TRPV4 receptor ligands
Described are receptor ligands of transient receptor potential cation channel subfamily V member 4 (TRPV4), pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating ocular disorders.
1 . A compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein:
L 1 is —C(O)—, —S(O 2 )—, or —S(O)—;
X is O or NR 1 ;
m is 1, 2, 3, or 4;
n is 0;
Ar 1 and Ar 2 are each independently selected from a 6-10 membered aryl or a 5-10 membered heteroaryl;
Z is CHR 2 R 3 , COR 4 , or NHR 5 ;
R 1 is selected from hydrogen and C 1 -C 4 alkyl;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, phosphate, C 1 -C 6 alkyl phosphate, C 4 -C 8 heterocyclyl, NR 6 R 7 , —OC(O)R 8 , —C(O)R 9 , —S(O) 2 R 10 , and —OS(O) 2 R 11 ;
R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, C 4 -C 8 cycloalkyl, C 4 -C 8 heterocyclyl, C 6 -C 8 aryl, C 5 -C 8 -heteroaryl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 6 -C 8 aryl-C 1 -C 6 alkyl, C 5 -C 8 heteroaryl-C 1 -C 6 alkyl, C 5 -C 8 heterocyclyl-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, hydroxy-C 3 -C 8 cycloalkyl, cyano-C 1 -C 6 alkyl, hydroxysulfonyl-C 1 -C 6 alkyl, phosphate-C 1 -C 6 alkyl, alkylphosphate-C 1 -C 6 alkyl, —COR 12 , and —CR 13 R 14 C(O)R 15 ;
R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, amino-C 1 -C 6 alkyl, C 4 -C 8 heterocyclyl, hydroxy-C 1 -C 6 alkyl, amino-C 4 -C 8 heterocyclyl, phosphate-C 1 -C 6 alkyl, and C 1 -C 6 alkyl phosphate;
R 13 and R 14 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and, C 1 -C 6 heteroalkyl, or optionally taken together with the atoms to which they are attached to form a ring; and
R 15 is hydroxy, C 1 -C 6 alkoxy or amino;
wherein each aryl, heteroaryl, cycloalkyl, or heterocycle is independently unsubstituted or substituted with one or more substituents independently selected from cyano, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino-C 1 -C 6 alkyl, haloalkyl, sulfonyl, —C(O)—C 1 -C 6 alkoxy, and —C(O)—NH 2 .
2 . The compound of claim 1 , or a pharmaceutical salt thereof, wherein L 1 is —S(O 2 )—.
3 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein Ar 1 is selected from a 5-membered heteroaryl, a 6-membered aryl, or a 6-membered heteroaryl,
wherein each aryl or heteroaryl is unsubstituted or substituted with one or two substituents independently selected from cyano, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloalkyl, sulfonyl, and —C(O)—C 1 -C 6 alkoxy.
4 . The compound of claim 3 , or a pharmaceutical salt thereof, wherein the halo is fluoro or chloro.
5 . The compound of claim 3 , or a pharmaceutical salt thereof, wherein the haloalkyl is trifluoromethyl.
6 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein Ar 1 is,
7 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein Ar 1 is
8 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein Ar 2 is selected from a 5-membered heteroaryl, a 6-membered aryl, or a 6-membered heteroaryl,
wherein each aryl or heteroaryl is unsubstituted or substituted with one or two substituents independently selected from cyano, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(O)—C 1 -C 6 alkoxy, and —C(O)—NH 2 .
9 . The compound of claim 8 , or a pharmaceutical salt thereof, wherein the halo is fluoro or chloro.
10 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein Ar 2 is
11 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein Ar 2 is
12 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein
Z is CHR 2 R 3 , COR 4 , or NHR 5 ;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 alkoxy, C 4 -C 8 heterocyclyl, phosphate, NR 6 R 7 , —OC(O)R 8 , and —S(O) 2 R 10 ;
R 4 is selected from the group consisting of hydroxy, C 1 -C 6 alkoxy, and NR 6 R 7 ;
R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —C(O)R 9 , and —S(O) 2 R 10 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 4 -C 8 heterocyclyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 5 -C 8 heteroaryl-C 1 -C 6 alkyl, C 5 -C 8 heterocyclyl-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, hydroxy-C 3 -C 8 cycloalkyl, cyano-C 1 -C 6 alkyl, hydroxysulfonyl-C 1 -C 6 alkyl, alkylphosphate-C 1 -C 6 alkyl, —COR 12 , and —CHR 13 C(O)R 14 ;
R 8 is C 6 -C 8 aryl or C 5 -C 8 -heteroaryl;
R 9 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, amino-C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, or —COR 12 ;
R 10 is amino-C 1 -C 6 alkyl;
R 12 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, amino-C 1 -C 6 alkyl, C 4 -C 8 heterocyclyl, amino-C 4 -C 8 heterocyclyl, phosphate-C 1 -C 6 alkyl, and C 1 -C 6 alkyl phosphate;
R 13 and R 14 are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; and
R 15 is selected from the group consisting of hydroxy, C 1 -C 6 alkoxy and amino.
13 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein Z is —CH 2 OH, —C(O)OH, —NH 2 , —NHC(O)CH 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 NH(CH 2 ) 2 OH, —CH 2 NH(CH 2 ) 3 OH, —CH 2 NH(C 5 H 9 O), —CH 2 NH(CH 2 ) 2 OCH 3 , —CH 2 NHCH 2 CH 3 , or —CH 2 NHCH 2 CH(OH)CH 3 .
14 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein m is 1.
15 . The compound of claim 1 , or a pharmaceutical salt thereof,
wherein X is O and n is 0.
16 . The compound of claim 1 , or a pharmaceutical salt thereof, wherein X is NR 1 .
17 . The compound of claim 16 , or a pharmaceutical salt thereof, wherein R 1 is hydrogen.
18 . The compound of claim 16 , or a pharmaceutical salt thereof,
wherein n is 0.
19 . The compound of claim 1 , selected from the group consisting of:
20 . A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
21 . A method for the treatment of a disorder associated with Transient Receptor Potential Cation Channel Subfamily V Member 4 (“TRPV4”) receptor activity in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 20 , and wherein the disorder is ocular hypertension.