Soluble guanylate cyclase activators
View Patent ↗Compounds of Formula I 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 the Formula I, to their use for the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical preparations which comprise compounds of the Formula I.
1. A compound having structural Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
is an 8- or 9-membered heteroaryl;
R a and R b are independently selected at each occurrence from the group consisting of —H and —C 1 -C 6 alkyl;
R c is independently selected at each occurrence from the group consisting of —C 1 -C 6 alkyl, —CF 3 , and aryl;
R 1 is independently selected at each occurrence from the group consisting of —H, halo, aryl, heteroaryl, —C 1 -C 6 alkyl, —C 3-10 cycloalkyl, —OR, —NO 2 , —CN, —CO 2 R a , —NR a R b , —S(O) p R c , thioxo, azido, —C(═O)R a , —OC(O)R a , —OC(═O)OR a , —OC(═O)NR a R b , —SO 2 NR a NR b , —NR a (C═O)R b , —NR a SO 2 R b , —NR a C(═O)OR b , —NR a C(O)NR a R b , —NR a SO 2 NR a R b , —C 2-10 alkenyl, and —C 2-10 alkynyl, said aryl, heteroaryl, alkyl, cycloalkyl, alkenyl and alkynyl optionally being substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl, —OR, oxo, aryl, heteroaryl, —C 3-10 cycloalkyl, —NO 2 , —CN, CO 2 R a , NR a R b , —S(O) p R c , thioxo, azido, —C(═O)R a , —O(C═O)R a , —OC(═O)OR a , —OC(═O)NR a R b , —SO 2 NR a NR b , —NR a (C═O)R b , —NRaSO 2 R b , —NR a C(═O)OR b , —NR a C(═O)NR a R b , —NR a SO 2 NR a R b and —CF 3 ;
R 2 is selected from the group consisting of —C 1 -C 6 alkyl, —(CR a 2 ) r OR, —(CR a 2 ) r S(O) p R c , —(CR a 2 ) r CF 3 , —(CR a 2 ) r —C 3-10 cycloalkyl, —(CR a 2 ) r aryl, —(CR a 2 ) r heteroaryl, —(CR a 2 ) r —C 2-10 alkenyl, —(CR a 2 ) r —C 2-10 alkynyl, and —(CR a 2 ) r C(O)Oalkyl, said alkyl, cycloalkyl, aryl, hetetoaryl, alkenyl and alkynyl being optionally substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl, —CF 3 , —CN and —OR;
R is independently selected at each occurrence from the group consisting of —H, —C 1 -C 6 alkyl, —CF 3 , and aryl;
R 3 and R 4 are independently selected from the group consisting of —H and —C 1 -C 6 alkyl;
when R 3 and R 4 are C 1 -C 6 alkyl they may optionally be joined to form a cycloalkyl;
m is 0, 1, 2, or 3;
p is 0, 1 or 2;
r is 0, 1, 2, 3, 4, 5, or 6; and
z is 0 or 1.
2. The compound of claim 1 having structural Formula II, or a pharmaceutically acceptable salt thereof,
wherein:
is an 8- or 9-membered heteroaryl;
R a is independently selected at each occurrence from the group consisting of —H and —C 1 -C 6 alkyl;
R 1 is independently selected at each occurrence from the group consisting of —H, halo, aryl, heteroaryl, —C 1 -C 6 alkyl and —C 3-10 cycloalkyl, said aryl, heteroaryl, alkyl and cycloalkyl optionally being substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl, and —CF 3 ;
R 2 is selected from the group consisting of —C 1 -C 6 alkyl, —(CR a 2 ) r CF 3 , —(CR a 2 ) r —C 3-10 cycloalkyl, —(CR a 2 ) r aryl, —(CR a 2 ) r heteroaryl, —(CR a 2 ) r alkenyl, —(CR a 2 ) r alkynyl, and —(CR a 2 ) r C(O)Oalkyl, said alkyl, cycloalkyl, aryl, hetetoaryl, alkenyl and alkynyl being optionally substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl, —CF 3 , —CN, and —OR;
R is independently selected at each occurrence from the group consisting of —H, —C 1 -C 6 alkyl and aryl;
R 3 and R 4 are independently selected from the group consisting of H and C 1 -C 6 alkyl;
when R 3 and R 4 are C 1 -C 6 alkyl they may optionally be joined to form a cycloalkyl;
m is 0, 1, 2 or 3; and
r is 0, 1, 2, 3, 4, 5, or 6.
