sGC STIMULATORS
The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts thereof and 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) and/or an increase in the concentration of cyclic Guanosine Monophosphate (cGMP), or both, or an upregulation of the NO pathway is desirable. In some embodiments, the compounds are those of Table I or a pharmaceutically acceptable salt thereof.
1 . A compound represented by Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
J C is selected from the group consisting of hydrogen, halogen C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms;
X is N or C(J C1 );
J C1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms;
each J B is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms;
J D is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms; and
n is an integer selected from 0, 1, 2, 3 or 4, provided that the compound is not one of the following:
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein the compound is represented by Formula IA:
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein J C1 is H, F, Cl, C 1-2 alkyl or C 1-2 fluoroalkyl substituted with 1 to 3 fluoro atoms.
4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein J C1 is H or F.
5 . The compound of claim 1 , wherein the compound is represented by Formula IB:
or a pharmaceutically acceptable salt thereof.
6 . The compound of any one of claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.
7 . The compound of any one of claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
8 . The compound of any one of claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein n is 1.
9 . The compound of any one of claims 1-8 , or a pharmaceutically acceptable salt thereof, wherein each J B is independently H, F, or C 1-4 alkyl or C 1-4 fluoroalkyl substituted with 1 to 3 fluoro atoms.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein each J B is independently H, F or C 1-4 alkyl.
11 . The compound of any one of claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3; and each J B is independently F, methyl or fluoromethyl substituted with 1 to 3 fluoro atoms.
12 . The compound of any one of claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3; and each J B is independently F or methyl.
13 . The compound of any one of claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein n is 2; and J B are both F or one of J B is F and the other is methyl.
14 . The compound of any one of claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein n is 3; and two of J B are F and the other is methyl.
15 . The compound of any one of claims 1-14 , or a pharmaceutically acceptable salt thereof, wherein J D is H, F, Cl, methyl, ethyl, fluoromethyl or fluoroethyl.
16 . The compound of any one of claims 1-14 , or a pharmaceutically acceptable salt thereof, wherein J D is H or F.
17 . The compound of any one of claims 1-16 , or a pharmaceutically acceptable salt thereof, wherein J C is H, Cl, F, methyl, ethyl, fluoromethyl, or fluoroethyl.
18 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein J C is H or F.
19 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein J C is H.
20 . The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 20 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 20 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 22 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 22 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 20 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
26 . A pharmaceutical composition comprising a compound of any one of claims 1-25 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
27 . A method of treating a disease in a subject in need thereof, comprising administering to the subject, alone or in combination therapy, a therapeutically effective amount of a compound of any one of claims 1-25 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 26 ; wherein the disease or disorder is one that would benefit from sGC stimulation or from an increase in the concentration of NO and/or cGMP.
28 . The method of claim 27 , wherein the method further comprising administering to the subject an additional therapeutic agent.