NSD family inhibitors and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11324729-B2
Application number	US-201816213564-A
Country	US
Kind code	B2
Filing date	Dec 7, 2018
Priority date	Dec 7, 2017
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

Provided herein are small molecule inhibitors of NSD1, NSD2 and/or NSD3 activity, and methods of use thereof for the treatment of disease, including leukemia, breast cancer, osteosarcoma, lung and prostate cancers and other solid tumors as well as other diseases dependent on the activity of NSD1, NSD2 and/or NSD3.

First claim

The invention claimed is:

1. A composition comprising a compound of Formula (IIb):

or a salt thereof;
wherein X is CH 2 or NH;
wherein R 2 is NH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 dihaloalkyl, C 1 -C 4 trihaloalkyl, and C 1 -C 4 aminoalkyl;
wherein R 4 is selected from H, halogen, OH, OCH 3 , OCH 2 CH 3 , CH 2 OH, NH 2 , CH 2 NH 3 , NHCH 3 , CH 3 , CH 2 CH 3 , CHCH 2 , trihalomethyl, trihaloethyl, dihalomethyl, dihaloethyl, halomethyl, and haloethyl;
wherein R 5 is selected from H, CH 3 , CH 2 CH 3 , OH, OCH 3 , NH 2 , and halogen;
wherein Z is NH, NCH 3 , S, O, CH 2 , or is absent;
wherein A is selected from a six-member aryl or heteroaryl ring, a heteroaryl bicyclic ring system comprising a five-member ring and a six-member ring, or absent;
wherein A, when present, is unsubstituted or substituted with one or more of halogen, OH, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , CH 2 OH, CH 2 OCH 3 , OCF 3 , OCH 2 CF 3 , NH 2 , CH 2 NH 3 , NHCH 3 , CH 3 , C 2 CH 3 , CHCH 2 , CH 2 CH(CH 3 ) 2 , SO 2 CHCH 2 , NO 2 , amide, trihalomethyl, trihaloethyl, dihalomethyl, dihaloethyl, halomethyl, and haloethyl;
wherein L is present or absent and is a 1-9 member alkyl, alkenyl, alkynyl, heteroalkyl, aminoalkyl, or amidealkyl chain optionally comprising one or more heteroatoms;
wherein Y is alkylacrylamide, alkylacrylimide, propenal, 3-buten-2-one, acrylamide, vinyl sulfonamide, propynamide, ethyl propenoate, propenanamide, propenenitrile, nitroethylene, or absent;
wherein R 7 is H, D, halogen, OH, NH 2 , CH 3 .

2. The composition of claim 1 , where the compound is selected from

3. The composition of claim 1 , wherein R2, R4, R5, R7, Z, A, L, and Y comprise any combination of the substituents depicted in the compounds

4. The composition of claim 1 , wherein A is selected from phenyl, indole, benzoisothiazole, benzothiophene, and benzoxazole.

5. The composition of claim 1 , wherein R 5 is F.

6. The composition of claim 1 , wherein R 7 is F.

Assignees

• Univ Michigan Regents

Inventors

• Cierpicki Tomasz
• Grembecka Jolanta
• Huang Huang
• Zari Sergei
• Cho Hyo Je
• Potopnyk Mykhaylo
• Dudkin Sergii
• Chen Wenbing
• Adam Yassir
• Howard Christina
• Kim Eungi

Classifications

• C07D277/84

  Naphthothiazoles · CPC title

• C07D277/64

  with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 · CPC title

• A61K31/428 Primary

  condensed with carbocyclic rings · CPC title

• C07D417/04

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

• C07D277/60

  condensed with carbocyclic rings or ring systems · CPC title