3. The compound of claim 2 , wherein
is selected from the group consisting of
where * indicates attachment to the pyrmidinyl ring and ** indicates attachment to the —CH 2 —R 2 of structural Formula II; and
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.
4. The compound of claim 2 wherein
is selected from the group consisting of
where * indicates attachment to the pyrmidinyl ring and ** indicates attachment to the —CH 2 —R 2 of structural Formula II; and
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.
5. The compound of claim 4 wherein R 3 is C 1 -C 6 alkyl and R 4 is C 1 -C 6 alkyl.
6. The compound of claim 5 wherein R 3 and R 4 are methyl.
7. The compound of claim 2 wherein
is a selected from the group consisting of
X 4 is selected from the group consisting of CH and N;
R a is independently selected at each occurrence from the group consisting of —H and —C 1 -C 6 alkyl;
R 1 is independently selected at each occurrence from the group consisting of —H, halo and —C 1 -C 6 alkyl, said alkyl optionally being substituted with one to three substituents selected from halo, —C 1 -C 6 alkyl, and —CF 3 ;
R 2 is selected from the group consisting of —C 1 -C 6 alkyl, —(CR a 2 ) r CF 3 , —(CR a 2 ) r —C 3-10 cycloalkyl, and —(CR a 2 ) r 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 is independently selected from —H, —C 1 -C 6 alkyl and aryl;
R 3 and R 4 are each C 1 -C 6 alkyl;
m is 0, 1, 2 or 3; and
r is 0, 1, 2, or 3.
8. A compound selected from the group consisting of:
Example
IUPAC NAME
1
4-amino-2-[5-chloro-3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
2
4-amino-5,5-dimethyl-2-[3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-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]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
4
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
5
4-amino-2-(5-fluoro-3-hexyl-1H-indazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-
d]pyrimidin-6-one
6
4-amino-2-[5-bromo-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
7
4-amino-5,5-dimethyl-2-[5-pyridin-4-yl-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
8
4-amino-5,5-dimethyl-2-[3-(4,4,4-trifluorobutyl)-1H-thieno[3,4-c]pyrazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
9
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[3,4-c]pyrazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
10
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-4,6-dihydro-1H-thieno[3,4-c]pyrazol-
1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
11
4-amino-2-[3-(2-cyclopentylethyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
12
4-amino-2-[3-(2-fluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
13
4-amino-2-[5-chloro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
14
4-amino-2-[5-fluoro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
15
4-amino-2-[5-chloro-3-(2,3-difluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
16
4-amino-2-[3-(2,3-difluorobenzyl)-5-fluoro-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
17
4-amino-2-[3-(2,3-difluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
18
4-amino-2-[3-(2-fluorobenzyl)-5-phenyl-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
19
4-amino-2-[5-fluoro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
20
4-amino-5,5-dimethyl-2-[5-pyridin-3-yl-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
21
4-amino-5,5-dimethyl-2-[5-(1-methyl-1H-pyrazol-4-yl)-3-(2,3,6-trifluorobenzyl)-1H-
indazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
22
4-amino-2-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-3(2,3,6-trifluorobenzyl)-1H-indazol-1-
yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
23
4-amino-2-[5-(3-furyl)-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
24
4-amino-5,5-dimethyl-2-[5-(4-methyl-3-thienyl)-3-(2,3,6-trifluorobenzyl)-1H-indazol-
yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
25
4-amino-2-[5-cyclopropyl-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
26
4-amino-5,5-dimethyl-2-[5-pyridin-4-yl-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl] -5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
27
4-amino-5,5-dimethyl-2-[5-phenyl-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
28
4-amino-2-[5-chloro-3-(pyrimidin-5-ylmethyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
29
4-amino-5,5-dimethyl-2-[5-(3-thienyl)-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
30
4-amino-2-[5-(5-fluoropyridin-3-yl)-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
31
4-amino-2-[5-(6-fluoropyridin-3-yl)-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
32
4-amino-5,5-dimethyl-2-{3-(2,3,6-trifluorobenzyl)-5-[5-(trifluoromethyl)pyridin-3-yl]-
1H-indazol-1-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
33
4-amino-2-[3-(6-bromo-2,3-difluorobenzyl)-5-chloro-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
34
4-amino-2-[3-(2-cyclopentylethyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
35
4-amino-2-(5-fluoro-3-pentyl-1H-indazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
36
4-amino-2-[5-fluoro-3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
37
4-amino-2-[3-(2-cyclopentylethyl)-5-fluoro-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
38
4-amino-2-[3-(2-cyclopentylethyl)-5-fluoro-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
39
4-amino-2-[5-fluoro-3-(4,4,4-trifluorobutyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
40
