Methods for using triazolo-pyrazinyl soluble guanylate cyclase activators in fibrotic disorders

Patent metadata

Field	Value
Publication number	US-10925876-B2
Application number	US-201716301936-A
Country	US
Kind code	B2
Filing date	May 12, 2017
Priority date	May 18, 2016
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

Provided are methods for treating or preventing a fibrotic disease selected from systemic sclerosis, cystic fibrosis, non-alcoholic steatohepatitis, Peyronie's disease, or interstitial lung disease; the method comprising administering a therapeutically effective amount of a compound of Formula (I) (wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as herein described) or a pharmaceutically acceptable salt thereof, to a patient in need of such therapy.

First claim

What is claimed is:

1. A method for treating or preventing systemic sclerosis; the method comprising administering a therapeutically effective amount of a compound having structural Formula I:

or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, 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) hydroxyl.

2. The method of claim 1 , wherein 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 ;
in the compound administered to the patient.

3. The method of claim 2 , wherein R 3 is aryl unsubstituted or substituted by one, two, or three R 6 in the compound administered to the patient.

4. The method of claim 1 , 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 in the compound administered to the patient.

5. The method of claim 1 , wherein R 5 is hydroxyl in the compound administered to the patient.

6. The method of claim 5 , 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 in the compound administered to the patient.

7. The method of claim 1 , wherein the compound administered to the patient is:
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]pyrimidin-6(7H)-one,
4-amino-5-cyclopropyl-5-(5-fluoropyridin-3-yl)-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-3-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-chlorophenyl)-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-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
(12) 4-amino-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-(6-cyclopropylpyridin-3-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-(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-2-(8-(3,3,4,4,4-pentafluorobutyl)-[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-(6-(1,1-difluoroethyl)pyridin-3-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-cyclopropyl-5-(5-methylpyridin-2-yl)-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,
6-(4-amino-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile,
4-amino-5-methyl-5-(5-methylpyridin-2-yl)-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-(1-isopropyl-1H-1,2,3-triazol-4-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-cyclopropyl-5-(5-methylpyrazin-2-yl)-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-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-(trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,
4-amino-5-methyl-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-(4,4,4-trifluorobutyl)-[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-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin

Assignees

• Merck Sharp & Dohme

Inventors

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

Classifications

• C07D235/00

  Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings · CPC title

• C07D249/16

  condensed with carbocyclic rings or ring systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• A61P43/00

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