sGC stimulators
The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts, pharmaceutical formulations comprising them as well as their phosphate ester prodrugs, and their uses alone or in combination with one or more additional agents, for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) and/or an increase in the concentration of cyclic Guanosine Monophosphate (cGMP), or both, or the upregulation of the NO pathway is desirable. The compounds are of Formula I.
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,
wherein:
Y is independently N or C;
ring B is a phenyl or a 5 or 6-membered heteroaryl ring, containing 1 or 2 ring heteroatoms independently selected from N, O and S;
n is an integer selected from 0 to 3; and each J B is independently halogen, —CN, a C 1-6 aliphatic or —OR B ;
wherein each J B that is a C 1-6 aliphatic is optionally and independently substituted with up to 3 instances of R 3 ;
each R B is independently hydrogen or a C 1-6 aliphatic; said C 1-6 aliphatic represented by R B is optionally and independently substituted with up to 3 instances of R 3a ;
each R 3 and R 3a is, in each instance, independently halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) or —O(C 1-4 haloalkyl);
Z is selected from the group consisting of hydrogen, —P(O)(OH) 2 , —P(O)(OH)O − M + , —P(O)(O − ) 2 (M + ) 2 , —P(O)(O − ) 2 D 2+ and —P(O)(O-Benzyl) 2 ; wherein M+ is a pharmaceutically acceptable monovalent cation and D 2+ is a pharmaceutically acceptable divalent cation;
m is 0 or 1;
R 1 is C 1-4 alkyl, C 1-4 fluoroalkyl, —C(O)NH 2 or hydrogen; and
R 2 is C 1-4 alkyl, C 1-4 fluoroalkyl or hydrogen;
both instances of R 4 are simultaneously hydrogen or both instances of R 4 , together with the carbon atom to which they are attached form a carbonyl group;
J D is hydrogen, halogen, methoxy or —CN
p is 1 or 2; and
each J C is independently hydrogen, halogen, C 1-4 aliphatic, C 1-4 alkoxy or —CN; wherein each said C 1-4 aliphatic and each said C 1-4 alkoxy is optionally and independently substituted by up to 3 instances of C 1-4 alkoxy, C 1-4 haloalkoxy, —OH or halogen.
2. The compound according to claim 1 , wherein the compound is of Formula IA, Formula IB, Formula II, Formula IIA or Formula IIB:
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein (i) J D is hydrogen, chloro, fluoro, methoxy or —CN; (ii) J D is methoxy; (iii) J D is hydrogen, chloro, fluoro or —CN; (iv) J D is hydrogen, chloro or fluoro; (v) J D is fluoro or hydrogen; (vi) J D is hydrogen; (vii) J D is fluoro; (viii) J D is —CN; (ix) J D is chloro; (x) each J C is independently hydrogen, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 fluoroalkyl, C 1-2 fluoroalkoxy, halogen or —CN, wherein each said C 1-2 alkyl and C 1-2 alkoxy is optionally and independently substituted by up to 3 instances of C 1-4 alkoxy, C 1-4 haloalkoxy, —OH or halogen; (xi) each J C is independently hydrogen, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 fluoroalkyl, C 1-2 fluoroalkoxy, halogen or —CN; (xii) each J C is independently hydrogen or halogen; (xiv) each J C is hydrogen; or (xv) each J C is independently fluoro or chloro.
4. The compound according to claim 1 , wherein the compound is of Formula IIIA, Formula IIIB, Formula IVA, Formula WB, Formula VA, Formula VIA, Formula VB or Formula VIB:
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , wherein (i) ring B is phenyl; (ii) ring B is a 5 or 6-membered heteroaryl ring, containing 1 or 2 ring heteroatoms independently selected from N, O and S; or (iii) ring B is a 6-membered heteroaryl ring, containing 1 to 2 ring nitrogen atoms.
6. The compound according to claim 1 , wherein (i) n is 1, 2 or 3, and each J B is independently halogen or C 1-6 aliphatic; (ii) n is 1 or 2 and each J B is independently halogen or C 1-6 aliphatic; (iii) n is 1 or 2 and each J B is fluoro; (iv) n is 1 and J B is fluoro.
