Urea compounds and compositions as SMARCA2/BRM ATPase inhibitors

Patent metadata

Field	Value
Publication number	US-12358906-B2
Application number	US-202418602126-A
Country	US
Kind code	B2
Filing date	Mar 12, 2024
Priority date	Aug 17, 2018
Publication date	Jul 15, 2025
Grant date	Jul 15, 2025

Abstract

A method of preparing compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein R 1 through R 6 are as defined herein.

First claim

What is claimed is:

1. A method of preparing a compound of formula I:

or a pharmaceutically acceptable salt thereof;
wherein said method comprises the step of reacting compound of Formula (I-1):

with a compound of Formula (I-2):

in the presence of a base;
wherein
R is a H or a nitro group;
R 1 and R 6 are as defined below or groups which may undergo further transformation to provide a compound of Formula (I-1) wherein
R 1 is selected from hydrogen, amino and hydroxy-substituted C 1-2 alkyl;
R 2 is hydrogen;
R 3 is selected from C 1-2 alkyl and halo-substituted-C 1-2 alkyl;
R 4 is hydrogen;
R 5 is selected from hydrogen and halo; and
R 6 is selected from hydrogen and halo.

2. The method of claim 1 wherein the step of reacting compound of Formula (I-1) with a compound of Formula (I-2) is carried out in a solvent selected from tetrahydrofuran (THF) and dioxane.

3. The method of claim 1 wherein the base is diisopropylethylamine (DIPEA).

4. The method of claim 1 wherein the step of reacting compound of Formula (I-1) with a compound of Formula (I-2) is carried out at room temperature or at a temperature of 60° C.

5. The method of claim 1 wherein the compound of Formula (I-2) is first deprotonated in the presence of a base which is lithium hexamethyldisilazide (LHMDS), followed by the reaction with the compound of Formula (I-1).

6. The method according to claim 1 further comprising the step of preparing the compound of Formula (I-1), wherein
said step comprises reacting compound of Formula (I-1a):

with a compound of Formula (I-1b):

in the presence of a base.

7. The method of claim 6 wherein the step of reacting compound of Formula (I-1a) and the compound of Formula (I-1b) is carried out in a solvent selected from dichloromethane and dioxane.

8. The method of claim 6 wherein the base is pyridine.

9. The method of claim 6 wherein the step of reacting compound of Formula (I-1a) and the compound of Formula (I-1b) is carried out at room temperature.

10. The method of claim 1 wherein in the compound of Formula (I),
R 1 is selected from hydrogen, amino and hydroxy-methyl;
R 2 is hydrogen;
R 3 is selected from methyl, difluoromethyl and trifluoromethyl;
R 4 is hydrogen;
R 5 is selected from hydrogen, chloro and fluoro; and
R 6 is selected from hydrogen and fluoro.

11. The method of claim 1 wherein the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 comprising the step of reacting a compound of Formula (I-1) which is:

wherein TBDMS is t-butyldimethylsilyl,
with a compound of Formula (I-2) which is:

in the presence of the base LHMDS in the solvent N,N-dimethylformamide (DMF) at room temperature to prepare compound having the following Formula:

which undergo further transformation by reaction with TBAF in THF at room temperature to generate compound of Formula (I):

13. The method of claim 12 further comprising the step of reacting:

in the presence of the base pyridine and in the solvent dichloromethane at room temperature to generate:

Assignees

• Novartis Ag

Inventors

• Adair Christopher
• Nakajima Katsumasa
• Ntaganda Rukundo
• Papillon Julien
• Smith Troy Douglas

Classifications

• A61K45/06

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title