4-amino-2-(5-chloro-3-pentyl-1H-indazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
41
4-amino-2-(3-butyl-5-chloro-1H-indazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-
d]pyrimidin-6-one
42
4-amino-2-[5-chloro-3-(4,4,4-trifluorobutyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
43
4-amino-2-(5-chloro-3-pent-4-en-1-yl-1H-indazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
44
4-amino-2-(3-but-3-en-1-yl-5-chloro-1H-indazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
45
4-amino-2-(5-chloro-3-propyl-1H-indazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
46
ethyl 3-[1-(4-amino-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-
5-chloro-1H-indazol-3-yl]propanoate
47
4-amino-2-[5-chloro-3-(3,3-dimethylbutyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
48
4-amino-2-[3-(2,3-difluorobenzyl)-1H-thieno[3,4-c]pyrazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
49
4-amino-2-[6-chloro-3-(2,3-difluorobenzyl)-1H-thieno[3,4-c]pyrazol-1-yl]-5,5-dimethyl-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
50
4-amino-2-[5-chloro-3-(2,3-difluorobenzyl)-1H-thieno[2,3-c]pyrazol-1-yl]-5,5-dimethyl-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
51
4-amino-2-[3-(2,3-difluorobenzyl)-1H-thieno[3,2-c]pyrazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
52
4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-thieno[2,3-c]pyrazol-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
53
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[3,2-c]pyrazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
54
4-amino-5,5-dimethyl-2-[5-methyl-3-(2,3,6-trifluorobenzyl)pyrazolo[4,3-c]pyrazol-
1(5H)-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
55
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[2,3-c]pyrazol-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
56
4-amino-5,5-dimethyl-2-[6-methyl-3-(2,3,6-trifluorobenzyl)pyrazolo[3,4-c]pyrazol-
1(6H)-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
57
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-pyrazolo[4,3-c]pyridin-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
58
4-amino-5,5-dimethyl-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
59
4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
60
4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
61
4-amino-5,5-dimethyl-2-[5-(2,3,6-trifluorobenzyl)imidazo[5,1-b][1,3]thiazol-7-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
62
4-amino-5,5-dimethyl-2-[1-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-3-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
63
4-amino-2-[3-(2,3-difluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
64
4-amino-2-[7-(2,3-difluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
65
4-amino-2-[3-(2,3-difluorobenzyl)-6-fluoroimidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
66
4-amino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
67
4-amino-2-[3-(2-fluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
68
4-amino-2-[6-fluoro-3-(2-fluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
69
4-amino-2-[6-chloro-3-(2-fluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
70
4-amino-2-[7-(2,3-difluorobenzyl)-2-methylimidazo[1,5-b]pyridazin-5-yl]-5,5-dimethyl-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
71
4-amino-2-[6-chloro-3-(2,3-difluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
72
4-amino-2-(3-benzylimidazo[1,5-a]pyridin-1-yl)-5,5-dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
73
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
74
4-amino-5,5-dimethyl-2[6-phenyl-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
75
4-amino-2-[6-(2-fluorophenyl)-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
76
4-amino-2-[6-(3-fluorophenyl)-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
77
4-amino-2-[6-(4-fluorophenyl)-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
78
4-amino-2-[6-(3-chlorophenyl)-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
79
4-amino-5,5-dimethyl-2-[6-(3-thienyl)-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-
yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
80
4-amino-2-[6-cyclopropyl-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
81
4-amino-5,5-dimethyl-2-[7-(3,3,3-trifluoropropyl)imidazo[1,5-b]pyridazin-5-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
82
4-amino-5,5-dimethyl-2-[3-(2,4,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
83
4-amino-2-[3-(2-chloro-6-fluoro-3-methylbenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
84
4-amino-2-[3-(2-cyclopentylethyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
85
4-amino-5,5-dimethyl-2-[7-(4,4,4-trifluorobutyl)imidazo[1,5-b]pyridazin-5-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
86
4-amino-5,5-dimethyl-2-[3-(4,4,4-trifluorobutyl)imidazo[1,5-a]pyridin-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
87
4-amino-5,5-dimethyl-2-{3-[2-(2-thienyl)ethyl]imidazo[1,5-a]pyridin-1-yl}-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
88
4-amino-2-[3-(2-cyclopropylethyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
89
4-amino-5,5-dimethyl-2-(3-pentylimidazo[1,5-a]pyridin-1-yl)-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
90
4-amino-5,5-dimethyl-2-(7-pentylimidazo[1,5-b]pyridazin-5-yl)-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
91
4-amino-5,5-dimethyl-2-[3-(3-methylbutyl)imidazo[1,5-a]pyridin-1-yl]-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
