Imidazo-pyrazine derivatives useful as soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-9796733-B2
Application number	US-201515315428-A
Country	US
Kind code	B2
Filing date	May 29, 2015
Priority date	Jun 4, 2014
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

A compound of Formula II 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 II, 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 II 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-(C 3-7 )cycloalkyl,
(5) (C 1-6 )alkyl-aryl, wherein aryl is unsubstituted or substituted by cyano, (C 3-6 )cycloalkyl, (C 1-6 )alkoxy, or one to three halo,
(6) aryl unsubstituted or substituted by cyano, (C 3-6 )cycloalkyl, (C 1-6 )alkoxy, or one to three halo, or
(7) (C 3-6 )cycloalkyl;

R 2 is
(1) (C 1-6 )alkyl,
(2) (C 1-6 )alkoxy, or
(3) (C 3-7 )cycloalkyl;

R 3 is
(1) (C 1-6 )alkyl,
(2) (C 3-6 )cycloalkyl,
(3) CO 2 (C 1-6 )alkyl,
(4) CONR 6a R 6b ,
(5) —N(H)C(O)(C 1-6 )alkyl,
(6) —N(H)(C 1-6 )alkyl,
(7) aryl unsubstituted or substituted by (C 1-6 )alkyl, halo(C 1-3 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkoxy, (C 3-6 )cycloalkyl, CO 2 (C 1-6 )alkyl, CONR 6a R 6b , or one to three halo,
(8) five- or six-membered heteroaryl containing one to three N, O or S heteroatoms, wherein heteroaryl is unsubstituted or substituted by one to two (C 1-6 )alkyl, halo(C 1-6 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkoxy, (C 3-6 )cycloalkyl or halo, or
(9) (C 2-6 )alkynyl,

R 4 is
(1) hydrogen,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) halo(C 1-6 )alkoxy,
(5) (C 1-6 )alkoxy,
(6) (C 3-7 )cycloalkyl, or
(7) cyano;

R 5 is
(1) hydrogen,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) halo,
(5) amino,
(6) (C 1-3 )alkyl-aryl,
(7) (C 1-3 )alkyl-(C 3-6 )cycloalkyl, or
(8) cyano;

each R ha and R 6b are independently
(1) hydrogen,
(2) (C 1-3 )alkyl, or
(3) (C 3-6 )cycloalkyl;

R 8a and R 8b are independently
(1) hydrogen,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) (C 1-6 )alkyl-C(O)—O—(C 1-6 )alkyl,
(5) (C 3-6 )cycloalkyl, unsubstituted or substituted by halo, or
(6) (C 1-3 )alkyl-(C 3-6 )cycloalkyl;

or R 8a and R 8b along with the nitrogen atom to which they are attached cyclize to form a 4- to 6-membered heterocyclyl containing one or two heteroatoms independently selected from N, O and S, wherein the heterocyclyl is unsubstituted or substituted by one to three R 9 ; and
R 9 is
(1) (C 1-3 )alkyl,
(2) halo,
(3) halo(C 1-3 )alkyl,
(4) (C 3-6 )cycloalkyl, or
(5) —S(O) 2 —(C 1-3 )alkyl.

2. A compound having structural Formula II:

or a pharmaceutically acceptable salt thereof wherein
R 1 is
(1) hydrogen,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) (C 1-6 )alkyl-(C 3-7 )cycloalkyl,
(5) (C 1-6 )alkyl-aryl, wherein aryl is unsubstituted or substituted by cyano, (C 3-6 )cycloalkyl, (C 1-6 )alkoxy, or one to three halo,
(6) aryl unsubstituted or substituted by cyano, (C 3-6 )cycloalkyl, (C 1-6 )alkoxy, or one to three halo, or
(7) (C 3-6 )cycloalkyl;

R 2 is
(1) (C 1-6 )alkyl,
(2) (C 1-6 )alkoxy, or
(3) (C 3-7 )cycloalkyl;

R 3 is
(1) (C 1-6 )alkyl,
(2) (C 3-6 )cycloalkyl,
(3) CO 2 (C 1-6 )alkyl,
(4) CONR 6a R 6b ,
(5) —N(H)C(O)(C 1-6 )alkyl,
(6) —N(H)(C 1-6 )alkyl,
(7) aryl unsubstituted or substituted by (C 1-6 )alkyl, halo(C 1-3 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkoxy, (C 3-6 )cycloalkyl, CO 2 (C 1-6 )alkyl, CONR 6a R 6b , or one to three halo,
(8) five- or six-membered heteroaryl containing one to three N, O or S heteroatoms, wherein heteroaryl is unsubstituted or substituted by one to two (C 1-6 )alkyl, halo(C 1-6 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkoxy, (C 3-6 )cycloalkyl or halo, or
(9) (C 2-6 )alkynyl,

R 4 is
(1) hydrogen,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) halo(C 1-6 )alkoxy,
(5) (C 1-6 )alkoxy,
(6) (C 3-7 )cycloalkyl, or
(7) cyano;

R 5 is
(1) hydrogen,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) halo,
(5) amino,
(6) (C 1-3 )alkyl-aryl,
(7) (C 1-3 )alkyl-(C 3-6 )cycloalkyl, or
(8) cyano; and

each R 6a and R 6b are independently
(1) hydrogen,
(2) (C 1-3 )alkyl, or
(3) (C 3-6 )cycloalkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: R 3 is (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 2-6 )alkynyl or CONR 6a R 6b .

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein: R 3 is

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein: R 2 is methyl, ethyl, isopropyl or cyclopropyl.

6. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein:

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is aryl unsubstituted or substituted by (C 1-6 )alkyl, halo(C 1-3 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkoxy, (C 3-6 )cycloalkyl, CO 2 (C 1-6 )alkyl, CONR 6a R 6b , or one to three halo; or five- or six-membered heteroaryl containing one to three N, O or S heteroatoms, wherein heteroaryl is unsubstituted or substituted by one to two (C 1-6 )alkyl, halo(C 1-6 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkoxy, (C 3-6 )cycloalkyl or halo.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R 3 is

9. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein: R 2 is methyl, ethyl, isopropyl or cyclopropyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: R 1 is (C 1-6 )alkyl or halo(C 1-6 )alkyl.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein: R 2 is methyl, ethyl, isopropyl or cyclopropyl.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein: R 1 (C 1-3 )alkyl-aryl, wherein aryl is unsubstituted or substituted by cyano, (C 3-6 )cycloalkyl, (C 1-3 )alkoxy, or one to three fluoro.

13. The compound of claim 11 or a pharmaceutically acceptable salt thereof wherein: R 2 is methyl, ethyl, isopropyl or cyclopropyl.

14. The compound of claim 1 , which is:
4-Amino-5-(4-chlorophenyl)-2-(8-ethylimidazo[1,2-a]pyrazin-6-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-Amino-5-(4-chlorophenyl)-5-methyl-2-(8-propylimidazo[1,2-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-amino-2-(8-(2-fluorophenethyl)imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-amino-2-(8-(3-fluorophenethyl)imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
6-(4-amino-5-(4-4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-(3-phenylpropyl)imidazo[1,2-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-amino-2-(8-(4-cyclopropylphenyl)imidazo[1,2-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one;
4-amino-5-(4-fluorophenyl)-2-(8-(4-methoxyphen

Assignees

• Merck Sharp & Dohme

Inventors

• Campbell Brian T
• Dong Guizhen
• Garfunkle Joie
• Kim Alexander
• Ornoski Olga
• Parker Jr Dann L
• Raghavan Subharekha
• Xu Libo
• Yang Zhiquang

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D519/00 Primary

  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

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/519

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