Pyrimidine derivatives as modulators of the 5-HT
Provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, that is a modulator of 5-HT 2A and can be used in treating diseases and disorders associated with 5-HT 2A serotonin receptor expression and/or activity. Thus, also provided are methods of treating 5HT 2A -related diseases and disorders.
1 . A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, 5-10 membered heteroaryl, 5-9 membered heterocycloalkyl, (C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 3 alkylene)-phenyl, (C 1 -C 3 haloalkylene)-phenyl, (C 1 -C 3 alkylene)-(5-10 membered heteroaryl), (C 1 -C 3 alkylene)-(5-9 membered heterocycloalkyl), (C 1 -C 3 alkylene)-O—(C 3 -C 6 cycloalkyl), and (C 1 -C 3 alkylene)-NH—(C 3 -C 6 cycloalkyl), wherein the alkyl, alkylene, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH 2 , C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), and phenyl;
R 2 is selected from 4-6 membered heterocycloalkyl, (C 1 -C 3 alkylene)-(4-10 membered heterocycloalkyl), and (C 1 -C 3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, —OH, —C 1 -C 3 alkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-C(O)OH, —C(O)H, —C(O)OH, —C(O)(C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkylene)-OH, —C(O)C(O)OH, and —SO 2 (C 1 -C 3 alkyl);
R 2A and R 2B are each independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-OH, (C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 3 alkylene)-S(═O)—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-SO 2 —(C 1 -C 3 alkyl), and C(═NH)(C 1 -C 3 alkyl);
or R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-9 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, —OH, C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-C(O)OH, —C(O)H, —C(O)(C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkylene)-OH, —C(O)C(O)OH, and —SO 2 (C 1 -C 3 alkyl), and optionally containing one additional heteroatom selected from the group of N, O, and S;
R 3 and R 4 are each independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
R 5 is selected from H and C 1 -C 6 alkyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and —O—(C 1 -C 3 alkyl).
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3 -C 6 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, —OH, C 1 -C 3 haloalkyl, —C 3 -C 6 cycloalkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), and phenyl.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, —CN, —NH 2 , C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl-, and —O—(C 1 -C 3 alkyl).
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 5-10 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, C 1 -C 3 alkyl, and —O—(C 1 -C 3 alkyl).
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 5-9 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C 3 alkyl.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 4-6 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from halogen, oxo, —OH, —C 1 -C 3 alkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-C(O)OH, —C(O)H, —C(O)(C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkylene)-OH, —C(O)C(O)OH, and —SO 2 (C 1 -C 3 alkyl).
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is (C 1 -C 3 alkylene)-(4-10 membered heterocycloalkyl), wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, —OH, —C 1 -C 3 alkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-C(O)OH, —C(O)H, —C(O)OH, —C(O)(C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkylene)-OH, —C(O)C(O)OH, and —SO 2 (C 1 -C 3 alkyl).
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is (C 1 -C 3 alkylene)-NR 2A R 2B .
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, where R 2A is selected from H and C 1 -C 3 alkyl.
11 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2B is selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl, (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-OH, (C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 3 alkylene)-S(═O)—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-SO 2 —(C 1 -C 3 alkyl), and C(═NH)(C 1 -C 3 alkyl).
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-9 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, —OH, C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-C(O)OH, —C(O)H, —C(O)(C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkylene)-OH, —C(O)C(O)OH, and —SO 2 (C 1 -C 3 alkyl), and optionally containing one additional heteroatom selected from the group of N, O, and S.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 3 and R 4 is H and the other is C 1 -C 6 alkyl.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 3 and R 4 is H and the other is methyl.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each C 1 -C 3 alkyl.
16 . The compound of claim 1 , having the structure of Formula (Ia)
wherein:
each R 1A is independently selected from halogen, —OH, —NH 2 , C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), and phenyl;
R 2 is selected from 4-6 membered heterocycloalkyl, (C 1 -C 3 alkylene)-(4-10 membered heterocycloalkyl), and (C 1 -C 3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, —OH, —C 1 -C 3 alkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-C(O)OH, —C(O)H, —C(O)OH, —C(O)(C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkylene)-OH, —C(O)C(O)OH, and —SO 2 (C 1 -C 3 alkyl);
R 2A and R 2B are each independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-OH, (C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 3 alkylene)-SO 2 —(C 1 -C 3 alkyl), and C(═NH)(C 1 -C 3 alkyl);
or R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-9 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, —OH, C 1 -C 3 alkyl, (C 1 -C 3 haloalkyl), —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-C(O)OH, —C(O)H, —C(O)(C 1 -C 3 alkyl), —C(O)(C 1 -C 3 alkylene)-OH, —C(O)C(O)OH, and —SO 2 (C 1 -C 3 alkyl), and optionally containing one additional heteroatom selected from the group of N, O, and S;
R 3 and R 4 are each independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
n is 0, 1, 2, 3, 4, or 5;
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 , having the structure of Formula (If):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, 5-10 membered heteroaryl, 5-9 membered heterocycloalkyl, (C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 3 alkylene)-phenyl, (C 1 -C 3 haloalkylene)-phenyl, (C 1 -C 3 alkylene)-(5-10 membered heteroaryl), (C 1 -C 3 alkylene)-(5-9 membered heterocycloalkyl), (C 1 -C 3 alkylene)-O—(C 3 -C 6 cycloalkyl), and (C 1 -C 3 alkylene)-NH—(C 3 -C 6 cycloalkyl), wherein the alkyl, alkylene, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH 2 , C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl-, —O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), and phenyl;
R 2A and R 2B are each independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, (C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-OH, (C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 3 alkylene)-S(═O)—(C 1 -C 3 alkyl), (C 1 -C 3 alkylene)-SO 2 —(C 1 -C 3 alkyl), and C(═NH)(C 1 -C 3 alkyl);
R 3 and R 4 are each independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
R 5 is selected from H and C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof.