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 compound of the formula:
or 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 compound of claim 1 , wherein the compound is of the formula:
or pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is of the formula:
or pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is of the formula:
or pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are joined to form a substituted or unsubstituted heterocyclic ring.
5. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
7. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is substituted or unsubstituted, C 1-6 alkyl.
8. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted t-butyl.
9. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 -L 3 - is
10. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is halogen or —CN.
11. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is substituted or unsubstituted phenyl.
12. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is 2-cyanophenyl.
13. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is
14. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is ═N—.
15. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2 is substituted or unsubstituted, C 1-6 alkyl; or —CN.
16. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2 is —CH 3 .
17. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 2 is
18. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are joined to form a substituted or unsubstituted heterocyclic ring.
19. The compound of claim 1 , wherein the compound is of the formula:
or pharmaceutically acceptable salt thereof.