Diaminopyrimidine benzenesulfone derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-10730860-B2
Application number	US-201816179759-A
Country	US
Kind code	B2
Filing date	Nov 2, 2018
Priority date	Jan 31, 2014
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

The present invention provides compounds of Formula (II) (e.g., compounds of Formula (I)), and pharmaceutically compositions thereof. Compounds of Formula (II) 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 method of treating a disease associated with aberrant activity of a bromodomain-containing protein or a bromodomain in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 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 when attached to a nitrogen atom;
each instance of R 2 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 D1 , —N(R D1 ) 2 , —SR D1 , —CN, —SCN, —C(═NR D1 )R D1 , —C(═NR D1 )OR D1 , —C(═NR D1 )N(R D1 ) 2 , —C(═O)R D1 , —C(═O)OR D1 , —C(═O)N(R D1 ) 2 , —NO 2 , —NR D1 C(═O)R D1 , —NR D1 C(═O)OR D1 , —NR D1 C(═O)N(R D1 ) 2 , —OC(═O)R D1 , —OC(═O)OR D1 , or —OC(═O)N(R D1 ) 2 , wherein each instance of R D1 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 D1 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R 3 and R 4 are each independently 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; or R 3 and R 4 are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R 5 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, or substituted or unsubstituted heteroaryl;
R 6 is halogen, substituted or unsubstituted phenyl, or —CN;
A is ═N— or ═C(R 2 )—;
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 ;
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 instances of R B1a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
p is 0 or an integer between 1 and 4, inclusive;
n is 0, 1, 2, 3, 4, 5, or 6;
L 1 , L 2 , and L 4 are each independently a bond,

L 3 is

R a1 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; and
each instance of R c1 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 c1a , —N(R c1a ) 2 , —SR c1a , —CN, —C(═O)R c1a , —C(═O)OR c1a , —C(═O)N(R c1a ) 2 , —NR c1a C(═O)R c1a , —NR c1a C(═O)OR c1a , —NR c1a C(═O)N(R c1a ) 2 , —OC(═O)R c1a , or —OC(═O)N(R c1a ) 2 , wherein each instance of R c1a 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 c1a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

2. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, selectively inhibits the activity of the bromodomain, compared to the activity of a kinase.

3. The method of claim 1 , wherein the bromodomain-containing protein is a bromo and extra terminal (BET) protein.

4. The method of claim 1 , wherein the bromodomain-containing protein is bromodomain-containing protein 2 (BRD2), bromodomain-containing protein 3 (BRD3), or bromodomain-containing protein 4 (BRD4).

5. The method of claim 1 , wherein the bromodomain-containing protein is a TBP (TATA box binding protein)-associated factor protein (TAF).

6. The method of claim 1 , wherein the bromodomain-containing protein is TAF1 or TAF1L.

7. The method of claim 1 , wherein the bromodomain-containing protein is CREB-binding protein (CBP).

8. The method of claim 1 , wherein the bromodomain-containing protein is E1A binding protein p300 (EP300).

9. The method of claim 1 , wherein the disease is an autoimmune disease, cardiovascular disease, viral infection, fibrotic disease, or metabolic disease.

10. The method of claim 1 , wherein the disease is rheumatoid arthritis, sepsis, atherogenesis, atherosclerosis, human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), human papillomavirus (HPV) infection, hepatitis C virus (HCV) infection, herpes simplex virus (HSV) infection, Ebola virus infection, severe acute respiratory syndrome (SARS), influenza, radiation poison

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James E
• Qi Jun
• Tanaka Minoru

Classifications

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title