Triazolo-pyrazinyl derivatives useful as soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-9822130-B2
Application number	US-201514945576-A
Country	US
Kind code	B2
Filing date	Nov 19, 2015
Priority date	Nov 21, 2014
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

A compound of Formula I

or a pharmaceutically acceptable salt thereof, are capable of modulating the body's production of cyclic guanosine monophosphate (“cGMP”) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of Formula I, or a pharmaceutically acceptable salt thereof, for their use in the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical compositions which comprise compounds of Formula I or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein
C* indicates a potential chiral carbon atom;
R 1 is
(1) hydrogen
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) (C 1-6 )alkyl-O—,
(5) halo(C 1-6 )alkyl-O—,
(6) (C 1-6 )alkyl-NH—,
(7) halo(C 1-6 )alkyl-NH—,
(8) —(C 1-3 )alkyl-(C 3-7 )cycloalkyl,
(9) —(C 1-3 )alkyl-aryl, wherein aryl is unsubstituted or substituted by one, two, or three R 7 ,
(10) aryl unsubstituted or substituted by one, two, or three R 7 ,
(11) (C 3-7 )cycloalkyl, or
(12) —(C 1-3 )alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of N, O, and S, and wherein heteroaryl is unsubstituted or substituted by one, two, or three R 7 ;

R 2 is
(1) (C 1-3 )alkyl, or
(2) (C 3-7 )cycloalkyl;

R 3 is
(1) aryl unsubstituted or substituted by one, two, or three R 6 ,
(2) five- or six-membered heteroaryl containing one, two, or three heteroatoms independently selected from N, O and S, wherein heteroaryl is unsubstituted or substituted by one, two, or three R 6 ,
(3) (C 1-3 )alkyl, or
(4) (C 3-7 )cycloalkyl;

R 4 is
(1) hydrogen,
(2) (C 1-3 )alkyl,
(3) halo(C 1-3 )alkyl, or
(4) (C 3-7 )cycloalkyl;

R 5 is
(1) hydrogen,
(2) hydroxy,
(3) —N(R 8a )(R 8b ),
(4) —COOH,
(5) —C(O)NH 2 ,
(6) (C 1-3 )alkyl,
(7) (C 3-7 )cycloalkyl, or
(8) four- to six-membered monocyclic heterocyclyl containing 1 N heteroatom, wherein the heterocyclyl is unsubstituted or substituted by one to two R 9 ;

each R 6 is independently
(1) (C 1-3 )alkyl,
(2) halo(C 1-3 )alkyl,
(3) (C 1-3 )alkoxy,
(4) halo(C 1-3 )alkoxy,
(5) (C 3-7 )cycloalkyl, unsubstituted or substituted by halo,
(6) halo,
(7) cyano,
(8) hydroxy,
(9) —NH 2 ,
(10) —(C 1-3 )alkyl-COOH, or
(11) —(C 1-3 )alkyl-COO(C 1-4 )alkyl;

each R 7 is independently
(1) (C 1-3 )alkoxy,
(2) halo,
(3) hydroxy, or
(4) (C 1-3 )alkyl;

R 8a and R 8b are independently
(1) hydrogen,
(2) (C 1-3 )alkyl, or
(3) (C 3-7 )cycloalkyl; and

R 9 is
(1) (C 1-3 )alkyl,
(2) halo(C 1-3 )alkyl, or
(3) hydroxy.

2. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein
C* indicates a potential chiral carbon atom;
R 1 is
(1) hydrogen
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) (C 1-6 )alkyl-O—,
(5) halo(C 1-6 )alkyl-O—,
(6) (C 1-6 )alkyl-NH—,
(7) halo(C 1-6 )alkyl-NH—,
(8) —(C 1-3 )alkyl—(C 3-7 )cycloalkyl,
(9) —(C 1-3 )alkyl-aryl, wherein aryl is unsubstituted or substituted by one, two, or three R 7 ,
(10) aryl unsubstituted or substituted by one, two, or three R 7 ,
(11) (C 3-7 )cycloalkyl, or
(12) —(C 1-3 )alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of N, O, and S, and wherein heteroaryl is unsubstituted or substituted by one, two, or three R 7 ;

R 2 is
(1) (C 1-3 )alkyl, or
(2) (C 3-7 )cycloalkyl;

R 3 is
(1) aryl unsubstituted or substituted by one, two, or three R 6 , or
(2) five- or six-membered heteroaryl containing one, two, or three heteroatoms independently selected from N, O and S, wherein heteroaryl is unsubstituted or substituted by one, two, or three R 6 ;

R 4 is
(1) hydrogen,
(2) (C 1-3 )alkyl,
(3) halo(C 1-3 )alkyl, or
(4) (C 3-7 )cycloalkyl;

R 5 is
(1) hydrogen,
(2) hydroxy,
(3) —N(R 8a )(R 8b ),
(4) —COOH,
(5) —C(O)NH 2 ,
(6) (C 1-3 )alkyl,
(7) (C 3-7 )cycloalkyl, or
(8) four- to six-membered monocyclic heterocyclyl containing 1 N heteroatom, wherein the heterocyclyl is unsubstituted or substituted by one to two R 9 ;

each R 6 is independently
(1) (C 1-3 )alkyl,
(2) halo(C 1-3 )alkyl,
(3) (C 1-3 )alkoxy,
(4) halo(C 1-3 )alkoxy,
(5) (C 3-7 )cycloalkyl, unsubstituted or substituted by halo,
(6) halo,
(7) cyano,
(8) hydroxy,
(9) —NH 2 ,
(10) —(C 1-3 )alkyl-COOH, or
(11) —(C 1-3 )alkyl-COO(C 1-4 )alkyl;

each R 7 is independently
(1) (C 1-3 )alkoxy,
(2) halo,
(3) hydroxy, or
(4) (C 1-3 )alkyl;

R 8a and R 8b are independently
(1) hydrogen,
(2) (C 1-3 )alkyl, or
(3) (C 3-7 )cycloalkyl; and

R 9 is
(1) (C 1-3 )alkyl,
(2) halo(C 1-3 )alkyl, or
(3) hydroxy.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: R 3 is aryl unsubstituted or substituted by one, two, or three R 6 .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: R 5 is —N(R 8a )(R 8b ).

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: R 1 is (C 1-6 )alkyl, halo(C 1-6 )alkyl, or —(C 1-3 )alkyl-aryl, wherein aryl is unsubstituted or substituted by one, two, or three R 7 .

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is hydroxy.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein: R 1 is (C 1-6 )alkyl, halo(C 1-6 )alkyl, or —(C 1-3 )alkyl-aryl, wherein aryl is unsubstituted or substituted by one, two, or three R 7 .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is five- or six-membered heteroaryl containing one, two, or three heteroatoms independently selected from the group consisting of N, O and S, wherein heteroaryl is unsubstituted or substituted by one, two, or three R 6 .

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein: R 5 is —N(R 8a )(R 8b ).

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof wherein: R 1 is (C 1-6 )alkyl, halo(C 1-6 )alkyl, or —(C 1-3 )alkyl-aryl, wherein aryl is unsubstituted or substituted by one, two, or three R 7 .

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R 5 is hydroxy.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof wherein: R 1 is (C 1-6 )alkyl, halo(C 1-6 )alkyl, or —(C 1-3 )alkyl-aryl, wherein aryl is unsubstituted or substituted by one, two, or three R 7 .

13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H )-one,
4-amino-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-(5-chloropyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-cyclopropyl-5-(3,4-difluorophenyl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]

Assignees

• Merck Sharp & Dohme

Inventors

• Berger Raphaelle
• Dong Guizhen
• Raghavan Subharekha
• Yang Zhiqiang

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title