Apoptosis signal-regulating kinase inhibitors

Patent metadata

Field	Value
Publication number	US-RE48150-E
Application number	US-201715397344-A
Country	US
Kind code	E1
Filing date	Jan 3, 2017
Priority date	Jul 2, 2010
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

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

wherein X 1 , X 2 , X 3 , X 4 , X 5 , R , R 1 , R 2 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.

The invention also relates to pharmaceutical compositions comprising one or more of the compounds of Formula (I), and to methods of preparing the compounds of Formula (I).

First claim

What is claimed is:

1. A compound selected from the group consisting of:
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-(4,4,4-trifluoro-3-hydroxybutan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-(3-methylbutan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-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;
4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
(S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-methyl-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide; and
(S)-4-(4-tert-butyl-1H-imidazol-1-yl)-5-methyl-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide;
or a pharmaceutically acceptable salt thereof.

2. The compound selected from the group consisting of:
6-cyclopropyl-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-3,4′-bipyridine-2′-carboxamide;
N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-3,4′-bipyridine-2′-carboxamide;
4-(4-cyclopropyl-H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-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-methylpicolinamide;

or a pharmaceutically acceptable salt thereof.

3. The compound selected from the group consisting of:
4-(1H-benzo[d]imidazol-1-yl)-N-(4-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)picolinamide;
N-(4-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)-3,4′-bipyridine-2′-carboxamide; and
N-(4-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)-6-methoxy-3,4′-bipyridine-2′-carboxamide;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising an a therapeutically effective amount of one or more compounds according to claim 1 and a pharmaceutically acceptable excipient.

5. A pharmaceutical composition comprising an a therapeutically effective amount of one or more compounds according to claim 2 and a pharmaceutically acceptable excipient.

6. A pharmaceutical composition comprising an a therapeutically effective amount of one or more compounds according to claim 3 and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 4, wherein the therapeutically effective amount is from 1 mg to 2 g.

8. The pharmaceutical composition of claim 5, wherein the therapeutically effective amount is from 1 mg to 2 g.

9. The pharmaceutical composition of claim 6, wherein the therapeutically effective amount is from 1 mg to 2 g.

Assignees

• Gilead Sciences Inc

Inventors

• Corkey Britton
• Notte Gregory
• Zablocki Jeff

Classifications

• A61K31/4427

  containing further heterocyclic ring systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D409/14 Primary

  containing three or more hetero rings · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title