Substituted [1,2,4]triazolo[4,3-a]pyrazines as BRD4 inhibitors

Patent metadata

Field	Value
Publication number	US-10328074-B2
Application number	US-201614995578-A
Country	US
Kind code	B2
Filing date	Jan 14, 2016
Priority date	Nov 16, 2012
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

Method for treating AML and MM by administration of a compound of the formula (I)

wherein the groups R 1 to R 3 have the meanings given in the specification.

First claim

The invention claimed is:

1. A method for inhibiting bromodomain protein 4 activity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the formula (I):

wherein:
R 1 is —C 1-3 alkyl or —C 1-3 haloalkyl;
R 2 is —NHR 4 , —C 1-5 alkyl, —C 1-5 haloalkyl, halogen or —S—C 1-3 alkyl;
R 3 is 5-12 membered heteroaryl, substituted with —X—R 10 and optionally further substituted with one or more groups independently selected from R 9 ;
R 4 is —C 1-5 alkyl or 5-12 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R 5 ;
R 5 is —C 1-5 alkyl, —C 1-5 haloalkyl or —C 1-3 alkylene-O—C 1-3 alkyl;
R 9 is —C 1-5 alkyl, —O—C 1-5 alkyl, —N(C 1-5 alkyl) 2 , halogen, —C 1-3 alkylene-O—C 1-3 alkyl, —C 1-5 alkylene-N(C 1-5 alkyl) 2 or 5-12 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with one or more groups independently selected from ═O and —C 1-3 alkyl, or
R 9 is —C 6-10 aryl or 5-12 membered heteroaryl, which aryl and heteroaryl are optionally and independently substituted with one or more groups selected from halogen, —C 1-3 alkyl, —O—C 1-3 alkyl, —C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —N(C 1-5 alkyl) 2 and —NH—C 1-5 alkyl;
X is —C 1-3 alkylene- or —O—; and
R 10 is —C 6-10 aryl or 5-12 membered heteroaryl, each optionally substituted with one or more groups selected from halogen, —C 1-3 alkyl, —O—C 1-3 alkyl, —C 1-3 haloalkyl and —O—C 1-3 haloalkyl;
or a pharmaceutically acceptable salt thereof, wherein the patient is treated for acute myeloid leukemia or multiple myeloma.

2. The method according to claim 1 , wherein R 1 is —CH 3 .

3. The method according to claim 1 , wherein R 2 is —NHR 4 and R 4 is optionally substituted 5-6 membered heterocycloalkyl.

4. The method according to claim 3 , wherein R 4 is tetrahydrofuranyl or piperidinyl, wherein piperidinyl is substituted with one group selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 and —(CH 2 ) 2 —O—CH 3 .

5. The method according to claim 1 , wherein R 2 is —NHR 4 and R 4 is —C 1-3 alkyl.

6. The method according to claim 5 , wherein R 4 is —CH 3 or —CH(CH 3 ) 2 .

7. The method according to claim 1 , wherein R 2 is —C 1-3 alkyl.

8. The method according to claim 1 , wherein R 3 is 5-9 membered heteroaryl substituted with —X—R 10 and optionally further substituted with one or more groups independently selected from R 9 .

9. The method according to claim 8 , wherein R 3 is pyrazolyl, imidazolyl, benzimidazolyl, imidazopyridinyl or imidazopyrimidinyl, each substituted with —X—R 10 and optionally further substituted with one or more groups independently selected from R 9 .

10. The method according to claim 9 , wherein R 3 is benzimidazolyl or imidazopyridinyl, each substituted with —CH 2 -phenyl, —CH 2 -pyridyl or —CH(CH 3 )-pyridyl and optionally further substituted with —C 1-3 alkyl or 5-12 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with one or more —C 1-3 alkyl.

11. The method according to claim 10 , wherein R 3 is imidazopyridinyl or benzimidazolyl each substituted with —CH 2 -phenyl, —CH(CH 3 )-pyridyl or —CH 2 -pyridyl and further substituted with —CH(CH 3 ) 2 , morpholinyl or piperazinyl, which morpholinyl and piperazinyl are optionally and independently substituted with one or more —C 1-3 alkyl.

12. The method according to claim 1 , wherein —X—R 10 is —CH 2 -phenyl, —CH(CH 3 )-phenyl, —CH 2 -pyridyl, —CH(CH 3 )-pyridyl or —O-phenyl, which phenyl and pyridyl are optionally and independently substituted with —F or —CH 3 .

13. The method according to claim 12 , wherein —X—R 10 is —CH 2 -phenyl, —CH(CH 3 )-phenyl, —CH 2 -pyridyl or —CH(CH 3 )-pyridyl, which phenyl and pyridyl are optionally and independently substituted with —F or —CH 3 .

14. The method according to claim 1 , wherein each R 9 is independently —C 1-3 alkyl, —O—C 1-3 alkyl, —N(C 1-3 alkyl) 2 , phenyl or 6 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with one or more groups independently selected from ═O and —C 1-3 alkyl.

15. The method according to claim 1 , wherein the compound is selected from the group consisting of:

Ex #
Structure

I-1

I-2

I-3

I-4

I-5

II-1

II-2

II-3

III-1

III-2

III-3

Assignees

• Boehringer Ingelheim Int

Inventors

• Engelhardt Harald
• Gianni Davide
• Smethurst Christian

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D473/32

  Nitrogen atom · CPC title