Myc modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-10017520-B2
Application number	US-201514965549-A
Country	US
Kind code	B2
Filing date	Dec 10, 2015
Priority date	Dec 10, 2014
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

The present disclosure provides compounds of Formula (I-a), Formula (I), and Formula (II). The compounds described herein may be Myc modulators (e.g., Myc inhibitors) and may be useful in treating in a subject in need thereof diseases associated with Myc and proliferative diseases (e.g., cancer). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including a compound described herein.

First claim

What is claimed is:

1. A compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein:
each instance of R A is independently hydrogen, 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 a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )S(═O)R a , —N(R a )S(═O)OR a , —N(R a )S(═O)N(R a ) 2 , —N(R a )S(═O) 2 R a , —N(R a )S(═O) 2 OR a , —N(R a )S(═O) 2 N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 , or two instances of R A are joined to form a substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl ring, or substituted or unsubstituted heteroaryl ring;
k is 0, 1, 2, or 3;
L is —NH—, —O—, or —S—;
X a is —NR B —, —O—, or —S—;
W a is —C(R A )═, or —N═;
R B is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R D is of the formula:

X 1 is —S—, —NR C —, or —CH 2 —;
each instance of R C is independently 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, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , or a nitrogen protecting group;
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, or two instances of R a are joined to form a substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl ring, or substituted or unsubstituted heteroaryl ring; and
Ring A is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; provided that the compound is not of the formula:

wherein the double bond labeled with “a” is in the (E)- or (Z)-configuration.

2. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
each instance of R A is independently 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 a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )S(═O)R a , —N(R a )S(═O)OR a , —N(R a )S(═O)N(R a ) 2 , —N(R a )S(═O) 2 R a , N(R a )S(═O) 2 OR a , —N(R a )S(═O) 2 N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 , or two instances of R A are joined to form a substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl ring, or substituted or unsubstituted heteroaryl ring;
each instance of R a is independently H, 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, or two instances of R a are joined to form a substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted heteroaryl ring;
k′ is 0, 1, 2, 3, or 4;
R B is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
X is —O— or —S—;
each double bond labeled with “a” is independently in the (E)- or (Z)-configuration; and
R C is hydrogen, 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, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , or a nitrogen protecting group;

provided that the compound is not of the formula:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W a is —N═.

4. The compound of claim 2 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R A is substituted or unsubstituted alkyl, halogen, —OR a , —N(R a ) 2 , —NO 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )C(═O)N(R a ) 2 , or —N(R a )S(═O) 2 R a .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein k is 0.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X a is —NR B —, and R B is hydrogen or substituted or unsubstituted C 1-6 alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X a is —O— or —S—.

10. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R C is substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted phenyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is of the

Assignees

• Massachusetts Inst Technology

Inventors

• Koehler Angela N
• Stefan Eric
• Caballero Francisco

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D417/12

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

• C07D471/04

  Ortho-condensed systems · CPC title