WDR5-MYC inhibitors

Patent metadata

Field	Value
Publication number	US-12545649-B2
Application number	US-202017777686-A
Country	US
Kind code	B2
Filing date	Nov 18, 2020
Priority date	Nov 18, 2019
Publication date	Feb 10, 2026
Grant date	Feb 10, 2026

Abstract

Substituted N-heteroaryl sulfonamide compounds inhibit WDR5-MYC interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject such as cancer cell proliferation.

First claim

What is claimed is:

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein
G is

R 1a is G 1 , hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)R b , —C 1-6 alkylene-G 1 , or —CH(G 1 ) 2 ;
R 1b is—SO 2 R a , hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)R b , —C(O)OR b , —C(O)N(R b ) 2 , or G 1 ;
R 1c is hydrogen or C 1-4 alkyl;
Q is

R a , at each occurrence, is independently C 1-8 alkyl, C 1-8 haloalkyl, G 1 , —C 1-6 alkylene-G 1 , —CH(G 1 ) 2 , or -G 1 -G 2 ,
R b , at each occurrence, is independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, G 1 , —C 1-6 alkylene-G 1 , —CH(G 1 ) 2 , or -G 1 -G 2 ,
G 1 and G 2 , at each occurrence, are independently a C 3-12 carbocyclyl, a 6- to 12-membered aryl, a 4- to 12-membered heterocyclyl, or a 5- to 12-membered heteroaryl, wherein G 1 and G 2 are independently unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, oxo, X 2 , and —C 1-6 alkylene-X 2 ;
X 2 is cyano, —OR 10 , —N(R 10 ) 2 , —C(O)R 10 , —SR 10 , —SOR 10 , —SO 2 R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —SO 2 N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)OR 10 , —N(R 10 )C(O)N(R 10 ) 2 , or —N(R 10 ) SO 2 R 10 ,
R 10 is hydrogen, C 1-4 alkyl, —C 1-4 haloalkyl, C 3-6 cycloalkyl, or —C 1-3 alkylene-C 3-6 cycloalkyl, wherein alternatvely two R 10 , together with a common nitrogen to which they attach, form a 4- to 8-membered heterocyclyl optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, and oxo;
R 6 is halogen, hydrogen, cyano, C(O)OH, SF 5 , NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, —C 1-6 alkylene-OH, —C 1-6 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, or a 4- to 7-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, and C 1-4 haloalkyl;
R 8 is halogen, hydrogen, cyano, SF 5 , NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, or C 3-6 cycloalkyl; and
R 7 and R 9 are independently hydrogen, halogen, cyano, SF 5 , NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, or C 3-6 cycloalkyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1a is G 1 , hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)G 1 , —C 1-6 alkylene-G 1 , or —CH(G 1 ) 2 ; and R 1b is —SO 2 C 1-8 alkyl, hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)G 1 , —C(O)G 1 -G 2 , —C(O)OC 1-8 alkyl, COOH, —C(O)NH 2 , —C(O)NHC 1-8 alkyl, —C(O)N(C 1-8 alkyl) 2 , or G 1 .

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
G 1 and G 2 are each independently a C 3-8 cycloalkyl, phenyl, or a 4- to 8-membered heterocyclyl, wherein G 1 and G 2 are independently unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OR 10 , —N(R 10 ) 2 , —C 1-6 alkylene-OR 10 , and —C 1-6 alkylene-N(R 10 ) 2 .

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1a is a C 3-6 cycloalkyl, C 1-8 alkyl, C 1-8 haloalkyl, —C(O) C 3-6 cycloalkyl, phenyl, —CH(C 3-6 cycloalkyl) 2 , —C 1-3 alkylene-C 3-6 cycloalkyl, or —C 1-3 alkylene-G 1 , wherein the phenyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, and —OC 1-4 alkyl; R 1b is —SO 2 C 1-8 alkyl, hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)G 1 , —C(O)G 1 -G 2 , —C(O)OC 1-8 alkyl, COOH, —C(O)NH 2 , —C(O)NHC 1-8 alkyl, or —C(O)N(C 1-8 alkyl) 2 ; R 1c is hydrogen or C 1-4 alkyl; and G 1 and G 2 are each independently a 4- to 8-membered heterocyclyl, wherein G 1 and G 2 are independently optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OR 10 , —N(R 10 ) 2 , —C 1-6 alkylene-OR 10 , or —C 1-6 alkylene-N(R 10 ) 2 .

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Q is

7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein
R 7 and R 9 are hydrogen.

8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 6 and R 8 are halogen.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Q is

10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein
R 8 is halogen.

11 . The compound of claim 1 selected from the group consisting of
5-Bromo-3-chloro-N-(1-cyclopentyl-2-(methylsulfonyl)-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-cyclopentyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-cyclobutyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-cyclohexyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-phenyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclopropylmethyl)-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclobutanecarbonyl)-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclopentanecarbonyl)-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-cyclopropyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-cyclopentyl-2-methyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide
5-Bromo-3-chloro-N-(1-cyclopentyl-2-ethyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-cyclopentyl-5-methyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-2-hydroxy-N-(1-isopentyl-1H-imidazol-4-yl) benzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclobutylmethyl)-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclopentylmethyl)-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-2-hydroxy-N-(1-((tetrahydrofuran-2-yl) methyl)-1H-imidazol-4-yl) benzenesulfonamide;
5-Bromo-2-hydroxy-N-(1-((tetrahydrofuran-2-yl) methyl)-1H-imidazol-4-yl) benzenesulfonamide;
5-Bromo-3-chloro-N-(1-cyclobutyl-2-methyl-1-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-(dicyclopropylmethyl)-1-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-2-hydroxy-N-(1-(2-(trifluoromethyl) phenyl)-1H-imidazol-4-yl) benzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclopropylmethyl)-2-methyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclopentylmethyl)-2-methyl-1H-imidazol-4-yl)-2-hydroxybenzenesulfonamide;
5-Bromo-3-chloro-N-(1-(cyclobutylmethyl)-2

Assignees

• Univ Vanderbilt

Inventors

• Chacon Simon Selena
• Waterson Alex
• Macdonald Jonathan D
• FESIK Stephen
• Stauffer Shaun R
• Tansey William P

Classifications

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D403/12

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

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/12

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