Inhibitors of enl/af9 yeats

Patent metadata

Field	Value
Publication number	US-2023027198-A1
Application number	US-202017757492-A
Country	US
Kind code	A1
Filing date	Dec 17, 2020
Priority date	Dec 17, 2019
Publication date	Jan 26, 2023
Grant date	—

Abstract

Methods and compositions for treating leukemia are disclosed. Acylated 6-aminoindoles, acylated 6-aminopyrrolopyridines and acylated 3-aminopyrrolo[3,2-c]pyridazines of the following formulainhibit ENL/AF9 YEATS and are therefore useful for treating leukemia.

First claim

1 . A compound of formula Ia

wherein:
X 1 , X 2 , and X 3 are independently chosen from N and CR 4 , with the provisos that
(1) no more than two of X 1 , X 2 , and X 3 are N; and
(2) when X 1 and/or X 2 are CR 4 , then X 3 is not N;

R 1 is chosen from: H, (C 1-6 )alkyl, aryl(C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 1-6 )alkyl, heterocyclyl, heterocyclyl(C 1-6 )alkyl, (C 1-6 )alkylamino(C 1-6 )alkyl, heterocyclylamino(C 1-6 )alkyl, heterocyclyl(C 1-6 )alkylamino(C 1-6 )alkyl, (C 3-12 )cycloalkylamino(C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 1-6 )alkylamino(C 1-6 )alkyl, arylamino(C 1-6 )alkyl, and aryl(C 1-6 )alkylamino(C 1-6 )alkyl;
R 4 is chosen from H, CH 3 , and Cl;
R 5 is chosen from 5- or 6-member carbocycle or heterocycle; bicyclic 5:6 carbocycle or heterocycle and bicyclic 6:6 carbocycle or heterocycle, not attached at a nitrogen of said heterocycle, wherein said carbocycle or heterocycle may be optionally substituted with one or more groups chosen from (C 1-8 )hydrocarbyl, (C 1-10 )oxaalkyl, halogen, (C 1-6 )haloalkyl, —SO 2 (C 1-6 )alkyl, —SO 2 NH(C 0-3 H 1-7 ), —CONH(C 0-3 H 1-7 ), —SO 2 NH(C 1-6 )oxaalkyl, —CN, CH 2 CN, CH 2 NH 2 , —NH 2 , NR 14 where R 14 is independently chosen from hydrogen, (C 1-6 )fluoroalkyl, and (C 1-3 )oxaalkyl, —CH 2 OH, benzyloxy, —C(═NH)—NH 2 , -A-Het and additionally, when R 5 is a 5- or 6-member heterocycle, bicyclic 5:6 heterocycle, quinoline, isoquinolin, quinazolin, or benzo[b][1,4]oxazine, ═O; wherein A is chosen from direct bond, —(C 1-6 )alkyl-, —(C 1-10 )oxaalkyl-, —CO(C 1-6 )alkyl-, —SO 2 (C 1-6 )alkyl-, —SO 2 NH(C 1-6 )alkyl-, and —CONH(C 1-6 )alkyl-; and Het is heterocyclyl optionally substituted with (C 1-6 )hydrocarbyl, (C 1-10 )oxaalkyl, (C 1-10 )oxaalkyl(C═O)—, hydroxy, ═O, or halogen and
with the provisos that
(1) when all of X 1 , X 2 , and X 3 are carbon and R 5 is optionally substituted phenyl, then R 5 is

 and
(2) R 5 is not a 1,3-disubstituted pyrazole or 5-oxaalkylindazole

R 6 is selected from: H, Me, F, and Cl;
R 7 is hydrogen or halogen; and
R 8 is chosen from (C 1-10 )oxaalkyl, heterocyclyl, and heterocyclyl(C 1-10 )oxaalkyl
R 11 , R 12 and R 13 are chosen from the following three groups:
(a) R 11 is H or CH 3 ;
R 12 is chosen from H, (C 1 -C 6 )hydrocarbyl, hydroxy(C 1 -C 6 )hydrocarbyl, and 5- or 6-membered monocyclic heterocyclyl, wherein said heterocycle may be optionally substituted with (C 1 -C 6 )hydrocarbyl, hydroxyl, or hydroxy(C 1 -C 6 )hydrocarbyl; and R 13 is hydrogen or methyl; or

(b) R 11 and R 12 taken together form an optionally substituted nitrogenous heterocycle attached via nitrogen, said nitrogenous heterocycle chosen from (a) a monocyclic aliphatic nitrogenous heterocycle, (b) a 5:5 or 5:6 bicyclic aliphatic nitrogenous heterocycle, (c) a spirobicyclic aliphatic nitrogenous heterocycle, and (d) an 8-azabicyclo[3.2.1]octane, wherein said optional substituents are independently chosen from (C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyloxy, —(C 1-10 )oxaalkyl, COOH, —SO 2 (C 1-6 )alkyl, ═O, ═S, ═NH, and additionally, when R 11 and R 12 taken together for a spirobicyclic aliphatic nitrogenous heterocycle, halogen; and R 13 is chosen from H, (C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyloxy, —(C 1-10 )oxaalkyl, —SO 2 (C 1-6 )alkyl, ═O, ═S, and ═NH; or
(c) R 11 is H; and
R 12 and R 13 taken together form a 3- to 7-membered aliphatic carbocycle, wherein said carbocycle may be optionally substituted with (C 1 -C 6 )hydrocarbyl, hydroxyl, or hydroxy(C 1 -C 6 )hydrocarbyl.

