Thiophen-2-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-9765067-B2
Application number	US-201515320813-A
Country	US
Kind code	B2
Filing date	Jul 2, 2015
Priority date	Jul 2, 2014
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

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
X is N or CH;
Z 1 is N or CR 1 ;
Z 2 is N or CH;
Z 4 is N or CR 4 ,
A is CHR A or O, wherein R A is hydrogen or C 1 -C 4 alkyl;
B is CHR A , O or N(H); wherein one or both of A and B is CHR A ;
R is hydrogen, C 1 -C 4 alkyl, monofluoromethyl, difluoromethyl 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)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , S(O) 2 C 1 -C 4 alkyl, C(O)C 3 -C 6 cycloalkyl, heterocycle, C(O)heterocycle, 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, C 3 -C 6 cycloalkyl or heterocycle, wherein each heterocycle has 4, 5 or 6 ring atoms and 1 or 2 ring oxygen atoms and which heterocycle is optionally substituted with 1 or 2 C 1 -C 4 alkyl or hydroxy substituents 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, and wherein the piperidinyl is optionally further substituted by hydroxy or by 1-4 independently selected C 1 -C 4 alkyl groups;
R 3 is hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, hydroxymethyl or C 1 -C 4 alkoxy, 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, halogen, C 1 -C 4 alkyl, hydroxylmethyl, haloC 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 5 is hydrogen, C 1 -C 4 alkyl, trifluoromethyl, halogen or C 3 -C 6 cycloalkyl; and
R 6 is hydrogen, C 1 -C 4 alkyl, halogen or C 3 -C 6 cycloalkyl.

2. The compound of claim 1 , wherein Z 1 is N, Z 2 is CH and Z 4 is CR 4 .

3. The compound of claim 1 , wherein Z 1 is CR 1 , Z 2 is CH and Z 4 is N.

4. The compound of claim 1 , wherein Z 1 is CR 1 , Z 2 is N and Z 4 is CR 4 .

5. A compound according to Formula (Ia)

Or a pharmaceutically acceptable salt thereof, wherein
X is N or CH;
A is CHR A or O, wherein R A is hydrogen or C 1 -C 4 alkyl;
B is CHR A , O or N(H); wherein one or both of A and B is CHR A ; or
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 or C 1 -C 4 alkoxy;
R 2 is piperidinyl which is N-substituted with C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl-C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C(O)C 1 -C 4 alkyl, which alkyl is optionally substituted with hydroxyl or amino, C(O)C 1 -C 4 alkyl, C(O)C 3 -C 6 cycloalkyl, which cycloalkyl is optionally substituted by hydroxy, C(O)CH 2 —C 3 -C 6 cycloalkyl C(O)haloC 1 -C 4 alkyl, C(O)heterocycle, C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , C(O)C 1 -C 4 alkoxy, wherein the piperidinyl is optionally further substituted by hydroxy or by 1-4 independently selected C 1 -C 4 alkyl groups and wherein the heterocycle is a 4 to 6 member saturated ring having 1 or 2 ring oxygen atoms and substituted with 0, 1, or 2 C 1 -C 4 alkyl groups;
R 3 is hydrogen, halogen, C 1 -C 4 alkyl, hydroxymethyl or C 1 -C 4 alkoxy; 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 is hydrogen, C 1 -C 4 alkyl, halogen or C 3 -C 6 cycloalkyl, and
R 6 is hydrogen, C 1 -C 4 alkyl, halogen or C 3 -C 6 cycloalkyl.

6. The compound of claim 5 , wherein R 2 is N-substituted piperidin-4-yl wherein the N-substituent is C(O)cyclopropyl, C(O)C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, or C(O)C 1 -C 4 alkoxy.

7. The compound of claim 5 , 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.

8. The compound of claim 5 , wherein R 1 is methyl and R 3 and R 4 are hydrogen.

9. The compound of claim 5 , wherein R 1 and R 4 are hydrogen and R 3 is ethyl.

10. The compound of claim 5 , wherein R 1 and R 4 are hydrogen and R 3 is methoxy.

11. The compound of claim 5 , wherein R 1 and R 3 are hydrogen and R 4 is methoxy.

12. The compound of claim 5 , wherein R is trifluoromethyl, methyl or ethyl.

13. The compound of claim 5 , wherein R is methyl or ethyl.

14. The compound of claim 5 , wherein R is trifluoromethyl.

15. The compound of claim 5 , wherein R 5 is hydrogen, C 1 -C 4 alkyl, cyclopropyl or trifluoromethyl and R 6 is hydrogen, C 1 -C 4 alkyl, cyclopropyl or chloro.

16. The compound of claim 5 , wherein
A is CH 2 ;
B is O or N(H);
R is methyl or ethyl;
R 1 is methyl;
R 2 is N-substituted piperidin-4-yl wherein the N-substituent is C(O)cyclopropyl, 2,2,2-trifluoroethyl or C(O)C 1 -C 4 alkyl;
R 3 is hydrogen, methyl, ethyl or methoxy;
R 4 is hydrogen;
R 5 is hydrogen, methyl, ethyl or trifluoromethyl; and R 6 is hydrogen, methyl, cyclopropyl or chloro, wherein at least one of R 5 or R 6 is not hydrogen.

17. A pharmaceutical composition comprising a compound of claim 5 , or a salt thereof, and a pharmaceutically acceptable excipient.

18. An ophthalmic pharmaceutical composition useful in the treatment of glaucoma and control of intraocular pressure comprising: an effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.

19. A method of treating glaucoma and controlling intraocular pressure comprising: applying a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof to an affected eye of a patient.

Assignees

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

Inventors

• Adams Christopher M
• Belanger David B
• Bevan Doug
• Ehara Takeru
• Ferrara Luciana
• Ji Nan
• Liu Donglei
• Meredith Erik
• Mogi Muneto
• Powers James
• Prasanna Ganesh
• Kato Mitsunori

Classifications

• A61P43/00

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

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/4439

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

• A61K9/0048

  Eye, e.g. artificial tears · CPC title