SUBSTITUTED [1,2,4]TRIAZOLO[4,3-a]PYRAZINES AS BRD4 INHIBITORS

Patent metadata

Field	Value
Publication number	US-2016129001-A1
Application number	US-201614995578-A
Country	US
Kind code	A1
Filing date	Jan 14, 2016
Priority date	Nov 16, 2012
Publication date	May 12, 2016
Grant date	—

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

1 . A method of treating AML or MM comprising administering to a patient having AML or MM 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 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 method according to claim 1 , wherein, in the compound of formula I, R 1 is —CH 3 .

3 . The method according to claim 2 , wherein, in the compound of formula I, R 2 is —NHR 4 and R 4 is an optionally substituted 5-6 membered heterocycloalkyl.

4 . The method according to claim 3 , wherein, in the compound of formula I, 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 .

5 . The method according to claim 2 , wherein, in the compound of formula I, R 2 is —NHR 4 and R 4 is —C 1-3 alkyl.

6 . The method according to claim 5 , wherein, in the compound of formula I, R 2 is —NHR 4 and R 4 is —CH 3 or —CH(CH 3 ) 2 .

7 . The method according to claim 2 , wherein, in the compound of formula I, R 2 is —C 1-3 alkyl.

8 . The method according to claim 7 , wherein, in the compound of formula I, 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 .

9 . The method according to claim 1 , wherein, in the compound of formula I, —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 .

10 . The method according to claim 9 , wherein, in the compound of formula I, in the compound of formula I, —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 .

11 . The method according to claim 8 , wherein, in the compound of formula I, 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 .

12 . The method according to claim 1 , wherein, in the compound of formula I, 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.

13 . The method according to claim 11 , wherein, in the compound of formula I, 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.

14 . The method according to claim 13 , wherein, in the compound of formula I, 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.

15 . The method of claim 1 wherein the compound of formula I 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

II

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

• C07D239/50

  Three nitrogen atoms · CPC title

• C07C211/50

  with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton · CPC title

• C07D473/32

  Nitrogen atom · CPC title