2 . A compound according to claim 1 of formula Ib

wherein R 11 and R 12 taken together form an optionally substituted nitrogenous heterocycle, Q, chosen from (a) a monocyclic aliphatic nitrogenous heterocycle, (b) a 5:5 or 5:6 bicyclic aliphatic nitrogenous heterocycle, (c) a spirobicyclic aliphatic nitrogenous heterocycle, and (d) an 8-azabicyclo[3.2.1]octane, wherein said optional substituents are independently chosen from (C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyloxy, —(C 1-10 )oxaalkyl, COOH, —SO 2 (C 1-6 )alkyl, ═O, ═S, ═NH, and additionally, when R 11 and R 12 taken together for a spirobicyclic aliphatic nitrogenous heterocycle, halogen;
R 1 is chosen from: H, (C 1-6 )alkyl, aryl(C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 1-6 )alkyl, heterocyclyl, heterocyclyl(C 1-6 )alkyl, (C 1-6 )alkylamino(C 1-6 )alkyl, heterocyclylamino(C 1-6 )alkyl, heterocyclyl(C 1-6 )alkylamino(C 1-6 )alkyl, (C 3-12 )cycloalkylamino(C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 1-6 )alkylamino(C 1-6 )alkyl, arylamino(C 1-6 )alkyl, and aryl(C 1-6 )alkylamino(C 1-6 )alkyl.

3 . A compound according to claim 1 wherein
R 11 is H; and
R 12 and R 13 taken together form a 3- to 7-membered aliphatic carbocycle, wherein said carbocycle may be optionally substituted with (C 1 -C 6 )hydrocarbyl, hydroxyl, or hydroxy(C 1 -C 6 )hydrocarbyl.

4 . A compound according to claim 1 wherein
R 11 is H or CH 3 ;
R 12 is chosen from H, (C 1 -C 6 )hydrocarbyl, hydroxy(C 1 -C 6 )hydrocarbyl, and 5- or 6-membered monocyclic heterocyclyl, wherein said heterocycle may be optionally substituted with (C 1 -C 6 )hydrocarbyl, hydroxyl, or hydroxy(C 1 -C 6 )hydrocarbyl; and
R 13 is hydrogen or methyl.

5 . A compound of claim 1 wherein R 5 is chosen from bicyclic 5:6 carbocycle or heterocycle and bicyclic 6:6 carbocycle or heterocycle, not attached at a nitrogen of said heterocycle, wherein said carbocycle or heterocycle may be optionally substituted with a group chosen from (C 1-6 )alkyl, (C 1-6 )alkoxy, halogen, (C 1-6 )haloalkyl, CH 2 CN, CH 2 NH 2 , —NH 2 , NR 14 where R 14 is independently chosen from hydrogen, (C 1-6 )fluoroalkyl, and (C 1-3 )oxaalkyl, —CH 2 OH, and -A-Het, and additionally, when R 5 is a 5- or 6-member heterocycle, bicyclic 5:6 heterocycle, quinoline, isoquinolin, quinazolin, or benzo[b][1,4]oxazine, ═O; wherein A is chosen from direct bond, —(C 1-6 )alkyl-, —(C 1-10 )oxaalkyl-, —CO(C 1-6 )alkyl-, —SO 2 (C 1-6 )alkyl-, —SO 2 NH(C 1-6 )alkyl-, and —CONH(C 1-6 )alkyl-; and Het is heterocyclyl optionally substituted with (C 1-6 )hydrocarbyl, (C 1-10 )oxaalkyl, (C 1-10 )oxaalkyl(C═O)—, hydroxy, ═O, or halogen.

6 . A compound of claim 1 wherein R 5 is chosen from bicyclic 5:6 carbocycle or heterocycle and bicyclic 6:6 carbocycle or heterocycle wherein said carbocycle or heterocycle may be optionally substituted with a group chosen from (C 1-6 )alkyl, (C 1-6 )alkoxy, halogen, and (C 1-6 )haloalkyl.

7 . A compound according to claim 2 wherein Q is a monocyclic aliphatic nitrogenous heterocycle optionally substituted with one or more groups chosen from (C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyloxy, —(C 1-10 )oxaalkyl, COOH, —SO 2 (C 1-6 )alkyl, ═O, ═S, and ═NH.

8 . A compound according to claim 2 wherein Q is a 5:5 or 5:6 bicyclic aliphatic nitrogenous heterocycle optionally substituted with one or more groups chosen from (C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyl, halo(C 1-10 )hydrocarbyloxy, —(C 1-10 )oxaalkyl, COOH, —SO 2 (C 1-6 )alkyl, ═O, ═S, and ═NH.

9 . A compound according to claim 2 wherein Q is a spirobicyclic aliphatic nitrogenous heterocycle.

10 . A compound according

Assignees

• Univ Rockefeller
• Bridge Medicines Llc

Inventors

• Khan Tanweer A
• Liverton Nigel
• Fukase Yoshiyuki
• Michino Mayako
• Stamford Andrew W
• Miller Michael W
• Huggins David
• Meinke Peter
• Allis David C
• Wan Liling
• Ladduwahetty Tammy
• VACCA Joseph

Classifications

• A61K45/06 Primary

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• 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

• A61P35/00

  Antineoplastic agents · CPC title