Diazepane derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9695172-B2
Application number	US-201515114895-A
Country	US
Kind code	B2
Filing date	Feb 2, 2015
Priority date	Jan 31, 2014
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

The present invention provides compounds of any one of Formulae (I), (II-C) (e.g., Formula (II)), and (III), and pharmaceutically compositions thereof. Compounds of any one of Formulae (I), (II-C), and (III) are believed to be binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
X 1 is —O—, —S—, or —C(R X1 ) 2 —, wherein each instance of R X1 is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
Y 1 is N or CR Y1 , wherein R Y1 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
Z 1 is —O—, —N(R Z1 )— or —C(R Z1 ) 2 —, wherein each instance of R Z1 is independently hydrogen, halogen, 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 when attached to a nitrogen atom, or two instances of R Z1 are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;
each instance of R A1 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 A1a , —N(R A1a ) 2 , —SR A1a , —CN, —SCN, —C(═NR A1a )R A1a , —C(═NR A1a )OR A1a , —C(═NR A1a )N(R A1a ) 2 , —C(═O)R A1a , —C(═O)OR A1a , —C(═O)N(R A1a ) 2 , —NO 2 , —NR A1a C(═O)R A1a , —NR A1a C(═O)OR A1a , —NR A1a C(═O)N(R A1a ) 2 , —OC(═O)R A1a , —OC(═O)OR A1a , or —OC(═O)N(R A1a ) 2 , wherein each instance of R A1a 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 R A1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
a is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
each instance of R B1 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 B1a , —N(R B1a ) 2 , —SR B1a , —CN, —SCN, —C(═NR B1a )R B1a , —C(═NR B1a )OR B1a , —C(═NR B1a )N(R B1a ) 2 , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)N(R B1a ) 2 , —NO 2 , —NR B1a C(═O)R B1a , —NR B1a C(═O)OR B1a , —NR B1a C(═O)N(R B1a ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , or —OC(═O)N(R B1a ) 2 , wherein each instance of R B1a 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 R B1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
b is 0, 1, 2, or 3;
R C1 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 an oxygen protecting group;
R D1 is 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 D1a , —N(R D1a ) 2 , —SR D1a , —CN, —SCN, —C(═NR D1a )R D1a , —C(═NR D1a )OR D1a , —C(═NR D1a )N(R D1a ) 2 , —C(═O)R D1a , —C(═O)OR D1a , —C(═O)N(R D1a ) 2 , —NO 2 , —NR D1a C(═O)R D1a , —NR D1a C(═O)OR D1a , —NR D1a C(═O)N(R D1a ) 2 , —OC(═O)R D1a , —OC(═O)OR D1a , or —OC(═O)N(R D1a ) 2 , wherein each instance of R D1a 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 R D1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R E1 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, or a nitrogen protecting group;
R F1 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, or a nitrogen protecting group;
R G1 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; and
R H1 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
or R G1 and R H1 are joined to form a substituted or unsubstituted phenyl ring.

2. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
each instance of R K1 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 K1a , —N(R K1a ) 2 , —SR K1a , —CN, —SCN, —C(═NR K1a )R K1a , —C(═NR K1a )OR K1a , —C(═NR K1a )N(R K1a ) 2 , —C(═O)R K1a , —C(═O)OR K1a , —C(═O)N(R K1a ) 2 , —NO 2 , —NR K1a C(═O)R K1a , —NR K1a C(═O)OR K1a , —NR K1a C(═O)N(R K1a ) 2 , —OC(═O)R K1a , —OC(═O)OR K1a , or —OC(═O)N(R K1a ) 2 , wherein each instance of R K1a 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 R K1a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
c is 0, 1, 2, 3, or 4.

3. The compound of

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James E
• Gray Nathanael S
• Qi Jun
• Mckeown Michael R
• Buckley Dennis

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title