Soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-9365574-B2
Application number	US-201113699046-A
Country	US
Kind code	B2
Filing date	May 24, 2011
Priority date	May 27, 2010
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

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:

or a pharmaceutically acceptable salt thereof, wherein

is a heteroaryl selected from

where * indicates attachment to the pyrimidinyl ring and ** indicates attachment to the —CH 2 —R 2 of structural Formula I;
Each X 1 , X 2 , X 3 and X 4 is independently N or CH, provided that no more than two of X 1 , X 2 , X 3 and X 4 is N;
Each R x and R y are independently H, C 3-10 cycloalkyl, or —C 1 -C 6 alkyl;
Each R 1 is independently —H, halo, OR, —C 1 -C 6 alkyl, aryl, heterocyclyl, heteroaryl, —C 3-10 cycloalkyl, —CN, —NR a C(O)R b , or —C(O)NR a R b , said aryl, heteroaryl, and cycloalkyl optionally being substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl, —OR, —CN, and —CF 3 ;
R 2 is —(CR d 2 ) t C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —(CR d 2 ) t OR, —(CR d 2 ) t SR, —(CR d 2 ) t CF 3 , —(CR d 2 ) t C 3-10 cycloalkyl, —(CR d 2 ) t -aryl, —(CR d 2 ) t -heterocyclyl or —(CR d 2 ) t heteroaryl, said alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl being optionally substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl, —CF 3 , —CN or —OR;
R 3 is (CR d 2 ) t -aryl, —(CR d 2 ) t -heteroaryl, —(CR d 2 ) t -heterocyclyl, —(CR d 2 ) t —C 3-10 cycloalkyl, —(CR d 2 ) t CN, —(CR d 2 ) t —C(O)NR a R b , —(CR d 2 ) t NR a C(O)R b , —(CR d 2 ) t —C(S)NR a R b , —(CR d 2 ) t —C(O)OR a , —(CR d 2 ) t —NR a C(O)OR a , —(CR d 2 ) t —NR a R b , or —OR a , said, aryl, heteroaryl or heterocyclyl are optionally substituted with from one to three substituents selected from R 5 ;
R 4 is —C 1 -C 6 alkyl, C 3-10 cycloalkyl, halo or CF 3 ;
Each R 5 is independently halo, OR, CN, —(CR d 2 ) t CF 3 , S(O) p R d , —(CR d 2 ) t C 3-10 cycloalkyl, or —C 1 -C 6 alkyl, said alkyl and cycloalkyl being optionally substituted with one to three substituents selected from halo or OR;
Each R 6 is independently halo, —C 1 -C 6 alkyl, OR, CN, CF 3 , aryl or heteroaryl, where said alkyl, aryl or heteroaryl are optionally substituted with halo, C 1 -C 6 alkyl or CF 3 ;
Each R is independently —H, —C 1 -C 6 alkyl, —CF 3 , or aryl;
Each R a and R b are independently —H, —C 1 -C 6 alkyl, aryl, heteroaryl, heterocyclyl, or —(CH 2 ) 0-3 —C 3-10 cycloalkyl, wherein said alkyl, heteroaryl, heterocyclyl, and cycloalkyl are optionally substituted with one to three substituents selected from R 6 ;
optionally, when R a and R b are —C 1 -C 6 alkyl and are attached to the same nitrogen atom, R a and R b may be cyclized to form a C 3 -C 6 cycloalkyl ring;

Each R d is independently —C 1 -C 6 alkyl, —CF 3 , or aryl;
Each R d is independently H, halo, —CF 3 or —C 1 -C 6 alkyl;
m is an integer selected from 1, 2, or 3;
p is an integer independently selected from 0, 1 or 2; and
t is an integer independently selected from 0, 1, 2, 3, or 4.

