Soluble guanylate cyclase stimulators

Patent metadata

Field	Value
Publication number	US-2018305366-A1
Application number	US-201816019964-A
Country	US
Kind code	A1
Filing date	Jun 27, 2018
Priority date	Dec 22, 2015
Publication date	Oct 25, 2018
Grant date	—

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

1 - 20 . (canceled)

21 . A method for treating a condition selected from cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, heart failure, pulmonary hypertension (WHO groups I, II, III, IV), angina pectoris, thrombosis, restenosis, myocardial infarction, stroke, cardiac insufficiency, fibrosis, pulmonary hypertonia, erectile dysfunction, asthma, acute respiratory distress syndrome (ARDS), chronic kidney disease, cystic fibrosis, sickle cell anemia, scleroderma, Raynaud's Syndrome, diabetes, diabetic retinopathy, cirrhosis of the liver, chronic obstructive pulmonary disease (COPD), acute lung injury, pulmonary fibrosis, or interstitial lung disease, comprising administering a therapeutically effective amount of a compound of the Formula (I)

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; (c.)

 (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, 1, 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,

or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

22 - 25 . (canceled)

26 . The method of claim 21 , wherein the condition is pulmonary hypertension (WHO groups I, II, III, IV).

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

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · 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

• 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P9/12

  Antihypertensives · CPC title