Xanthine derivatives and uses thereof as inhibitors of bromodomains of BET proteins

Patent metadata

Field	Value
Publication number	US-11180510-B2
Application number	US-201816762069-A
Country	US
Kind code	B2
Filing date	Nov 6, 2018
Priority date	Nov 6, 2017
Publication date	Nov 23, 2021
Grant date	Nov 23, 2021

Abstract

The present invention relates to a compound having the following formula (I): (I) wherein: —R is a (C 1 -C 6 )alkyl group; —R″ is preferably H; —Ar is a (C 5 -C 12 )arylene radical; —X 1 is —C(═O)—or —SO 2 —; and —R′ is chosen from the group consisting of possibly substituted (C 1 -C 6 )alkyl, heteroaryl, (C 5 -C 12 )aryl, and (hetero)cycloalkyl groups, or a pharmaceutically acceptable salt and/or tautomeric form thereof, or its racemates, diastereomers or enantiomers.

First claim

The invention claimed is:

1. A compound having the following formula (I):

wherein:
R is a (C 1 -C 6 )alkyl group;
R″ is H or a group having the following formula (A):

wherein R 1 is H or a (C 1 -C 6 )alkyl group;
Ar is a (C 5 -C 12 )arylene radical;
X 1 is —C(═O)— or —SO 2 —; and
R′ is selected from the group consisting of:
(C 1 -C 6 )alkyl groups, optionally substituted with one or more substituents selected from the group consisting of:
(C 5 -C 12 )aryl, optionally substituted by a (C 1 -C 6 )alkyl group,
—OR a , R a being H or (C 1 -C 6 )alkyl,
—NH 2 ,
NH—C(═O)—O—(C 1 -C 6 )alkyl, and
(hetero)cycloalkyl;

heteroaryl groups,
optionally substituted with one or more substituents selected from the group consisting of:
(C 1 -C 6 )alkyl,
(C 5 -C 12 )aryl, and
heteroaryl groups, optionally substituted by a (C 1 -C 6 )alkyl group;

(C 5 -C 12 )aryl groups, optionally fused with one heterocycloalkyl or heteroaryl group, optionally substituted with one or more substituents selected from the group consisting of (C 1 -C 6 )alkyl, and COR 2 , R 2 being a (C 1 -C 6 )alkyl group;

said aryl group being optionally substituted with one or more substituents selected from the group consisting of:
(C 1 -C 6 )alkyl,
(C 5 -C 12 )aryl,
heteroaryl, optionally substituted by a (C 1 -C 6 )alkyl group,
halogen,
—CH 2 -heteroaryl,
heterocycloalkyl, optionally fused with a phenyl group,
—NO 2 ,
—OR a , R a being selected from the group consisting of:
H,
(C 1 -C 6 )alkyl,
(C 5 -C 12 )aryl, optionally substituted with a substituent chosen from the halo(C 1 -C 6 )alkyl groups,
cycloalkyl,
heteroaryl, optionally substituted with a (C 1 -C 6 )alkyl group,
heterocycloalkyl, optionally substituted with a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkylene-(C 2 -C 6 )alkynyl group, and
—CH 2 —(C 5 -C 12 )aryl,

—C(═O)—R e , R e being a heterocycloalkyl,
—NR b R c , R b and R c , being, independently of one another, H or (C 1 -C 6 )alkyl, and
—NHC(═O)R d , R d being a (C 1 -C 6 )alkyl group; and

(hetero)cycloalkyl groups, comprising 5 or 6 atoms and optionally one heteroatom, optionally substituted with one or more substituents selected from the group consisting of:
(C 1 -C 6 )alkyl,
—C(═O)R d , R d being a (C 1 -C 6 )alkyl group,
—OR d , R d being a (C 1 -C 6 )alkyl group,
—CH 2 —OR d , R d being a (C 1 -C 6 )alkyl group,
(C 5 -C 12 )aryl,
—C(═O)OR a , R d being a (C 1 -C 6 )alkyl group,
—CH 2 —NHC(═O)OR a , R d being a (C 1 -C 6 )alkyl group, and
—NHC(═O)OR a , R d being a (C 1 -C 6 )alkyl group;

or a pharmaceutically acceptable salt and/or tautomeric form thereof, or its racemates, diastereomers or enantiomers.

