Carboxamide derivatives

Patent metadata

Field	Value
Publication number	US-9931319-B2
Application number	US-201615197091-A
Country	US
Kind code	B2
Filing date	Jun 29, 2016
Priority date	May 14, 2014
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;

a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

The invention claimed is:

1. A method of treating pulmonary arterial hypertension, fibrosis, rheumatoid arthritis, fracture healing, glaucoma, hereditary hemorrhagic telangiectasia, proteinuria, wound healing, COPD, or asthma, in a subject suffering from any one of pulmonary arterial hypertension, fibrosis, rheumatoid arthritis, fracture healing, glaucoma, hereditary hemorrhagic telangiectasia, proteinuria, wound healing, COPD, or asthma comprising: administering to said subject a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R 1 is (C 3 -C 6 )alkyl or (C 3 -C 6 )cycloalkyl;
R 2 is methyl;
R 3 is

R 4 and R 5 are independently selected from hydrogen, halo, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or —(C 1 -C 2 )alkyl(C 1 -C 2 )alkoxy; or
R 2 and R 4 may be taken together with the carbon atoms to which they are attached to form an azepine ring and R 5 is H;
R 6 is halo, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or —(C 1 -C 2 )alkyl(C 1 -C 2 )alkoxy;
OR

R 1 is 2-fluorophenyl;
R 2 is methyl; and
R 3 is phenyl, substituted with one or two substituents independently selected from chloro and cyclopropyl.

2. The method according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is iso-propyl, cyclobutyl or cyclohexyl.

3. The method according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexyl.

4. The method according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is

R 4 and R 6 are independently selected from chloro, fluoro, cyclopropyl, methyl, methoxy, trifluoromethoxy, trifluoromethyl; and
R 5 is hydrogen.

5. The method according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is

R 4 and R 6 are independently selected from chloro and cyclopropyl; and
R 5 is hydrogen.

6. The method according to claim 1 which is selected from the group consisting of:
1-(2-Chloro-4-methoxyphenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1-(2,4-dichlorophenyl)-5-methyl- 1H- 1,2,3 -triazole-4-carboxamide;
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1-(4-methoxy-2-(trifluoromethyl)phenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1-(4-methoxy-3-methylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(2-Chloro-4-(trifluoromethoxy)phenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(4-Chlorophenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,
1-(2,4-Dichlorophenyl)-N-(2-(2-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(4-Chlorophenyl)-N-(2-(2-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,
1-(2-Chloro-4-(trifluoromethoxy)phenyl)-N-(2-(2-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(2-Chloro-4-cyclopropylphenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(2-Chloro-4-cyclopropylphenyl)-N-(2-(2-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(2-Chloro-4-cyclopropylphenyl)-N-(2-cyclohexyl-1-methyl-d 3 ,5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(4-Chloro-2-cyclopropylphenyl)-N-(2-(2-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
1-(4-Chloro-2-cyclopropylphenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1-(2-cyclopropyl-4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide;
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-8-(trifluoromethoxy)-5,6-dihydro-4H-benzo[f][1,2,3]triazolo[1,5-a]azepine-3-carboxamide; and
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,
or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 wherein the disease or disorder is selected from pulmonary arterial hypertension (PAH), Fibrosis, Rheumatoid Arthritis, and Fracture healing.

8. The method according to claim 1 wherein the disease or disorder is selected from glaucoma, hereditary hemorrhagic telangiectasia (HHT), proteinuria, wound healing, COPD and asthma.

9. The method according to claim 1 , wherein the compound is 1-(2-chloro-4-cyclopropylphenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide having the following formula:

10. The method according to claim 1 , wherein the compound is 1-(2-Chloro-4-methoxyphenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide having the following formula:

11. The method according to claim 1 , wherein the compound is 1-(4-Chloro-2-cyclopropylphenyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide having the following formula:

Assignees

• Edwards Anne Marie
• Ahmed Mahbub
• Pulz Robert Alexander
• Rooney Lisa Ann
• Smith Nichola
• Troxler Thomas Josef
• Novartis Ag

Inventors

• Edwards Anne-Marie
• Ahmed Mahbub
• Pulz Robert Alexander
• Rooney Lisa Ann
• Smith Nichola
• Troxler Thomas Josef

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title