Fused pyrazine derivatives useful as soluble guanylate cyclase stimulators
The invention provides certain fused pyrazine compounds of the Formula (I) or a pharmaceutically acceptable salts thereof, wherein X, Y, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , and the subscript t 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 or disorders 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 disorders and for preparing pharmaceuticals for this purpose.
1. A compound of the Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R 4b ) or N;
Y is C(H) or N;
R 1 is:
(a.) (C 1 -C 3 )alkyl-R 2 ;
R 2 is phenyl, pyridyl, C 3 -C 8 cycloalkyl, or C 5 -C 7 cycloalkenyl, wherein R 2 is unsubstituted or substituted by 1 to 3 R 2a ;
each R 2a is independently halo, (C 1 -C 3 )alkyl, or (C 1 -C 3 )fluoroalkyl; or
(b.)(C 1 -C 6 )alkyl, wherein said alkyl is unsubstituted or substituted by 1 to 6 fluoro;
R 3 is (C 1 -C 3 )alkyl or (C 3 -C 6 )cycloalkyl;
R 4a is H or (C 1 -C 3 )alkyl;
R 4b is H or NH 2 ;
R 5a and R 5b are independently H or (C 1 -C 6 )alkyl, wherein said alkyl is unsubstituted or substituted by 1 to 6 substituents independently selected from fluoro or hydroxyl; or
alternatively, R 5a and R 5b together with the nitrogen atom to which they are attached form ring C 5 which is an azetidinyl, pyrrolyl, piperidinyl, piperazinyl, or azepinyl ring, wherein ring C 5 is unsubstituted or substituted by 1 to 3 substituents which are independently halo, hydroxyl, (C 1 -C 3 )alkyl, or (C 1 -C 3 )fluoroalkyl;
each R 6 is independently halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )fluoroalkyl, or cyano; and
the subscript t is 0, 1, 2, or 3; and
with the proviso that the compound is not:
4-amino-5-(5-hydroxypyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one;
4-amino-5-(5-hydroxypyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidine-6(7H)-one; or
4-amino-5-cyclopropyl-5-(5-hydroxypyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidine-6(7H)-one.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is C(R 4b ).
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4b is H.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is C(H).
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is N.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1 -C 3 )alkyl-R 2 ,
R 2 is phenyl, C 3 -C 8 cycloalkyl, or C 5 -C 7 cycloalkenyl, wherein R 2 is unsubstituted or substituted by 1 to 3 R 2a ; and
each R 2a is independently halo, (C 1 -C 3 )alkyl, or (C 1 -C 3 )fluoroalkyl.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 2 —R 2 .
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted phenyl or phenyl substituted by 1 to 3 R 2a .
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4a is H.
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are H.
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the subscript t is 0 or 1.
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
the group
15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein:
X is C(H) or N;
Y is C(H) or N;
R 1 is —CH 2 —R 2 ;
R 2 is unsubstituted phenyl or phenyl substituted by 1 to 3 R 2a ;
each R 2a is independently halo, (C 1 -C 3 )alkyl, or (C 1 -C 3 )fluoroalkyl;
R 3 is methyl;
R 5a and R 5b are H; and
the subscript t is 0 or 1.
16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition of claim 16 , further comprising one or more additional active agents selected from an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a neutral endopeptidase inhibitor, an aldosterone antagonist, a renin inhibitor, an endothelin receptor antagonist, an aldosterone synthase inhibitor, a phosphodiesterase-5 inhibitor, a vasodilator, a calcium channel blocker, a potassium channel activator, a diuretic, a sympatholitic, a beta-adrenergic blocking drug, an alpha adrenergic blocking drug, a central alpha adrenergic agonist, a peripheral vasodilator, a lipid lowering agent, metabolic altering agent, a β 2 agonist, an anticholinergic, a corticosteroid or a corticosteroid analog.
18. A method for treating 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.
19. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.