Pyrimidine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

Patent metadata

Field	Value
Publication number	US-12559462-B2
Application number	US-202118249762-A
Country	US
Kind code	B2
Filing date	Oct 26, 2021
Priority date	Oct 27, 2020
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

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.

First claim

What is claimed is:

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 substitut

Assignees

• Arena Pharm Inc

Inventors

• Semple Graeme
• Tran Thuy-Anh

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title