7. The compound according to claim 5 , wherein the compound is of Formula VIIA, Formula VIIIA, Formula VIIB or Formula VIIIB:
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 , wherein (i) R 1 is C 1-2 alkyl, C 1-2 fluoroalkyl, hydrogen or —C(O)NH 2 ; (ii) R 1 is C 1-2 fluoroalkyl or —C(O)NH 2 ; (iii) R 2 is C 1-2 fluoroalkyl, C 1-2 alkyl or hydrogen; or (iv) R 2 is C 1-2 fluoroalkyl.
9. The compound of claim 8 , wherein (i) R 1 is trifluoromethyl or —C(O)NH 2 and R 2 is trifluoromethyl; (ii) R 1 and R 2 are both hydrogen or C 1-2 alkyl; or one of R 1 and R 2 is hydrogen and the other is C 1-2 fluoroalkyl; (iii) R 1 and R 2 are both hydrogen; (iv) R 1 and R 2 are both methyl; or (v) one of R 1 and R 2 is hydrogen and the other is trifluoromethyl.
10. The compound of claim 1 selected from:
wherein J D is selected from hydrogen or fluoro.
11. The compound according to claim 1 , wherein (i) Z is —P(O)(OH) 2 ; (ii) Z is —P(O)(OH)O − M + or —P(O)(O − ) 2 (M + ) 2 ; and M + is Na + , K + , Cs + or the monovalent cation of an organic amine; or (iii) Z is —P(O)(O − ) 2 D 2+ ; and D 2+ is Ca 2+ , Zn 2+ , Mg 2+ or the divalent cation of an organic amine.
12. The compound according to claim 1 selected from the group consisting of
13. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient or carrier.
14. A method of treating a disease in a subject in need thereof that would benefit from sGC stimulation or from an increase in the concentration of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP), the method comprising administering a therapeutically effective amount of a compound of claim 1 to the subject in need of treatment.
15. The method according to claim 14 , further comprising administering to the subject an effective amount of a suitable therapeutic agent.
16. A compound selected from:
17. A compound represented by the following formula:
wherein:
n is an integer selected from 0 to 3; and each J B is independently halogen, —CN, a C 1-6 aliphatic or —OR B ;
wherein each J B that is a C 1-6 aliphatic is optionally and independently substituted with up to 3 instances of R 3 ;
each R B is independently hydrogen or a C 1-6 aliphatic; said C 1-6 aliphatic represented by R B is optionally and independently substituted with up to 3 instances of R 3a ;
each R 3 and R 3a is, in each instance, independently halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) or —O(C 1-4 haloalkyl);
J C is independently hydrogen, halogen, C 1-4 aliphatic, C 1-4 alkoxy or —CN; wherein each said C 1-4 aliphatic and each said C 1-4 alkoxy is optionally and independently substituted by up to 3 instances of C 1-4 alkoxy, C 1-4 haloalkoxy, —OH or halogen; and
J D is hydrogen, halogen, methoxy or —CN.
18. The compound of claim 17 , wherein (i) J D is hydrogen, chloro, fluoro, methoxy or —CN; or (ii) J D is fluoro.
19. The compound of claim 17 , wherein (i) J C is hydrogen, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 fluoroalkyl, C 1-2 fluoroalkoxy, halogen or —CN, wherein each said C 1-2 alkyl and C 1-2 alkoxy is optionally and independently substituted by up to 3 instances of C 1-4 alkoxy, C 1-4 haloalkoxy, —OH or halogen; (ii) J C is hydrogen or halogen; or (iii) J C is hydrogen.
20. The compound of claim 17 , wherein (i) n is 1, 2 or 3, and each J B is independently halogen or C 1-6 aliphatic; (ii) n is 1 or 2 and each J B is independently halogen or C 1-6 aliphatic; (iii) n is 1 or 2 and each J B is fluoro; or (iv) n is 1 and J B is fluoro.
21. The compound of claim 10 selected from:
22. The compound of claim 21 represented by formula:
23. The compound of claim 12 represented by:
24. The compound of claim 12 represented by