Cyclohexen-1-yl-pyridin-2-yl-1h-pyrazole-4-carboxylic acid derivatives and the use thereof as soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-9957254-B2
Application number	US-201515320815-A
Country	US
Kind code	B2
Filing date	Jul 2, 2015
Priority date	Jul 2, 2014
Publication date	May 1, 2018
Grant date	May 1, 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

What is claimed is:

1. A compound according to Formula (I)

Or a pharmaceutically acceptable salt thereof, wherein
n is 0 or 1;
X is N or CH;
Z is N(H), O or CH 2 ;
Z 1 is CR 4 or N;
R is hydrogen, C 1 -C 4 alkyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
R 1 is hydrogen, halogen, C 1 -C 4 alkyl or trifluoromethyl
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, S(O) 2 C 1 -C 4 alkyl, C(O)C 3 -C 6 cycloalkyl, C(O)haloC 1 -C 4 alkyl, C(O)C 1 -C 4 alkoxy, C(O)C 1 -C 4 alkenoxy, heteroaryl or CO(O) 2 benzyl, wherein each cycloalkyl is optionally substituted by hydroxy and each alkyl or alkoxy is optionally substituted by hydroxyl, C 1 -C 4 alkoxy or C 3 -C 6 cycloalkyl and wherein each heteroaryl has 5 or 6 ring atoms, 1, 2 or 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with 1 or 2 C 1 -C 4 alkyl substituents, which piperidinyl ring is further optionally substituted by hydroxyl;
R 3 is hydrogen, halogen or C 1 -C 4 alkyl; or
R 2 and R 3 , taken in combination, form a 5 or 6 member fused saturated azacyclic ring optionally substituted with benzyl or 5 or 6 member heteroarylmethyl, which heteroaryl has 1 or 2 ring heteroatoms independently selected from N, O and S;
R 4 is hydrogen or C 1 -C 4 alkyl;
R 5 and R 5a are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
R 5 and R 5a , taken in combination form a spirocyclic cyclopropyl ring; and
when n is 0, R 6 and R 6a are each hydrogen and when n is 1, R 6 and R 6a are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
R 6 and R 6a , taken in combination form a spirocyclic cyclopropyl ring.

2. A compound according to Formula (Ia)

Or a pharmaceutically acceptable salt thereof, wherein
X is N or CH;
Z is O or CH 2 ;
R is C 1 -C 4 alkyl or trifluoromethyl;
R 1 and R 4 are each independently selected from hydrogen, halogen or C 1 -C 4 alkyl; or
R 4 is haloC 1 -C 4 alkyl;
R 2 is piperidinyl which is N-substituted with C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C(O)C 1 -C 4 alkyl which is optionally substituted with hydroxyl or amino, C(O)C 3 -C 6 cycloalkyl, C(O)C 1 -C 4 alkoxy, C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , S(O) 2 C 1 -C 4 alkyl, S(O) 2 C 3 -C 6 cycloalkyl or C(O)heteroaryl which heteroaryl has 5 or 6 ring atoms and 1 or 2 ring heteroatoms independently selected from the group consisting of N, O and S;
R 3 is hydrogen or C 1 -C 4 alkyl; or
R 2 and R 3 , taken in combination form a 6 member fused saturated azacyclic ring optionally substituted with benzyl or 5, 6, 9 or 10 member heteroarylmethyl, which heteroaryl has 1 or 2 rings and 1 or 2 ring heteroatoms independently selected from N, O and S;
R 5 and R 5a are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
R 5 and R 5a , taken in combination form a spirocyclic cyclopropyl ring; and
R 6 and R 6a are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
R 6 and R 6a , taken in combination form a spirocyclic cyclopropyl ring.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is O.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is N-substituted piperidin-4-yl wherein the N-substituent is haloC 1 -C 4 alkyl, C(O)cyclopropyl, S(O) 2 cyclopropyl, S(O) 2 )C 1 -C 4 alkyl, C(O)cyclobutyl, C(O)N(C 1 -C 4 alkyl) 2 , C(O)C 1 -C 4 alkyl, C(O)C 1 -C 4 alkoxy or C(O)C 1 -C 4 alkyl substituted with hydroxyl or amino.

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is N-substituted piperidin-4-yl wherein the N-substituent is 2,2,2-trifluoroethyl, C(O)cyclopropyl, C(O)(1-hydroxyethyl), S(O) 2 ethyl, S(O) 2 cyclopropyl, C(O)ethyl, C(O)iso-propyl, C(O)N(methyl) 2 or C(O)N(ethyl) 2 .

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl and R 3 and R 4 are hydrogen.

7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 4 are hydrogen; and R 3 is ethyl.

8. The compound of claim 2 , wherein R 5 is methyl and R 5a , R 6 and R 6a are hydrogen; or R 6 is methyl and R 5 , R 5a and R 6a are hydrogen.

9. The compound of claim 2 , wherein R 5 and R 5a are methyl, or R 5 and R 5a , taken in combination form a spirocyclic cyclopropyl ring; and R 6 and R 6a are hydrogen.

10. The compound of claim 2 , wherein R is methyl or ethyl.

11. The compound of claim 2 , wherein R is trifluoromethyl.

12. The compound of claim 2 , wherein X is N.

13. A pharmaceutical composition comprising a compound of claim 2 , or a salt thereof, and a pharmaceutically acceptable excipient.

14. A method of treating glaucoma and controlling intraocular pressure comprising: applying a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof to an affected eye of a patient in need of said treatment.

15. A compound according to claim 1 which is 1-(6-(2-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)methyl)-3-methylcyclohex-1-en-1-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxy c acid having the following formula:

or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 1 which is 1-(6-(2-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)methyl)-3-methylcyclohex-1-en-1-yl)pyridin-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid having the following formula:

or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1 which is 1-(6-(2-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)methyl)-3-methylcyclohex-1-en-1-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid having the following formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• Adams Christopher M
• Belanger David B
• Bevan Doug
• Bolduc Philippe
• Ehara Takeru
• Ferrara Luciana
• Ji Nan
• Kato Mitsunori
• Meredith Erik
• Mogi Muneto
• Powers James J
• Prasanna Ganesh
• Novartis Ag

Inventors

• Adams Christopher M
• Belanger David B
• Bevan Doug
• Bolduc Philippe
• Ehara Takeru
• Ferrara Luciana
• Ji Nan
• Kato Mitsunori
• 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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/4545

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