Bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9908885-B2
Application number	US-201615130503-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Apr 15, 2015
Publication date	Mar 6, 2018
Grant date	Mar 6, 2018

Abstract

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.

First claim

We claim:

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.

Assignees

• Celgene Quanticel Res Inc

Inventors

• Bennett Michael John
• Betancort Juan Manuel
• Boloor Amogh
• Kaldor Stephen W
• Stafford Jeffrey Alan
• Veal James Marvin

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title