Diaminopyrimidine benzenesulfone derivatives and uses thereof
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.
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 poisoning, scleroderma, idiopathic pulmonary fibrosis, graft-versus-host disease (GVHD), diabetes, or obesity.
11. The method of claim 10 , wherein the diabetes is type II diabetes or gestational diabetes.
12. The method of claim 10 , wherein the disease is obesity.
13. The method of claim 1 , wherein the subject is a human.
14. The method of claim 1 , wherein the disease is a proliferative disease.
15. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are joined to form a substituted or unsubstituted heterocyclic ring.
18. The method of claim 1 , wherein R 1 is substituted or unsubstituted C 1-6 alkyl.
19. The method of claim 1 , wherein R 1 -L 3 - is
20. The method of claim 1 , wherein R 6 is halogen or —CN.
21. The method of claim 1 , wherein R 6 is substituted or unsubstituted phenyl.
22. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.