SGC stimulators
The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations comprising them and their uses thereof, alone or in combination with one or more additional agents, for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine Monophosphate (cGMP), or both, or an 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:
the core formed by rings E and A along with the substituents (J c ) p is represented by the following formula:
wherein the C atom with a symbol * represents the attachment point to the ring containing G, Z, and Q; and the C atom with a symbol ** represents the point of attachment of the 2 instances of J;
W is;
wherein each J is independently selected from hydrogen and methyl; n is 1; and J B is halogen; and
each J C is independently selected from hydrogen, halogen, C 1-4 aliphatic, C 1-4 alkoxy or —CN; wherein each said C 1-4 aliphatic and 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;
Q, G and Z are each independently N, S or O, wherein at least two of Q, G and Z are N;
q is 0, 1 or 2;
R 10 is C 1-6 alkyl optionally and independently substituted with 0-3 occurrences of R 15 , phenyl optionally and independently substituted with 0-3 occurrences of R 15 , 5- or 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 1 , C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 15 or 3-8 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 15 ; wherein each of said 5- to 6-membered heteroaryl ring and each of said 3-8 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;
R 11 is H, —NR a2 R b2 , —C(O)NR a2 R b2 , —C(O)R 15a , —SO 2 R b2 , —SR b2 , halo, —OCF 3 , —CN, hydroxyl, C 2-6 alkenyl optionally and independently substituted with 0-2 occurrences of R b2 , C 2-6 alkynyl optionally and independently substituted with 0-2 occurrences of R b2 ; C 1-6 alkyl optionally and independently substituted with 0-5 occurrences of R 15 , C 1-6 alkoxy optionally and independently substituted with 0-5 occurrences of R 15 , phenyl optionally and independently substituted with 0-3 occurrences of R 15 , 5- to 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 15 , C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 15 or 3-8 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 15 ; wherein each of said 5- to 6-membered heteroaryl and each of said 3-8 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S; or
when R 10 is a substituent of Z, R 10 and R 11 , taken together with Z and the carbon to which R 11 is attached, form a 3-10 membered heterocyclic ring optionally and independently substituted with 0-3 occurrences of R 15 ; wherein each of said 3-10 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;
R 15 is halo, —OR b2 , —SR b2 , —NR a2 R b2 , —C(O)R b2 , —C(O)NR a2 R b2 , —NR b2 C(O)OR b2 , —OC(O)NR a2 R b2 , C 2-4 alkenoxy, C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 18 , phenyl optionally and independently substituted with 0-3 occurrences of R 18 , 5- or 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 18 or 3-10 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 18 ; wherein each of said 5- or 6-membered heteroaryl ring and each of said 3-10 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;
R 15a is C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 18 , phenyl optionally and independently substituted with 0-3 occurrences of R 18 , 5- or 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 18 or 3-10 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 18 ; wherein each of said 5- or 6-membered heteroaryl ring and each of said 3-10 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;
each R 18 is independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or phenyl;
R a2 is hydrogen, —C(O)R b2 , C 1-6 alkyl or C 1-6 haloalkyl; and
R b2 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.
2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein a J B is ortho to the attachment of the methylene linker between ring B and the core of the molecule.
3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is one of Formula III, or a pharmaceutically acceptable salt thereof, or any of its tautomers thereof.
4. A compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 11 is H, NR a2 R b2 , —C(O)NR a2 R b2 , —C(O)R 15a , —SO 2 R b2 , —SR b2 , halo, —OCF 3 , —CN, hydroxyl, C 2-6 alkenyl optionally and independently substituted with 0-2 occurrences of R b2 , C 2-6 alkynyl optionally and independently substituted with 0-2 occurrences of R b2 ; C 1-6 alkyl optionally and independently substituted with 0-5 occurrences of R 15 , C 1-6 alkoxy optionally and independently substituted with 0-3 occurrences of R 15 , phenyl optionally and independently substituted with 0-3 occurrences of R 15 , 5- or 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 15 , C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 15 or 3-8 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 15 .
5. A compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 11 is H or C 1-6 alkyl optionally and independently substituted with 0-5 occurrences of R 15 .
6. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 15 is halo in each instance.
7. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein q is 0.
8. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.
9. A compound according to claim 1 , wherein said compound is of Formula VI, or a pharmaceutically acceptable salt thereof:
wherein:
each J B is halo;
n is 1;
R 11 is H, halo, —NR a2 R b2 , C 1-4 alkyl, 5- to 6-membered heteroaryl, or C 3-6 cycloalkyl, wherein the C 1-4 alkyl, 5- to 6-membered heteroaryl, and C 3-6 cycloalkyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo;
R a2 is hydrogen or C 1-4 alkyl; and
R b2 is hydrogen or C 1-4 alkyl.
10. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from those listed below: