Azaindole compounds as histone methyltransferase inhibitors

Patent metadata

Field	Value
Publication number	US-11111243-B2
Application number	US-201816002408-A
Country	US
Kind code	B2
Filing date	Jun 7, 2018
Priority date	Jun 9, 2017
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

The present disclosure provides certain angular tricyclic compounds that are histone methyltransferases G9a and/or GLP inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of G9a and/or GLP such as cancers and hemoglobinopathies (e.g., beta-thalassemia and sickle cell disease). Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

First claim

What is claimed:

1. A compound of Formula (I):

wherein:
X is CR 1 ;
Y is CR 2 ;
Q is N and P, T, and U are independently CH or C (when R 4 or R 5 is attached);
Z is NR 6 , wherein R 6 is hydrogen, alkyl, or cycloalkyl;
one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cycloalkyl;
R 3 is —W-alkylene-R 7 , wherein:
—W-alkylene- is —O—(CH 2 ) 1-3 * or —O—(CH 2 ) 2 —O—(CH 2 ) 2 —*, wherein * indicates the point of attachment to R 7 ;
R 7 is —NR a NR b , wherein R a and R b are alkyl; or R a and R b together with the nitrogen to which they are attached form pyrrolidinyl, wherein said pyrrolidinyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;

R 4 and R 5 are independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, halo, hydroxy, haloalkoxy, alkoxy, cyano, NH 2 , NR c R d , alkoxyalkylamino, hydroxyalkylamino, aminoalkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, alkoxyalkyloxy, or phenyl, wherein the phenyl or the cycloalkyl, either alone or as part of another group are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl of R 4 and R 5 is optionally substituted with cycloalkyl, and the alkenyl and the alkynyl of R 4 and R 5 are independently optionally substituted with hydroxy or cycloalkyl;
R c is hydrogen, alkyl, or cycloalkyl;
R d is alkyl or cycloalkyl; and
v and w are independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is hydrogen and the other is alkoxy.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —NR a NR b , wherein R a and R b are alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently methyl, ethyl, n-propyl or isopropyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 , halo, alkyl, hydroxy, alkoxy, cycloalkyl, or hydroxyalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, or cyclopentyl, wherein the cyclopropyl, the cyclobutyl, and the cyclopentyl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH 2 , alkylamino, dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is NH 2 , NR c NR d , alkoxyalkylamino, hydroxyalkylamino or aminoalkylamino; R c is hydrogen, alkyl, or cycloalkyl; and R d is alkyl or cycloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, or tert-butyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of:

Cmpd

No.
Structure

5

6

8

9

10

12

14

20

21

29

31

32

34

Assignees

• Global Blood Therapeutics Inc

Inventors

• Yu Chul
• Yu Ming
• Zancanella Manuel
• Li Zhe

Classifications

• C07D519/00

  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

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title