Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-10208018-B2
Application number	US-201515320810-A
Country	US
Kind code	B2
Filing date	Jul 2, 2015
Priority date	Jul 2, 2014
Publication date	Feb 19, 2019
Grant date	Feb 19, 2019

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

What is claimed is:

1. A compound according to Formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein
X is N;
Y is CH;
A is CH 2 , O or N(H);
R is hydrogen, C 1 -C 4 alkyl or trifluoromethyl;
R 1 is hydrogen, halogen or C 1 -C 4 alkyl;
R 2 is piperidinyl which is N-substituted with C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 4 alkyl, C(O)C 1 -C 4 alkyl, C(O)C 3 -C 6 cycloalkyl, C(O)haloC 1 -C 4 alkyl or C(O)C 1 -C 4 alkoxy;
R 3 is hydrogen or C 1 -C 4 alkyl;
R 4 is hydrogen or C 1 -C 4 alkyl and
R 5 is hydrogen, halogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.

2. The compound of claim 1 which is represented by the formula (Ib):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein Y is CH and A is N(H); or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 2 is N-substituted piperidin-4-yl wherein the N-substituent is 2,2,2-trifluoroethyl, C(O)cyclopropyl or C(O)C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R 1 is hydrogen or methyl; R 3 is hydrogen, methyl or ethyl, wherein at least one of R 1 or R 3 is hydrogen; and R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 1 is methyl; and R 3 and R 4 are hydrogen; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein R 1 and R 4 are hydrogen and R 3 is ethyl; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R is trifluoromethyl, methyl or ethyl; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R is trifluoromethyl; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein R is methyl or ethyl; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is a compound according to Formula (II):

Wherein
A is O, CH 2 or NH;
R is methyl, ethyl or trifluoromethyl;
R 6 is 2,2,2-trifluoroethyl, C(O)cyclopropyl or C(O)C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is a compound according to Formula (III):

Wherein
A is O or NH;
R is methyl, ethyl or trifluoromethyl;
R 6 is 2,2,2-trifluoroethyl, C(O)cyclopropyl or C(O)C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

13. The compound of claim 11 , wherein A is NH; R is methyl or ethyl; and R 6 is C(O)cyclopropyl or C(O)C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A compound of claim 1 , selected from the group consisting of: (−)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (+)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (±)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)-6-methyl-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (+)-(S)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (+)-(S)-1-(6-(3-(2-methyl-4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (+)-(S)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid; (+)-(S)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (+)-(S)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid; (+)-(S)-5-ethyl-1-(6-(3-(2-methyl-4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid; (+)-(S)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid; (+)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (−)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (−)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (+)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (−)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (+)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (−)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid; (+)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid; (±)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-6-methyl-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (±)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid; (±)-5-ethyl-1-(6-(3-((2-methyl-4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid; (+)-(S)-1-(6-(3-(4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (S)-1-(6-(3-(4-(1-(Ethoxycarbonyl)piperidin-4-yl)-3-ethylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid; (+)-1-(6-(3-(4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylbenzyl)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (−)-1-(6-(3-(4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylbenzyl)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; (−)-1-(6-(3-(4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-3-ethylbenzyl)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid; (+)-1-(6-(3-(4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-3-ethylbenzyl)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid; (−)-1-(6-(3-(4-(1-(Cyc

Assignees

• Adams Christopher M
• Bevan Doug
• Capparelli Michael Paul
• Ehara Takeru
• Ferrara Luciana
• Ji Nan
• Kato Mitsunori
• Mainolfi Nello
• Meredith Erik
• Mogi Muneto
• Powers James J
• Prasanna Ganesh
• Novartis Ag

Inventors

• Adams Christopher M
• Bevan Doug
• Capparelli Michael Paul
• Ehara Takeru
• Ferrara Luciana
• Ji Nan
• Kato Mitsunori
• Mainolfi Nello
• Meredith Erik
• Mogi Muneto
• Powers James J
• Prasanna Ganesh

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title