Soluble guanylate cyclase stimulators

Patent metadata

Field	Value
Publication number	US-10030027-B2
Application number	US-201615384429-A
Country	US
Kind code	B2
Filing date	Dec 20, 2016
Priority date	Dec 22, 2015
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The invention provides compounds of the Formula (I)

or a pharmaceutically acceptable salts thereof, wherein X, Y, Z, R 1 , R 2 , R 4 , R a , and the subscripts m, p, and q are as described herein. The compounds or their pharmaceutically acceptable salts can modulate 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 also provides pharmaceutical compositions which comprise compounds of Formula (I) or pharmaceutically acceptable salts thereof. The invention also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose.

First claim

The invention claimed is:

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
X is C(H) or N;
each R 1 is independently halo, hydroxy, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or —O—C 1 -C 3 alkyl;
R 2 is:
(a.) C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl of R 2 is unsubstituted or substituted by 1 to 6 moieties independently selected from fluoro or —O—C 1 -C 3 alkyl;
(b.) ring C 2 , wherein ring C 2 is:
(i.) C 3 -C 12 cycloalkyl;
(ii.) phenyl;
(iii.) a 5- or 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O, or S; or
(iv.) a 5- or 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N, O, or S;
wherein ring C 2 is unsubstituted or substituted by 1 to 3 moieties independently selected from halo, cyano, C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, or oxo;

R 4 is C 1 -C 6 alkyl, CF 3 , or C 3 -C 6 cycloalkyl;
ring C 3 is:
(a.) phenyl;
(b.) a 5- or 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms selected from N, O, or S;
(c.) a 5- or 6-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, O, or S; or
(d.) C 3 -C 6 cycloalkyl;
each R a is independently selected from halo, cyano, C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, oxo, or hydroxy;

Y is:
(a.) a bond;
(b.) a group of the formula

wherein R Y1 and R Y2 are independently H, C 1 -C 3 alkyl, hydroxy, fluoro, C 1 -C 3 hydroxyalkyl, or amino; or alternatively R Y1 and R Y2 , together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl;
R Y3 and R Y4 are independently H, C 1 -C 3 alkyl, hydroxy, fluoro, or C 1 -C 3 hydroxyalkyl; or alternatively R Y3 and R Y4 , together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl;

(c.) a group of the formula

(d.) ring A H , wherein ring A H is C 3 -C 6 cycloalkyl or phenyl, wherein ring A H is unsubstituted or substituted by 1 to 3 moieties independently selected from halo or C 1 -C 3 alkyl;
(e.) a group —CH═CH—; or
(f.) a group

Z is:
(a.) —CO 2 H; (b.) —C(O)N(H)OH;

(f.) —SO 3 H; (g.) —P(═O)(OH) 2 ; or (h.) —C(O)N(H)S(O) 2 CH 3 ;

the subscript m is 0, 1, or 2;
the subscript p is 0, 2, or 3;
the subscript q is 0 or 1;
the subscript r1 is 0, 1, 2, 3, or 4; and
the subscript r2 is 0 or 1.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof,
wherein:
ring C 3 is:
(a.) phenyl;
(b.) a 5- or 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms selected from N, O, or S;
(c.) a 5- or 6-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, O, or S; or
(d.) C 3 -C 6 cycloalkyl;

each R a is independently selected from halo, cyano, C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, or oxo;
Y is:
(a.) a bond;
(b.) a group of the formula

wherein R Y1 and R Y2 are independently H, C 1 -C 3 alkyl, hydroxy, fluoro, or C 1 -C 3 hydroxyalkyl; or alternatively R Y1 and R Y2 , together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl;
R Y3 and R Y4 are independently H, C 1 -C 3 alkyl, hydroxy, fluoro, or C 1 -C 3 hydroxyalkyl; or alternatively R Y3 and R Y4 , together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl;

(c.) a group of the formula

 or
(d.) ring A H , wherein ring A H is C 3 -C 6 cycloalkyl or phenyl, wherein ring A H is unsubstituted or substituted by 1 to 3 moieties independently selected from halo or C 1 -C 3 alkyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the subscript q is 1, and R 2 is C 2 -C 3 alkyl which is unsubstituted or substituted by 1 to 5 fluoro.

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the subscript q is 1;
R 2 is ring C 2 ;
ring C 2 is phenyl, cyclohexyl, adamantyl, pyridyl, or tetrahydropyranyl;
wherein ring C 2 is unsubstituted or independently substituted by 1 to 3 fluoro or methyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring C 3 is phenyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, or pyridyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof; wherein Y is the group of the formula

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is the group of the formula

8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
the subscript r1 is 1;
the subscript r2 is 0; and
R Y1 and R Y2 are independently H or C 1 -C 3 alkyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is (a.) —CO 2 H; (b.) —C(O)N(H)OH;

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein Z is
—CO 2 H.

11. The compound of claim 1 , wherein X is C(H).

12. The compound of claim 1 , wherein X is N.

13. The compound of claim 1 , wherein R 4 is methyl or cyclopropyl.

14. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the Formula (IA)

wherein
X is C(H) or N;
R 1 is methyl or halo;
C 3 is phenyl or thiazolyl;
R a is methyl, cyano, or halo;
R Y1 and R Y2 are independently H or methyl;
the subscript m is 0 or 1; and
the subscript p is 0 or 1.

15. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the Formula (IB)

wherein
X is C(H) or N;
R 1 is methyl or halo;
R 2 is ring C 2 , wherein ring C 2 is:
(i.) C 3 -C 12 cycloalkyl;
(ii.) phenyl;
(iii.) a 5- or 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O, or S; or
(iv.) a 5- or 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N, O, or S;
wherein ring C 2 is unsubstituted or substituted by 1 to 3 moieties independently selected from halo, cyano, C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, or oxo

C 3 is phenyl, thiaz

Assignees

• Merck Sharp & Dohme

Inventors

• Berger Raphaelle
• Chen Yi-Heng
• Li Guoqing
• Garfunkle Joie
• Li hong-dong
• Miao Shouwu
• Raghavan Subharekha
• Smith Cameron J
• Stelmach John
• Whitehead Alan
• Zhang Rui
• Zhang Yong
• Fu Jianmin
• Ji Gang
• Jiang Falong

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61K45/06

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

• 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