P2X3 modulators
View Patent ↗Provided herein are P2X3 modulators and methods of utilizing P2X3 modulators in the treatment of diseases, disorders, or conditions. Also described herein are pharmaceutical compositions containing such compounds.
1 . A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
X is C(R 2 ) or N;
Y is C(R 2 ) or N;
Z is a bond, CH 2 , or O;
R 1 is C 1 -C 6 haloalkyl;
each R 2 is independently selected from hydrogen, deuterium, halogen, —CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl;
R 3 is selected from hydrogen, deuterium, halogen, —CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, —OR 7 , —N(R 7 ) 2 , —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 10 S(═O) 2 R 8 , —S(═O) 2 R 8 , and —S(═O) 2 N(R 7 ) 2 ;
each R 4 is independently selected from deuterium, halogen, —CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl; or two R 4 are combined to form a bridged heterocycloalkyl ring;
R 5 is —C(═O)N(R 9 )(R 10 ), —C(═O)OR 9 , —S(═O)R 15 , —S(═O) 2 R 15 , —S(═O)(═NH)R 15 , —C 2 -C 9 heterocycloalkyl-N(R 9 )(R 10 ), or —C 1 -C 6 haloalkyl-N(R 9 )(R 10 );
R 6 is selected from —C(═O)OR 11 , —C(═O)R 11 , and —C(═O)N(R 12 )(R 13 );
each R 7 is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
each R 8 is independently selected from C 1 -C 6 alkyl;
R 9 , R 10 , R 12 , and R 13 are independently selected from hydrogen, deuterium, and C 1 -C 6 alkyl;
R 11 is C 1 -C 6 alkyl or —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl;
R 14 is C 1 -C 6 alkyl;
R 15 is C 1 -C 6 alkyl;
n is 0, 1, 2, or 3;
p is 1, 2, or 3; and
q is 0, 1, 2, 3, or 4.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halogen or C 1 -C 6 alkyl.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia′):
5 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia″):
6 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Z is O and p is 1.
7 . The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 2 ) and Y is C(R 2 ).
8 . The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 is hydrogen.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1.
10 . The compound of claim 9 , wherein q is 0.
11 . The compound of claim 10 , wherein R 5 is —C(O)N(R 9 )(R 10 ).
12 . The compound of claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is hydrogen.
13 . The compound of claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is —C(O)OR 11 .
14 . The compound of claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is C 1 -C 6 alkyl.
15 . A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
16 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients.
17 . A method for treating a disorder associated with P2X3 activity in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.
18 . A method for treating pain, a urinary tract disorder, cough, endometriosis, endometriosis-associated pain, and endometriosis-associated symptoms in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.
19 . The method of claim 17 , further comprising the administration of a second therapeutic agent.
20 . The method of claim 18 , further comprising the administration of a second therapeutic agent.