2. The compound according to claim 1 , wherein

is a heteroaryl selected from

where * indicates attachment to the pyrimidinyl ring and ** indicates attachment to the —CH 2 —R 2 of structural Formula I;
X 1 , X 2 , X 3 and X 4 are independently selected from N or CH, provided that no more than one of X 1 , X 2 , X 3 and X 4 is N;
or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein R 3 is aryl, heteroaryl, heterocyclyl, CN, —C(O)NR a R b , —NR a C(O)R b , —C(O)OR a , or —OR a , said aryl, heteroaryl or heterocyclyl are optionally substituted with from one to three substituents selected from halo, OR, CN, S(O) p R c , or —C 1 -C 6 alkyl, said alkyl being optionally substituted with one to three substituents selected from halo or OR;
or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 having structural Formula III:

or a pharmaceutically acceptable salt thereof,
wherein
X 4 is CH or N;
Each R is independently —H, —C 1 -C 6 alkyl, —CF 3 , or aryl;
Each R a is independently —H or —C 1 -C 6 alkyl;
Each R b is independently —H, —C 1 -C 6 alkyl, —C 3-10 cycloalkyl or heteroaryl, wherein said alkyl, cycloalkyl and heteroaryl are optionally substituted with one to three substituents selected R 6 ;
Each R d is independently —C 1 -C 6 alkyl, —CF 3 , or aryl;
Each R d is independently H, halo, —CF 3 or —C 1 -C 6 alkyl;
Each R 1 is independently —H, OR, CN, halo or —C 1 -C 6 alkyl;
R 2 is —(CR d 2 ) t C 1 -C 6 alkyl, —(CR d 2 ) t CF 3 , —(CR d 2 ) t —C 3-10 cycloalkyl, or —(CR d 2 ) t aryl, said alkyl, cycloalkyl and aryl being optionally substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl and —CF 3 ;
R 3 is aryl, heteroaryl, heterocyclyl, CN, —C(O)NR a R b , —NR a C(O)R b , —C(O)OR a , or —OR a , said aryl, heteroaryl or heterocyclyl are optionally substituted with from one to three substituent selected R 5 ;
R 4 is —CH 3 or C 3-10 cycloalkyl;
Each R 5 is independently halo, OR, CN, S(O) p R d , or —C 1 -C 6 alkyl, said alkyl being optionally substituted with one to three substituents selected from halo or OR;
Each R 6 is independently halo, —C 1 -C 6 alkyl, OR, CN, CF 3 , aryl or heteroaryl, where said alkyl, aryl or heteroaryl are optionally substituted with halo, C 1 -C 6 alkyl or CF 3 ;
m is an integer selected from 1, 2, or 3;
p is an integer independently selected from 0, 1 or 2; and
t is an integer independently selected from 0, 1, 2, 3, or 4.

5. The compound according to claim 1 , which is

1
4-amino-2-[5-chloro-3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5-methyl-5-

phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,

2
4-amino-2-[5-chloro-3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5-

methyl-5-phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,

3
4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5-methyl-5-

phenyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,

4
4-amino-2-[5-chloro-3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5-

methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-5,7-dihydro-6H-pyrrolo[2,3-

d]pyrimidin-6-one,

5
4-amino-2-[3-(2-fluorobenzyl)-1H-indazol-1-yl]-5-methyl-5-phenyl-5,7-

dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,

6
4-amino-2-[5-chloro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-5-methyl-5-

Assignees

• Raghavan Subharekha
• Stelmach John E
• Smith Cameron J
• Li Hong
• Whitehead Alan
• Waddell Sherman T
• Chen Yi-Heng
• Miao Shouwu
• Ornoski Olga A
• Garfunkle Joie
• Liao Xibin
• Chang Jiang
• Han Xiaoqing
• Guo Jian
• Groeper Jonathan A
• Brockunier Linda L
• Rosauer Keith
• Parmee Emma R
• Merck Sharp & Dohme

Inventors

• Raghavan Subharekha
• Stelmach John E
• Smith Cameron J
• Li Hong
• Whitehead Alan
• Waddell Sherman T
• Chen Yi-Heng
• Miao Shouwu
• Ornoski Olga A
• Garfunkle Joie
• Liao Xibin
• Chang Jiang
• Han Xiaoqing
• Guo Jian
• Groeper Jonathan A
• Brockunier Linda L
• Rosauer Keith
• Parmee Emma R

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · 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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title