92
4-amino-5,5-dimethyl-2-[3-methyl-5-(2,3,6-trifluorobenzyl)imidazo[5,1-b][1,3]thiazol-
7-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
93
4-amino-5,5-dimethyl-2-[2-methyl-5-(2,3,6-trifluorobenzyl)imidazo[5,1-b][1,3]thiazol-
7-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
94
4-amino-2-[5-(2-fluorobenzyl)imidazo[5,1-b][1,3]thiazol-7-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
95
4-amino-5,5-dimethyl-2-[1-(3,3,3-trifluoropropyl)-1H-indazol-3-yl]-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one
96
4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,8-
dihydropyrido[2,3-d]pyrimidin-7(6H)-one
97
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,8-
dihydropyrido[2,3-d]pyrimidin-7(6H)-one
98
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[3,4-c]pyrazol-1-yl]-5,8-
dihydropyrido[2,3-d]pyrimidin-7(6H)-one
99
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-4,6-dihydro-1H-thieno[3,4-c]pyrazol-
1-yl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one
100
4-amino-2-[5-chloro-3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5-ethyl-5-methyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
101
4-amino-2-[5-chloro-3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5-methyl-5-propyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
102
4-amino-2-[5-chloro-3-(3,3-dimethylbutyl)-1H-indazol-1-yl]-5-ethyl-5-methyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
103
4-amino-5-ethyl-2-[3-(2-fluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5-methyl-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
104
4-amino-5,5-dimethyl-2-[3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5,7-dihydro-
6H-pyrrolo[2,3-d]pyrimidin-6-one
105
4-amino-2-[5-fluoro-3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
106
4-amino-2-[5-chloro-3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
107
4-amino-5,5-dimethyl-2-[3-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[4,3-b]pyridin-1-
yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
108
4-amino-5,5-dimethyl-2-[3-(3,3,4,4,4-pentafluorobutyl)imidazo[1,5-a]pyridin-1-yl]-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
109
4-amino-2-[6-fluoro-3-(3,3,4,4,4-pentafluorobutyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
110
4-amino-2-[6-chloro-3-(3,3,4,4,4-pentafluorobutyl)imidazo[1,5-a]pyridin-1-yl]-5,5-
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
111
4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
and the pharmaceutically acceptable salts thereof.
9. The compound of claim 8 selected from the group consisting of:
4-amino-2-[5-chloro-3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[3,4-c]pyrazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-thieno[2,3-c]pyrazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
4-amino-5,5-dimethyl-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[3-(2,3-difluorobenzyl)-6-fluoroimidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[3-(2-cyclopentylethyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-c]pyrimidin-6-one;
4-amino-5,5-dimethyl-2-[3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-c]pyrimidin-6-one;
4-amino-2-[5-fluoro-3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[5-chloro-3-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-5,5-dimethyl-2-[3-(3,3,4,4,4-pentafluorobutyl)imidazo[1,5-a]pyridin-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[6-fluoro-3-(3,3,4,4,4-pentafluorobutyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[6-chloro-3-(3,3,4,4,4-pentafluorobutyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;
and the pharmaceutically acceptable salts thereof.
10. A method for activating soluble guanylate cyclase comprising the step of administering an amount efficacious of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
11. A method for the treatment of pulmonary hypertension, comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
12. A method for the treatment of hypertension comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
13. A method for the treatment of heart failure comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
14. A pharmaceutical composition comprised of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 comprising one or more pharmaceutically active agents in addition to the compound of claim 1 or a pharmaceutically acceptable salt thereof.
16. The pharmaceutical composition of claim 15 wherein the one or more additional active agents is selected from the group consisting of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a neutral endopeptidase inhibitor, an aldosterone antagonist, a renin inhibitor, an endothelin receptors antagonist, a vasodilator, a calcium channel blocker, a potassium channel activator, a diuretic, a sympatholytic, a beta-adrenergic blocking drug, an alpha adrenergic blocking drug, a central alpha adrenergic agonist, a peripheral vasodilator, a lipid lowering agent and a metabolic altering agent.
17. The compound of claim 1 that is 4-amino-2-[5-chloro-3-(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 that is 4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 that is 4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-c]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 that is 4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-c]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
or a pharmaceutically acceptable salt thereof.