Bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-10023592-B2
Application number	US-201715436340-A
Country	US
Kind code	B2
Filing date	Feb 17, 2017
Priority date	Oct 18, 2013
Publication date	Jul 17, 2018
Grant date	Jul 17, 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

I claim:

1. A method for inhibiting a histone demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (XXIV)

wherein the compound of Formula (XXIV) includes a pharmaceutically acceptable salt thereof, and wherein:
R 13 is —Y—Z; wherein
Y is a bond or —CH 2 —; and
Z is selected from —SO 2 R 21 , —N(R 22 )SO 2 R 21 , —SO 2 N(R 22 ) 2 , —N(R 22 )SO 2 N(R 22 ) 2 , —CON(R 22 ) 2 , —N(R 22 )CO 2 R 21 , —N(R 22 )CON(R 22 ) 2 , —N(R 22 )COR 21 , —COR 21 , —OC(O)N(R 22 ) 2 , —OSO 2 N(R 22 ) 2 , —N(R 22 )SO 3 R 21 , or —N(R 22 ) 2 , wherein
each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and
each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 14 is hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 15 is halogen or U—V, wherein
U is a bond, —O—, or —CH 2 —, and
V is —CN, alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

R B is

wherein
X6 is C—R 7 , wherein R 7 is hydrogen or halogen, and
X7 is C—R 8 , wherein R 8 is hydrogen or halogen;

or
R B is

wherein
X5 is C—R 5 , wherein R 5 is hydrogen or halogen, and
R 6 is hydrogen, alkyl, alkoxy, or halogen;

or

wherein
Ring B is optionally substituted 5-membered heterocyclyl ring containing at least one oxygen or sulfur atom.

2. The method of claim 1 , wherein Z is —SO 2 R 21 , —N(R 22 )SO 2 R 21 , —SO 2 R 21 , or —N(R 22 ) 2 .

3. The method of claim 1 , wherein R 21 is heterocyclyl or heterocyclylalkyl.

4. The method of claim 1 , wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl.

5. The method of claim 1 , wherein R 21 is alkyl, and the alkyl is C 1 -C 4 alkyl.

6. The method of claim 1 , wherein R 22 is alkyl, cycloalkyl, or aralkyl.

7. The method of claim 1 , wherein R 22 is hydrogen or methyl.

8. The method of claim 1 , wherein V is alkyl, aryl, aralkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or alkynyl.

9. The method of claim 1 , wherein Y is a bond; Z is —N(R 22 )SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.

10. The method of claim 1 , wherein Y is a bond; Z is —SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.

11. The method of claim 1 , wherein R B is

wherein X6 is C—R 7 , wherein R 7 is hydrogen or halogen, and X7 is C—R 8 , wherein R 8 is hydrogen or halogen.

12. The method of claim 11 , wherein R 7 is halogen and R 8 is hydrogen.

13. The method of claim 11 , wherein R 7 is hydrogen and R 8 is halogen.

14. The method of claim 11 , wherein both R 7 and R 8 are hydrogen.

15. A method of treating a histone demethylase-associated cancer wherein the cancer is selected from Burkitt lymphoma, promyelocytic leukemia, non-small cell lung cancer, NUT midline carcinoma, or breast cancer in a subject comprising administering a therapeutically effective dose of a compound of Formula (XXIV)

wherein the compound of Formula (XXIV) includes a pharmaceutically acceptable salt thereof, and wherein:
R 13 is —Y—Z; wherein
Y is selected from a bond or —CH 2 —, and
Z is selected from —SO 2 R 21 , —N(R 22 )SO 2 R 21 , —SO 2 N(R 22 ) 2 , —N(R 22 )SO 2 N(R 22 ) 2 , —CON(R 22 ) 2 , —N(R 22 )CO 2 R 21 , —N(R 22 )CON(R 22 ) 2 , —N(R 22 )COR 21 , —COR 21 , —OC(O)N(R 22 ) 2 , —OSO 2 N(R 22 ) 2 , —N(R 22 )SO 3 R 21 , or —N(R 22 ) 2 , and wherein
each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and
each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 14 is hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 15 is halogen or U—V, wherein
U is a bond, —O—, or —CH 2 —, and
V is —CN, alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

R B is

wherein
X6 is C—R 7 , wherein R 7 is hydrogen or halogen, and
X7 is C—R 5 , wherein R 8 is hydrogen or halogen;

or
R B is

wherein
X5 is C—R 5 , wherein R 5 is hydrogen or halogen, and
R 6 is hydrogen, alkyl, alkoxy, or halogen;

or
R B is

wherein
Ring B is an optionally substituted 5-membered heterocyclyl ring containing at least one oxygen or sulfur atom.

16. The method of claim 15 , wherein Z is —SO 2 R 21 , —N(R 22 )SO 2 R 21 , or —N(R 22 ) 2 .

17. The method of claim 15 , wherein R 21 is heterocyclyl or heterocyclylalkyl.

18. The method of claim 15 , wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl.

19. The method of claim 15 , wherein R 21 is alkyl, and the alkyl is C 1 -C 4 alkyl.

20. The method of claim 15 , wherein R 22 is alkyl, cycloalkyl, or aralkyl.

21. The method of claim 15 , wherein R 22 is hydrogen or methyl.

22. The method of claim 15 , wherein R 14 is hydrogen.

23. The method of claim 15 , wherein V is alkyl, aryl, aralkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or alkynyl.

24. The method of claim 15 , wherein Y is a bond; Z is —N(R 22 )SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.

25. The method of claim 15 , wherein Y is a bond; Z is —SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.

26. The method of claim 15 , wherein R B is

wherein X6 is C—R 7 , wherein R 7 is hydrogen or halogen;
and X7 is C—R 8 , wherein R 8 is hydrogen or halogen.

27. The method of claim 26 , wherein R 7 is halogen and R 8 is hydrogen.

Assignees

• Celgene Quanticel Res Inc

Inventors

• Boloor Amogh

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title