WDR5-MYC inhibitors

Patent metadata

Field	Value
Publication number	US-12398097-B2
Application number	US-202017631114-A
Country	US
Kind code	B2
Filing date	Jul 29, 2020
Priority date	Jul 29, 2019
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

Substituted N-phenyl 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

The invention claimed is:

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

wherein
Y is —XR 5b , C(O)OH, or C(O)OC 1-4 alkyl;
X is O, S, N, or NR 5a ,
R 0 is hydrogen or halogen;
R 1 is halogen, cyano, SF 5 , C 1-6 alkyl, C 2-6 alkenyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, or R 1G ;
R 1G is C 3-6 cycloalkyl, C 5-6 cycloalkenyl, phenyl, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein R 1G is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo or a cyclic ketal thereof, C 1-4 alkyl, and C 1-4 haloalkyl;
R 2 is hydrogen, C 1-4 alkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, halogen, or OH;
R 3 is C(O)OR 3a , C(O)NR 3b R 3c , C(O)R 3a , SR 3d , S(O)R 3d , S(O) 2 R 3d , S(O) 2 NR 3b R 3c , NO 2 , NR 3b C(O)R 3c , or NR 3b C(O)NR 3b R 3c ,
R 3a is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, -L 1 -R 30 , G 1 , or -L 1 -G 2 ;
R 3b and R 3c are independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, -L 1 -R 30 , G 1 , or -L 1 -G 2 , wherein
R 3b and R 3c together with the nitrogen to which they attach optionally form a 3- to 8-membered heterocyclyl, the heterocyclyl being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, OH, —OC 1-4 alkyl, —OC 1-4 haloalkyl, —C 1-6 alkylene-OH, —C 1-6 alkylene-OC 1-4 alkyl, NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —S(O) 2 C 1-4 alkyl; or
R 3b and R 3c together with the intervening —NC(O)— or —NC(O)N(R 3b )—, optionally form a 5- to 8-membered heterocyclyl, the heterocyclyl being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, OH, —OC 1-4 alkyl, —OC 1-4 haloalkyl, NH 2 , —NHC 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;

R 3d is C 1-8 alkyl, C 1-8 haloalkyl, -L 1 -R 30 , G 1 , or -L 1 -G 2 ;
L 1 is C 1-6 alkylene, wherein the C 1-6 alkylene is optionally substituted with halogen, OH, COOH, —C(O)OC 1-4 alkyl, C(O)NH 2 , —C(O)NHC 1-4 alkyl, or —C(O)N(C 1-4 alkyl) 2 ;
R 30 is —OR 30a , —SR 30a , —NR 30b R 30c , COOH, —C(O)OC 1-4 alkyl, C(O)NH 2 , —C(O)NHC 1-4 alkyl, or —C(O)N(C 1-4 alkyl) 2 ;
R 30a , R 30b , and R 30c are independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, G 1 , or -L 2 G 2 ;
L 2 is C 1-3 alkylene;
G 1 , at each occurrence, is independently C 3-10 carbocyclyl, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocyclyl, wherein G 1 is attached to the parent molecular moiety at a carbon atom of G 1 and optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, OH, —OC 1-4 alkyl, —OC 1-4 haloalkyl, NH 2 , —NHC 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;
G 2 , at each occurrence, is independently C 3-10 carbocyclyl, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocyclyl, wherein G 2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, OH, —OC 1-4 alkyl, —OC 1-4 haloalkyl, NH 2 , —NHC 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;
R 4 is hydrogen, halogen, OH, —OC 1-4 alkyl, —OC 1-4 haloalkyl, —OC 3-6 cycloalkyl, NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHC 3-6 cycloalkyl, —N(C 1-4 alkyl) (C 3-6 cycloalkyl), or —N(C 3-6 cycloalkyl) 2 ;
R 5a is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or —C 1-3 alkylene-C 3-6 cycloalkyl;
R 5b is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or —C 1-3 alkylene-C 3-6 cycloalkyl;
alternatively, R 5a and R 5b , together with the nitrogen to which they attach form a 3- to 8-membered heterocyclyl, the heterocyclyl being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, OH, —OC 1-4 alkyl, —OC 1-4 haloalkyl, —C 1-6 alkylene-OH, and —C 1-6 alkylene-OC 1-4 alkyl;
R 6 is hydrogen, halogen, 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;
alternatively, R 5b and R 6 , together with the intervening atoms form a 5- to 6-membered heteroaryl or a 5- to 7-membered heterocycle, wherein the heteroaryl and heterocycle 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 7 is hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, or —OC 1-4 haloalkyl; and
R 8 is halogen, cyano, C 1-2 alkyl, C 1-2 haloalkyl, —OC 1-2 alkyl, or —OC 1-2 haloalkyl;
provided the compound of formula (I) is not
3-[[(6-methyl-8-quinolinyl)sulfonyl]amino]-5-(trifluoromethyl)-benzoic acid;
3-[[(5-bromo-2-methoxyphenyl)sulfonyl]amino]-5-(trifluoromethyl)-benzoic acid; or
3-[[(3-bromo-5-chloro-2-methoxyphenyl)sulfonyl]amino]-5-(trifluoromethyl)-benzoic acid.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is OH or hydrogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is OH, hydrogen, or C 1-4 alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C(O)OR 3a , C(O)NR 3b R 3c , S(O)R 3d , S(O) 2 R 3d , NO 2 , NR 3b C(O)R 3c , or NR 3b C(O)NR 3b R 3c .

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C(O)OH.

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C(O)NR 3b R 3c .

7. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C(O)OH, C(O)NH 2 , C(O)NHCH 3 , C(O)NHCH 2 CH 2 OCH 3 , C(O)NHCH 2 CH 2 N (CH 3 ) 2 , NO 2 , S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 CH (CH 3 ) 2 , S(O) 2 CH 2 CH 2 N (CH 2 CH 3 ) 2 , S(O) 2 CH 2 CH 2 N (CH (CH 3 ) 2 ) 2 , S(O) 2 CH 2 CH 2 CH 2 N (CH (CH 3 ) 2 ) 2 , S (O) CH 3 , S (O) CH 2 CH 3 ,

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, SF 5 , C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 haloalkyl, or R 1G , wherein R 1G is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, and C 1-4 haloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —XR 5b , X is O; and R 5b is hydrogen of C 1-4 alkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —XR 5b ; X is O; and R 5b and R 6 , together with the intervening atoms form a 5- to 7-membered heterocycle containing 1-2 oxygen atoms, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, and C 1-4 haloalkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —XR 5b , X is N; and R 5b and R 6 , together with the intervening atoms form a 6-membered heteroaryl containing 1-2 nitrogen atoms, the heteroaryl being optionally substituted with 1-4 substitue

Assignees

• Univ Vanderbilt

Inventors

• Tansey William P
• Fesik Stephen W
• Stauffer Shaun R
• Waterson Alex G
• Han Changho
• Alvarado Joseph R
• Macdonald Jonathan D
• Chacon Simon Selena
• Nikhar Sameer S
• Kuznetsov Alexey

Classifications

• C07D333/24

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D333/20

  by nitrogen atoms (nitro, nitroso radicals C07D333/12) · CPC title

• C07D309/22

  Radicals substituted by oxygen atoms · CPC title

• C07D309/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D309/10

  Oxygen atoms · CPC title