Soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-9783552-B2
Application number	US-201415103148-A
Country	US
Kind code	B2
Filing date	Dec 5, 2014
Priority date	Dec 11, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 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 preparations 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:
X 1 and X 2 are each independently CR or N;
R is —H, halo or cyclopropyl;
R 1 is —H or —C 1-6 alkyl unsubstituted or substituted with one to three of —F;
R 2 is (a) —C 1-6 alkyl unsubstituted or substituted with
(i) one to six of —F,
(ii) —C 3-6 cycloalkyl unsubstituted or substituted with one to three of —F or
(iii) phenyl unsubstituted or independently substituted at each occurrence with one to three of halo, —CN, —CH 3 or —OCH 3 ,

 (b) —C 3-6 cycloalkyl unsubstituted or substituted with one to three of —F, or
 (c) phenyl unsubstituted or independently substituted at each occurrence with one to three of halo, —CN, —CH 3 or —OCH 3 ;
R 2a is —H or —C 1-3 alkyl unsubstituted or substituted with one to three of —F;
R 2b is —H or —C 1-3 alkyl unsubstituted or substituted with one to three of —F;
or R 2b is —H and R 2 and R 2a are joined together with the carbon to which they are both attached to represent
(a) —C 3-6 cycloalkyl unsubstituted or substituted with one to three of —F, or
(b) a 4 to 6 membered heterocycle comprised of carbons and one or two heteroatoms independently selected from N, O or S, wherein the heterocycle is unsubstituted or independently substituted at each occurrence with one to three of halo, —CN, —CH 3 or —OCH 3 ;

R 3 is —C 1-6 alkyl or —C 3-6 cycloalkyl;
R 4 is (a) —C 1-6 alkyl,
(b) —OC 1-6 alkyl
(c) —C 2-6 alkynyl,
(d) —C 3-6 cycloalkyl,
(e) —COO—C 1-6 alkyl
(f) —NHR a ,
(g) —NH—C(O)—R a ,
(h) —C(O)NHR a ,
(i) —CN,
(j) phenyl unsubstituted or substituted with one to three substituents independently selected at each occurrence from halo, —C 1-6 alkyl, —OC 1-6 alkyl, —OH or —CN; or
(k) phenyl substituted with a 5 or 6 membered heteroaryl comprised of carbon atoms, one to three of N, and zero or one of O, wherein the heteroaryl is unsubstituted or substituted with —C 1-3 alkyl;

R a is (a) —H, (b) —C 1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from —OH, one to three of —F,
(c) —C 1-3 alkyl-C 3-6 cycloalkyl, (d) —C 3-6 cycloalkyl, or (e) a 5 or 6 membered heteroaryl comprised of carbon atoms and one to three heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with —C 1-3 alkyl;

R 5 is —H, —OR 6 or —NHR 6 ; and
R 6 is —H, —C 1-6 alkyl or —C 3-6 cycloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: X 1 and X 2 are each independently CH or N,
R 1 is —H or —C 1-3 alkyl;
R 3 is —C 1-6 alkyl or —C 3-6 cycloalkyl; and
R 5 is —H, —OH or —NH 2 .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
X 1 and X 2 are each independently CH or N,
R 1 is —H or —C 1-3 alkyl;
R 2 is (a) —C 1-6 alkyl substituted with
(i) one to six of —F,
(ii) —C 3-6 cycloalkyl substituted with one to three of —F or
(iii) phenyl substituted with one to three of —F,

 (b) —C 3-6 cycloalkyl substituted with one to three of —F, or
 (c) phenyl substituted with one to three of —F;
R 3 is —C 1-6 alkyl or —C 3-6 cycloalkyl;
R 4 is (a) —C 1-6 alkyl,
(b) —OC 1-6 alkyl
(c) —C 2-3 alkynyl,
(d) —C 3-6 cycloalkyl,
(e) —COO—C 1-3 alkyl,
(f) —NHR a ,
(g) —NH—C(O)—R a ,
(h) —C(O)NHR a ,
(i) —CN,
(j) phenyl unsubstituted or substituted with one to three substituents independently selected at each occurrence from halo, —C 1-3 alkyl, —OC 1-3 alkyl, —OH or —CN; or
(k) phenyl substituted with a 5 or 6 membered heteroaryl comprised of carbon atoms, one to three of N, and zero or one of O, wherein the heteroaryl is unsubstituted or substituted with —C 1-3 alkyl;

R a is (a) —H,
(b) —C 1-6 alkyl unsubstituted or substituted with one or more substituents independently selected from —OH and one to three of —F,
(c) —C 1-3 alkyl-C 3-6 cycloalkyl,
(d) —C 3-6 cycloalkyl, or
(e) 5 or 6 membered heteroaryl comprised of carbon atoms and one to three of N, wherein the heteroaryl is unsubstituted or substituted with —C 1-3 alkyl; and

R 5 is —H, —OH or —NH 2 .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is
(a) —C 1-6 alkyl substituted with
(i) one to six of —F,
(ii) —C 3-6 cycloalkyl substituted with one to three of —F, or
(iii) phenyl substituted with one to three of —F,

(b) —C 3-6 cycloalkyl substituted with one to three of —F, or
(c) phenyl substituted with one to three of —F.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein is R 3 is —C 1-3 alkyl or cyclopropyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein is R 4 is
(a) —C 1-4 alkyl,
(b) —OC 1-4 alkyl,
(c) —C 2-3 alkynyl,
(d) —C 3-6 cycloalkyl,
(e) —COO—C 1-3 alkyl
(f) —NHR a ,
(g) —NH—C(O)—R a ,
(h) —C(O)NHR a ,
(i) —CN,
(j) phenyl unsubstituted or substituted with one to three substituents independently selected at each occurrence from —F, —Br, —C 1-3 alkyl, —OC 1-3 alkyl, —OH or —CN; or
(k) phenyl substituted with pyridyl, oxadiazolyl or pyrazolyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R a is (a) —H, (b) —C 1-4 alkyl unsubstituted or substituted with one or more substituents independently selected from —OH and one to three of —F, (c) —CH 2 —C 3-6 cycloalkyl, (d) —C 3-6 cycloalkyl, or (e) a heteroaryl which is pyridyl or pyrazolyl, wherein the heteroaryl is unsubstituted or substituted with —C 1-3 alkyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is —H, —CH 3 , —CD 3 , —CH 2 CH 3 or -CD 2 CD 3 .

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 is —NH 2 .

10. The compound of claim 1 , having the structural Formula Ia or a pharmaceutically acceptable salt thereof:

11. The compound of claim 1 , having the structural Formula Ib or a pharmaceutically acceptable salt thereof:

12. The compound of claim 1 , which is:
4-Amino-5-methyl-2-(1-methyl-6-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-5-(4-fluorophenyl)-5-methyl-2-(6-(3,3,4,4,4-pentafluorobutyl)-1-trideuteriomethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-5-methyl-2-(1-methyl-6-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-5-methyl-2-(1-methyl-6-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-2-(6-((3,3-difluorocyclobutyl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-2-(6-(2,3-difluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-2-(1-ethyl-6-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-methyl-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-5-(4-fluorophenyl)-5-methyl-2-(6-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;

Assignees

• Merck Sharp & Dohme

Inventors

• Han Xiaoqing
• Whitehead Alan
• Raghavan Subharekha
• Cernak Timothy A
• Dreher Spencer
• Groeper Jonathan
• Guo Jian
• Zhang Yong

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/519

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