Soluble guanylate cyclase stimulators
View Patent ↗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.
1. A method for treating a condition selected from cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, heart failure, pulmonary hypertension, 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;
(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.
2. The method of claim 1 , wherein the condition is pulmonary hypertension.
3. The method of claim 1 , wherein the compound administered is:
3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic acid;
3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid;
3-(3-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic acid;
3-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid;
3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid;
3-{2-[4-amino-2-{6-chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic acid;
3-(2-{4-amino-2[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid;
3-(2-{4-amino-2-[1-(2,3-difluorobenzyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid; or
3-(2-{4-amino-2[1-(cyclohexylmethyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid,
or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 , wherein the condition is pulmonary hypertension.
5. The method of claim 4 , wherein the condition is pulmonary arterial hypertension.
6. The method of claim 4 , wherein the condition is WHO Group III pulmonary hypertension.
7. The method of claim 4 , wherein the condition is WHO Group IV pulmonary hypertension.
8. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein the condition is pulmonary hypertension.
10. The method of claim 9 , wherein the condition is pulmonary arterial hypertension.
11. The method of claim 9 , wherein the condition is WHO Group III pulmonary hypertension.
12. The method of claim 9 , wherein the condition is WHO Group IV pulmonary hypertension.
13. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the condition is pulmonary hypertension.
15. The method of claim 14 , wherein the condition is pulmonary arterial hypertension.
16. The method of claim 14 , wherein the condition is WHO Group III pulmonary hypertension.
17. The method of claim 14 , wherein the condition is WHO Group IV pulmonary hypertension.
18. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 , wherein the condition is pulmonary hypertension.
20. The method of claim 19 , wherein the condition is pulmonary arterial hypertension.
21. The method of claim 19 , wherein the condition is WHO Group III pulmonary hypertension.
22. The method of claim 19 , wherein the condition is WHO Group IV pulmonary hypertension.
23. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
24. The method of claim 23 , wherein the condition is pulmonary hypertension.
25. The method of claim 24 , wherein the condition is pulmonary arterial hypertension.
26. The method of claim 24 , wherein the condition is WHO Group III pulmonary hypertension.
27. The method of claim 24 , wherein the condition is WHO Group IV pulmonary hypertension.
28. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
29. The method of claim 28 , wherein the condition is pulmonary hypertension.
30. The method of claim 29 , wherein the condition is pulmonary arterial hypertension.
31. The method of claim 29 , wherein the condition is WHO Group III pulmonary hypertension.
32. The method of claim 29 , wherein the condition is WHO Group IV pulmonary hypertension.
33. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
34. The method of claim 33 , wherein the condition is pulmonary hypertension.
35. The method of claim 34 , wherein the condition is pulmonary arterial hypertension.
36. The method of claim 34 , wherein the condition is WHO Group III pulmonary hypertension.
37. The method of claim 34 , wherein the condition is WHO Group IV pulmonary hypertension.
38. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
39. The method of claim 38 , wherein the condition is pulmonary hypertension.
40. The method of claim 39 , wherein the condition is pulmonary arterial hypertension.
41. The method of claim 39 , wherein the condition is WHO Group III pulmonary hypertension.
42. The method of claim 39 , wherein the condition is WHO Group IV pulmonary hypertension.
43. The method of claim 1 , wherein the compound administered is
or a pharmaceutically salt thereof.
44. The method of claim 43 , wherein the condition is pulmonary hypertension.
45. The method of claim 44 , wherein the condition is pulmonary arterial hypertension.
46. The method of claim 44 , wherein the condition is WHO Group III pulmonary hypertension.
47. The method of claim 44 , wherein the condition is WHO Group IV pulmonary hypertension.
48. The method of claim 1 , wherein the compound administered is
or a pharmaceutically acceptable salt thereof.
49. The method of claim 48 , wherein the condition is pulmonary hypertension.
50. The method of claim 49 , wherein the condition is pulmonary arterial hypertension.
51. The method of claim 49 , wherein the condition is WHO Group III pulmonary hypertension.
52. The method of claim 49 , wherein the condition is WHO Group IV pulmonary hypertension.