Heteroaryl amide inhibitors of CD38

Patent metadata

Field	Value
Publication number	US-12509451-B2
Application number	US-202118248325-A
Country	US
Kind code	B2
Filing date	Oct 8, 2021
Priority date	Oct 9, 2020
Publication date	Dec 30, 2025
Grant date	Dec 30, 2025

Abstract

Disclosed are heteroaryl amide inhibitors of CD38 and methods of making and using the same in disease and disorder treatment.

First claim

The invention claimed is:

1 . A compound of Formula I or a pharmaceutically acceptable salt, ester, or prodrug thereof

or
a compound of Formula I* or a pharmaceutically acceptable salt, ester, or prodrug thereof

wherein:
—X—Y—Z— is ═CR 1 —CR 2 ═CR 3 —, ═N—CR 2 ═CR 3 —, ═CR 1 —N═CR 3 — or ═CR 1 —CR 2 ═N if the compound is of Formula I;
—X—Y—Z— is CR 1 —CR 2 ═C, N—CR 2 ═C, or CR 1 —N═C if the compound is of Formula I*;
R 1 is selected from the group consisting of H, halo, —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and perfluoro(C 1 -C 6 )alkoxy-; wherein (C 1 -C 6 )alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 , and —OCF 3 ;
R 2 is H, halo, —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkoxy-, cycloalkyl, cycloalkyl-O—, heterocycloalkyl, heterocycloalkyl-O—, aryl, aryl-O—, R 5 —(C(R 4 ) 2 ) n —O—, or (R 6 ) 2 N—; wherein (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 , and —OCF 3 ;
R 3 is H, halo, (C 1 -C 3 )alkyl, —CF 3 , (C 1 -C 3 )alkoxy, —OCF 3 , or (R 7 ) 2 N—; wherein R 7 is H or (C 1 -C 3 )alkyl;
n is an integer from one to three;
each R 4 is independently H or (C 1 -C 3 )alkyl; wherein (C 1 -C 3 ) alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 , and —OCF 3 ;
R 5 is selected from the group consisting of (C 1 -C 3 ) alkyl, perfluoro (C 1 -C 3 )alkyl, HO—(C 2 -C 4 )alkyl-, cycloalkyl, heterocycloalkyl, and aryl; wherein (C 1 -C 3 )alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 , and —OCF 3 ;
R 6 is independently H or (C 1 -C 3 )alkyl; wherein (C 1 -C 3 ) alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 ) alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 , and —OCF 3 ;
W is

R 8 is H, —CH 3 or —CF 3 ;
Het is a heterocycle of the formulae

each R 9 is independently selected from H, halo, (C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 6 )alkoxy, —OCF 3 , —CN, (R 11 ) 2 N—, R 12 (O)(C═O)—, R 12 O((C 1 -C 3 )alkyl)-(NR 11 )—, R 13 —(C═O)—(NR 11 )—, and (R 11 ) 2 N—(C═O)—;
each R 10 is independently selected from H, (C 1 -C 3 ) alkyl, —CF 3 , —OCH 3 , —OCF 3 , —CN, (R 11 ) 2 N—, R 12 (O)(C═O)—, R 12 O—((C 1 -C 3 )alkyl)-(NR 11 )—, R 13 —(C═O)—(NR 11 )—, and (R 11 ) 2 N—(C═O);
R 11 is independently H or (C 1 -C 3 ) alkyl;
R 12 is H or (C 1 -C 3 )alkyl; and
R 13 is (C 1 -C 3 )alkyl.

2 . A compound according to claim 1 , wherein in the compound of Formula I or I*, R 8 is —CH 3 or —CF 3 ; and W is

3 . A compound according to claim 1 , wherein in the compound of Formula I or I*, R 8 is —CH 3 or —CF 3 ; and W is

4 . A compound according to claim 1 , wherein in the compound of Formula I or I*, R 8 is —CH 3 or —CF 3 ; and W is

5 . A compound according to claim 1 , wherein in the compound of Formula I or I*, R 8 is —CH 3 or —CF 3 ; and W is

6 . A compound according to claim 1 , wherein in the compound of Formula I or I *:
R 8 is —CH 3 or —CF 3 ; and W is

7 . A compound according to claim 1 , wherein in the compound of Formula I or I *:
R 8 is —CH 3 or —CF 3 ; and W is

8 . A compound according to claim 1 , wherein:
R 2 is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-, perfluoro(C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkoxy-, cycloalkyl, cycloalkyl-O—, heterocycloalkyl, aryl, R 5 —(C(R 4 ) 2 ) n —O— and (R 6 ) 2 N—; wherein (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl and aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 and —OCF 3 ; each R 4 is independently H or (C 1 -C 3 ) alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 and —OCF 3 ; R 5 is selected from the group consisting of (C 1 -C 3 )alkyl, cycloalkyl, heterocycloalkyl, and aryl; wherein (C 1 -C 3 )alky, cycloalkyl, heterocycloalkyl and aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 , and —OCF 3 ; and R 6 is independently H or (C 1 -C 3 ) alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 and —OCF 3 .

9 . A compound according to claim 1 , wherein R 3 is selected from the group consisting of H, halo, (C 1 -C 3 )alkyl, —CF 3 , —OCH 3 , —OCF 3 , and (R 7 ) 2 N—; and wherein R 7 is H or (C 1 -C 3 )alkyl.

10 . A compound according to claim 1 , wherein R 1 is selected from the group consisting of H, F, —CH 3 , and —OCH 3 .

11 . A compound according to claim 1 , wherein:
R 2 is selected from the group consisting of H, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy-, perfluoro(C 1 -C 3 )alkyl, perfluoro(C 1 -C 3 )alkoxy-, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O—, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, R 5 —(C(R 4 ) 2 ) n —O— and (R 6 ) 2 N—; wherein (C 1 -C 3 )alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkyl-O—, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, —CN, (C 1 -C 3 )alkyl, —NH 2 , (C 1 -C 3 )alkyl-(NH)—, ((C 1 -C 3 )alkyl) 2 N—, —CF 3 , —OCH 3 , and —OCF 3 ; each R 4 is independently H or (C 1 -C 3 ) alkyl optionally substituted with 1-3 substituents independently selected from the group consis

Assignees

• Napa Therapeutics Ltd
• Buck Inst Res Aging

Inventors

• Volkmann Robert A
• Coe Jotham W
• Verdin Eric
• Perrone Rosalba
• Jackson Margaret
• Nelson Frederick R
• Silva Elena
• Felstead Steve

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title