-regulating kinase (“ASK1”) inhibitory activity, and are thus useful in the treatment of ASK1-mediated conditions, including autoimmune disorders, inflammatory diseases, cardiovascular diseases, diabetes, diabetic nephropathy, cardio-renal diseases, including kidney disease, fibrotic diseases, respiratory diseases, COPD, idiopathic pulmonary fibrosis, acute lung injury, acute and chronic liver diseases, and neurodegenerative diseases.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein:
R 1 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one to three halogen atoms;
R 2 is hydrogen or C 1 -C 6 alkyl wherein the alkyl is optionally substituted with halo;
R 3 is hydrogen or C 1 -C 3 alkyl;
R 4 is hydrogen or C 1 -C 3 alkyl;
R 5 is hydrogen, C 1 -C 3 alkyl, OR a or —NHR a ;
R 6 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl wherein the cycloalkyl is optionally substituted with C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or 1 or 2 halogen atoms;
R a and R b are independently hydrogen, C 1 -C 3 alkyl or R a and R b combine with the nitrogen atom to which they are attached to form a four to six member heterocyclic ring optionally containing a heteroatom chosen from oxygen and nitrogen, wherein the heterocyclic ring is optionally substituted by one or two substituents independently chosen from alkyl of 1-4 carbon atoms and hydroxyl;
or a pharmaceutically acceptable salt or enantiomer thereof.

2. The compound of claim 1 , wherein:
R 1 is cyclopropyl or 1,1,1-trifluoropropan-2-yl;
R 2 , R 3 , R 4 and R 5 are all hydrogen; and
R 6 is cyclopropyl.

3. The compound of claim 2 , wherein R 1 and R 6 are both cyclopropyl.

4. The compound of claim 3 , chosen from:
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-morpholinopicolinamide;
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-(3-hydroxy-3-methylazetidin-1-yl)picolinamide;
5-(azetidin-1-yl)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-(pyrrolidin-1-yl)picolinamide;
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-(piperidin-1-yl)picolinamide;
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-(4-hydroxy-4-methylpiperidin-1-yl)picolinamide;
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-(4-methylpiperazin-1-yl)picolinamide; and
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-morpholinopicolinamide.

5. The compound of claim 1 , wherein:
R 1 is 1,1,1-trifluoropropan-2-yl;
R 2 , R 3 , R 4 and R 5 are all hydrogen; and
R 6 is cyclopropyl.

6. The compound of claim 5 , chosen from:
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-morpholino-N-(2-(4-(1,1,1-trifluoropropan-2yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(3-hydroxy-3-methylazetidin-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(dimethylamino)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-5-(azetidin-1-yl)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(pyrrolidin-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(3-hydroxypyrrolidin-1-yl)-N-(2-(4-((S)-1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(piperidin-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(4-hydroxy-4-methylpiperidin-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide; and
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-(4-methylpiperazin-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide.

7. A pharmaceutical composition comprising a compound according to claim 4 and at least one pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising a compound according to claim 6 and at least one pharmaceutically acceptable excipient.

Assignees

• Gilead Sciences Inc

Inventors

• Notte Gregory

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title