Bromodomain inhibitors
The present invention relates to substituted heterocyclic derivative compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of cancer and neoplastic disease.
1. A compound of Formula III, or a pharmaceutically acceptable salt thereof,
wherein,
Ring C is an optionally substituted 5- or 6-membered heteroaryl ring containing at least one O, S or N atom;
X2 is N or CR 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;
X3 is N or CR 13 , wherein R 13 is —Y—Z, in which
Y is a bond, —CH 2 —, or —CH(C 1 -C 4 alkyl)-;
Z is —SO 2 R b , —N(R a )SO 2 R b , —SO 2 N(R a ) 2 , —N(R a )SO 2 N(R a ) 2 , —CON(R a ) 2 , —N(R a )CO 2 R a , —N(R a )CON(R a ) 2 , —N(R a )COR a , —OC(O)N(R a ) 2 , —OSO 2 N(R a ) 2 , or —N(R a )SO 3 R b ; wherein
each R a is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
R b is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
X4 is N or C—R 14 , wherein R 14 is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; and
G is described by:
wherein,
R 22 is alkyl;
R 23 is hydrogen, halogen, or alkyl; or, optionally, when R 23 is alkyl, then R 22 and R 23 join to form an optionally substituted ring;
R 25 is hydrogen, halogen, alkyl, alkoxy, or alkenyl;
R 26 is hydrogen, halogen, alkyl, alkoxy, aminoalkyl, or alkenyl; or, optionally,
when R 23 is hydrogen, R 25 is not hydrogen, and R 26 is not hydrogen or halogen, then
R 25 and R 26 join to form an optionally substituted cycloalkyl, heterocyclyl, or C 6 -aryl ring;
provided that the compound of Formula III is neither
4-(2-ethyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one, nor
4-(2-cyclopropyl-5-(methylsulfonyl)benzofuran-7-yl)-2-methylisoquinolin-1(2H)-one.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X2 is N.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X3 is N.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X4 is N.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X2 is C—R 12 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X3 is C—R 13 .
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X4 is C—R 14 .
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring C is an optionally substituted 5- or 6-membered heterocyclyl ring containing at least one S or N atom.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring C is an optionally substituted 5- or 6-membered heteroaryl ring that contains at least one S atom.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring C is an optionally substituted 5- or 6-membered heteroaryl ring that contains at least one N atom.
15. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5- or 6-membered heterocyclyl ring contains at least one S atom.
16. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5- or 6-membered heterocyclyl ring contains at least one N atom.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X2 is C—R 12 , X3 is C—R 13 , and X4 is C—R 14 .
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein ring C is selected to provide one of the following:
and wherein:
R 1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and
R 3 is hydrogen, halogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein ring C is selected to provide one of the following:
20. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:
R 13 is —Y—Z, in which Y is s a bond or —CH 2 —, Z is —SO 2 R b , —N(R a )SO 2 R b or —SO 2 N(R a ) 2 , each R a is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R b is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
R 1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and
R 3 is hydrogen, halogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
21. The compound of any one of claim 18 or 19 - 20 , or a pharmaceutically acceptable salt thereof, wherein:
R 13 is —Y—Z, in which Y is a bond or —CH 2 —, Z is —SO 2 R b or —N(R a )SO 2 R b , in which each R a is independently hydrogen or alkyl, and R b is alkyl;
R 1 is alkyl; and
R 3 is alkyl, cycloalkyl, or aryl.
22. A pharmaceutical composition comprising the compound of claim 1 .
23. An oral dosage form comprising the pharmaceutical composition of claim 22 .
24. A medicament comprising the pharmaceutical composition of claim 22 for use in the therapeutic treatment of cancer or other neoplastic disease.