EZH2 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10633371-B2
Application number	US-201716095188-A
Country	US
Kind code	B2
Filing date	Apr 21, 2017
Priority date	Apr 22, 2016
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

The present disclosure provides compounds of any one of Formulae (I), (II), and (III). The compounds described herein are inhibitors of histone methyltransferases (e.g., enhancer of zeste homolog 1 (EZH1) and enhancer of zeste homolog 2 (EZH2)) and are useful in treating and/or preventing a broad range of diseases (e.g., proliferative diseases). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R A1 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a1 ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a1 ) 2 , —OC(═O)R a , —OC(═O)OR a ,—OC(═O)N(R a1 ) 2 , a tag, or

each instance of R a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each instance of R a1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or two instances of R a1 are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring;
R A is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R B is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or R A and R B are joined to form a substituted or unsubstituted, carbocyclic ring, or a substituted or unsubstituted, heterocyclic ring;
R C is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R A2 is substituted or unsubstituted acyl, substituted or unsubstituted C 4-10 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, a tag, or a warhead;
R A3 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
R A20 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, —OR a , or —N(R a1 ) 2 ;
R A4 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R A5 is of the formula:

 wherein:
R A6 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, —OR a , or —N(R a1 ) 2 ;
R A7 is hydrogen, halogen, substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, —OR a , or —N(R a1 ) 2 ;
R A8 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, —OR a , or —N(R a1 ) 2 ;
R A9 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, —OR a , or —N(R a1 ) 2 ;
R A10 is —OR a ,—N(R a1 ) 2 , or a warhead;
each instance of R A11 is independently halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, —OR a , or —N(R a1 ) 2 ;
n is 0, 1, 2, 3, or 4;
R A12 is hydrogen, substituted or unsubstituted C 1-6 alkyl, a nitrogen protecting group, or a warhead;
each instance of R A13 is independently halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, —OR a , or —N(R a1 ) 2 ;
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
R A14 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, —OR a , or —N(R a1 ) 2 ;
R A15 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, —OR a , or —N(R a1 ) 2 ;
R A16 is hydrogen, halogen, substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, —OR a , or —N(R a1 ) 2 ; and
R A17 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6 alkyl, a nitrogen protecting group, or a warhead; and

each instance of the warhead is independently:

wherein:
L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 P—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L 4 is a bond or an optionally substituted, branched or unbranched C 1-6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substi

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James E
• Paulk Joshiawa
• Qi Jun

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/12

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

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title