2. The compound of claim 1 , having the following formula (II):

wherein R and R′ are as defined in claim 1 .

3. The compound of claim 1 , having the following formula (III):

wherein:
Ar, R, and R″ are as defined in claim 1 ;
R′ is selected from the group consisting of:
(C 1 -C 6 )alkyl groups, optionally substituted with one or more substituents selected from the group consisting of:
(C 5 -C 12 )aryl, optionally substituted by a (C 1 -C 6 )alkyl group,
—OR a , R a being H or (C 1 -C 6 )alkyl,
—NH 2 ,
NH—C(═O)—O—(C 1 -C 6 )alkyl, and
(hetero)cycloalkyl;

heteroaryl groups,
optionally substituted with one or more substituents selected from the group consisting of:
(C 1 -C 6 )alkyl,
(C 5 -C 12 )aryl, and
heteroaryl groups, optionally substituted by a (C 1 -C 6 )alkyl group; and

(C 5 -C 12 )aryl groups, optionally fused with one heterocycloalkyl or heteroaryl group, optionally substituted with one or more substituents selected from the group consisting of: (C 1 -C 6 )alkyl or COR 2 , R 2 being a (C 1 -C 6 )alkyl group;

said aryl group being optionally substituted with one or more substituents selected from the group consisting of:
(C 1 -C 6 )alkyl,
(C 5 -C 12 )aryl,
heteroaryl, optionally substituted by a (C 1 -C 6 )alkyl group,
halogen,
—CH 2 -heteroaryl,
heterocycloalkyl, optionally fused with a phenyl group,
—NO 2 ,
—OR a , R a being selected from the group consisting of:
H,
(C 1 -C 6 )alkyl,
(C 5 -C 12 )aryl, optionally substituted with a halo(C 1 -C 6 )alkyl group,
cycloalkyl,
heteroaryl, optionally substituted with a (C 1 -C 6 )alkyl group,
heterocycloalkyl, optionally substituted with a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkylene-(C 2 -C 6 )alkynyl group, and
—CH 2 —(C 5 -C 12 )aryl,

—C(═O)—R e , R e being a heterocycloalkyl,
—NR b R c , R b and R c , being, independently of one another, H or (C 1 -C 6 )alkyl, and
—NHC(═O)R d , R d being a (C 1 -C 6 )alkyl group.

4. The compound of claim 1 , wherein Ar is a phenylene (—C 6 H 4 —) radical.

5. The compound of claim 1 , wherein R″ is H.

6. The compound of claim 1 , wherein R is methyl or ethyl.

7. The compound of claim 1 , having the following formula (IV):

wherein:
R is methyl or ethyl, and
X 1 and R′ are as defined in claim 1 .

8. The compound having the following formula (V):

wherein:
X 2 is a cycloalkylene or phenylene group, and
R 2 is a (C 1 -C 6 )alkyl group, substituted by a heteroaryl group, said heteroaryl group being optionally substituted by a (C 1 -C 6 )alkyl group,

or a pharmaceutically acceptable salt and/or tautomeric form thereof, or its racemates, diastereomers or enantiomers.

9. The compound of claim 1 , further comprising an excipient suitable for use as a medicament.

10. A pharmaceutical composition, comprising a compound according to claim 1 , and at least one pharmaceutically acceptable excipient.

11. A method of treating a condition selected from the group consisting of cancer, inflammatory disease, sepsis, autoimmune disease, neurodegenerative disease, cardiovascular disorder, renal disorder, viral infection, and obesity comprising administering to a patient in need thereof a pharmaceutically acceptable amount of the compound of claim 1 .

Assignees

• Centre Nat Rech Scient
• Univ Aix Marseille
• Inst Nat Sante Rech Med

Inventors

• Betzi Stéphane
• Combes Sébastien
• Collette Yves
• Hoffer Laurent
• Morelli Xavier
• Raux Brigit
• Roche Philippe
• Voitovich Iuliia

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D473/04

  two oxygen atoms · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D333/20

  by nitrogen atoms (nitro, nitroso radicals C07D333/12) · CPC title

• C07D409/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title