Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors

Patent metadata

Field	Value
Publication number	US-9266891-B2
Application number	US-201314076510-A
Country	US
Kind code	B2
Filing date	Nov 11, 2013
Priority date	Nov 16, 2012
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

Disclosed are compounds of the formula (I)

wherein the groups R 1 to R 3 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation pharmaceutical preparations containing such compounds and their uses as a medicament.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein,
R 1 is —C 1-3 alkyl or —C 1-3 haloalkyl;
R 2 is selected from —NHR 4 , —C 1-5 alkyl, —C 1-5 haloalkyl, halogen and —S—C 1-3 alkyl;
R 3 is a 5-12 membered heteroaryl, which group is substituted with —X—R 10 and optionally further substituted with one or more groups independently selected from R 9 ;
R 4 is selected from —C 1-5 alkyl and 5-12 membered heterocycloalkyl, which heterocycloalkyl can be optionally substituted with one or more groups independently selected from R 5 ;
R 5 is selected from —C 1-5 alkyl, —C 1-5 haloalkyl and —C 1-3 alkylene-O—C 1-3 alkyl;
R 9 is selected from —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 and 5-12 membered heterocycloalkyl, wherein the heterocycloalkyl group can be optionally substituted with one or more groups independently selected from ═O and —C 1-3 alkyl, or
R 9 is selected from —C 6-10 aryl and 5-12 membered heteroaryl, wherein the aryl and heteroaryl groups can be 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—;
R 10 is —C 6-10 aryl or 5-12 membered heteroaryl, each of which groups can be 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.

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

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

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

5. The compound according to claim 4 , wherein R 3 is selected from pyrazolyl, imidazolyl, benzimidazolyl, imidazopyridinyl and imidazopyrimidinyl and R 3 is substituted with —X—R 10 and R 3 is optionally further substituted with one or more groups independently selected from R 9 .

6. The compound according to claim 5 , wherein R 3 is imidazopyridinyl or benzimidazolyl 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 wherein the heterocycloalkyl group can be optionally substituted with one or more groups independently selected from —C 1-3 alkyl.

7. The compound according to claim 6 , wherein R 3 is imidazopyridinyl or benzimidazolyl substituted with —CH 2 -phenyl, —CH(CH 3 )-pyridyl or —CH 2 -pyridyl and further substituted with —CH(CH 3 ) 2 morpholinyl or piperazinyl, wherein the morpholinyl or piperazinyl groups is optionally substituted with one or more groups selected from —C 1-3 alkyl.

8. The compound according to claim 2 , wherein R 2 is —NHR 4 and R 4 is an optionally substituted 5-6 membered heterocycloalkyl.

9. The compound according to claim 8 , wherein R 4 is tetrahydrofuran or piperidine, wherein the piperidine 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 .

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

11. The compound according to claim 10 , wherein R 2 is —NHR 4 and R 4 is —CH 3 or —CH(CH 3 ) 2 .

12. The compound according to claim 1 , wherein —X—R 10 is selected from —CH 2 -phenyl, —CH(CH 3 )-phenyl, —CH 2 -pyridyl, —CH(CH 3 )-pyridyl and —O-phenyl, each of which phenyl or pyridyl groups is optionally substituted with —F or —CH 3 .

13. The compound according to claim 12 , wherein —X—R 10 is selected from —CH 2 -phenyl, —CH 2 -pyridyl, —CH(CH 3 )-phenyl and —CH(CH 3 )-pyridyl, each of which pyridyl or phenyl group is optionally substituted with —F or —CH 3 .

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

15. A pharmaceutical composition comprising a
therapeutically effective amount of a compound according to claim 1 in combination with one or more pharmaceutically acceptable excipients and/or carriers.

16. A method for inhibiting bromodomain protein 4 activity, comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 .

17. A compound selected from

Ex #
Structure

I-1

I-2

I-3

I-4

I-5

II-1

II-2

II-3

III-1

Assignees

• Engelhardt Harald
• Gianni Davide
• Smethurst Christian
• Boehringer Ingelheim Int

Inventors

• Engelhardt Harald
• Gianni Davide
• Smethurst Christian

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title