Soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-9284301-B2
Application number	US-201113636760-A
Country	US
Kind code	B2
Filing date	Mar 22, 2011
Priority date	Mar 25, 2010
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

The invention relates to compounds having the structure of Formula (I) and pharmaceutically acceptable salts thereof, which are soluble guanylate cyclase activators. The compounds 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 compounds are useful for treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, pulmonary hypertension, angina pectoris, thromboses, restenosis, myocardial infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes, or cirrhosis of the liver.

First claim

What is claimed is:

1. A compound selected from the group consisting of:
1) 2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine,
2) 5-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
3) 5-(2-methylpyridin-4-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
4) 5-quinolin-5-yl-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
5) 5-pyridin-4-yl-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
6) 5-pyridin-3-yl-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
7) 2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-amine,
8) 5-(5-fluoropyridin-3-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
9) 5-(2-methoxypyridin-3-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
10) 5-(4-methylpyridin-3-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
11) 5-(4-methoxypyridin-3-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
12) 5-(1-methyl-1H-pyrazol-4-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
13) 5-(1-methyl-1H-pyrazol-5-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
14) 5-(7-fluoroquinolin-4-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
15) 2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[2-(trifluoromethyl)quinolin-4-yl]pyrimidin-4-amine,
16) 5-(3-fluoropyridin-4-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
17) 2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[2-(trifluoromethyl)pyridin-4-yl]pyrimidin-4-amine,
18) 2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[2-(trifluoromethyl)quinolin-4-yl]pyrimidin-4-amine,
19) 5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
20) 5-pyridin-4-yl-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
21) 5-pyridin-3-yl-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
22) 5-(4-methoxypyridin-3-yl)-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
23) 5-(4-methylpyridin-3-yl)-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
24) 5-quinolin-5-yl-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
25) 5-(2-methylpyridin-4-yl)-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
26) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-pyridin-4-ylpyrimidin-4-amine,
27) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine,
28) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(2-methylpyridin-4-yl)pyrimidin-4-amine,
29) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-quinolin-5-ylpyrimidin-4-amine,
30) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[2-(trifluoromethyl)pyridin-4-yl]pyrimidin-4-amine,
31) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-pyridin-3-ylpyrimidin-4-amine,
32) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(4-methoxypyridin-3-yl)pyrimidin-4-amine,
33) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-amine,
34) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(4-methylpyridin-3-yl)pyrimidin-4-amine,
35) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine,
36) 2-[7-(2-chloro-3,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrimidin-4-amine,
37) 2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine,
38) 5-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
39) 2-[7-(3-chloro-2,6-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine,
40) 2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[2-(trifluoromethyl)pyridin-4-yl]pyrimidin-4-amine,
41) 2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-amine,
42) 5-[3-(methylsulfonyl)phenyl]-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
43) 2-[7-(2-chloro-3,5-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[3-(methylsulfonyl)phenyl]pyrimidin-4-amine,
44) 5-[2-(methylsulfonyl)phenyl]-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
45) 5-[4-(methylsulfonyl)phenyl]-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
46) 5-(3-methoxyphenyl)-2-[7-(2,3,5-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine;
47) 5-(2-methoxypyridin-3-yl)-2-[7-(2,3,4-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
48) 5-(4-methoxypyridin-3-yl)-2-[7-(2,3,4-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
49) 2-[7-(2,3,4-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-amine,
50) 5-pyridin-4-yl-2-[7-(2,3,4-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
51) 5-(1-methyl-1H-pyrazol-5-yl)-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
52) 5-[3-(methylsulfonyl)phenyl]-2-[7-(2,3,4-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-4-amine,
53) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-pyridin-3-ylpyrimidin-4-amine,
54) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-quinolin-5-ylpyrimidin-4-amine,
55) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-pyridin-4-ylpyrimidin-4-amine,
56) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine,
57) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-amine,
58) 5-(5-fluoropyridin-3-yl)-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]pyrimidin-4-amine,
59) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-(2-methoxypyridin-3-yl)pyrimidin-4-amine,
60) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-(4-methylpyridin-3-yl)pyrimidin-4-amine,
61) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-(2-methylpyridin-4-yl)pyrimidin-4-amine,
62) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-(4-methoxypyridin-3-yl)pyrimidin-4-amine,
63) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5′-bipyrimidin-4-amine,
64) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine,
65) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine,
66) 5-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]pyrimidin-4-amine,
67) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-[2-(trifluoromethyl)pyridin-4-yl]pyrimidin-4-amine,
68) 5-(3-fluoropyridin-4-yl)-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]pyrimidin-4-amine,
69) 2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-[2-(trifluoromethyl)quinolin-4-yl]pyrimidin-4-amine,
70) 5-(6-fluoroquinolin-4-yl)-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]pyrimidin-4-ami

Assignees

• Schmidt Darby
• Raghavan Subharekha
• Stelmach John
• Guo Jian
• Groeper Jonathan
• Brockunier Linda
• Rosauer Keith
• Shen Hong
• Liang Rui
• Ding Fa-Xiang
• Merck Sharp & Dohme

Inventors

• Schmidt Darby
• Raghavan Subharekha
• Stelmach John
• Guo Jian
• Groeper Jonathan
• Brockunier Linda
• Rosauer Keith
• Shen Hong
• Liang Rui
• Ding Fa-Xiang

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

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title