Phosphorus prodrugs of pyrazolo-substituted pyrimidine sGC stimulators
The present patent application discloses the compounds according to Formula (I) shown below, or pharmaceutically acceptable salts thereof wherein J B , n, R 1 , R 2 , R 3 , R 4 , R 5 , m and X as defined herein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each J B is independently halogen;
R 1 is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or —C(O)NH 2 ;
R 2 is hydrogen, C 1-4 alkyl, or C 1-4 fluoroalkyl; or
R 1 and R 2 , together with the carbon atom to which they are attached, form an unsubstituted C 3-7 cycloaliphatic ring or an unsubstituted 3- to 7-membered heterocyclic ring, wherein the heterocyclic ring contains 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
R 3 is hydrogen, halogen, cyano, or —NH 2 ;
each R 4 is independently hydrogen; or
two R 4 , together with the carbon atom to which they are attached, form a carbonyl;
R 5 is hydrogen or methyl;
X is:
M + is a pharmaceutically acceptable monovalent cation;
D 2+ is a pharmaceutically acceptable divalent cation;
m is 0 or 1; and
n is 0, 1, 2, 3, or 4.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
(i) R 1 is C 1-4 fluoroalkyl; and
R 2 is C 1-4 fluoroalkyl; or
(ii) R is C 1-2 fluoroalkyl; and
R 2 is C 1-2 fluoroalkyl; or
(iii) R 1 is trifluoromethyl; and
R 2 is trifluoromethyl.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, fluoro, or chloro.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is:
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is:
and
M + is Na + , K + , Cs + , or the monovalent cation of an organic amine.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is:
and
D 2+ is Mg 2+ , Ca 2+ , Zn 2+ , or the divalent cation of an organic amine.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
11. The compound according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein:
(i) each J B is independently fluoro; or
(ii) each J B is independently chloro; or
(iii) each J B is independently chloro or fluoro.
12. The compound according to claim 1 , wherein the compound is of Formula V:
or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 , wherein the compound is of Formula VI:
or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising one or more excipients and a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.