Optically active azabicyclo ring derivative

Patent metadata

Field	Value
Publication number	US-12263167-B2
Application number	US-202418412308-A
Country	US
Kind code	B2
Filing date	Jan 12, 2024
Priority date	Aug 27, 2018
Publication date	Apr 1, 2025
Grant date	Apr 1, 2025

Abstract

The compound of formula (1a) wherein p is 1 or 2, R1-R4 are hydrogen atom or the like, and a-d are 1 or 2, or a pharmaceutically acceptable salt thereof, which has an antitumor effect by inhibiting the binding between a MLL fusion protein that is infused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.

First claim

The invention claimed is:

1. A compound of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, a halogen atom, —OR 7 , or M-Q; or R 1 and R 2 and/or R 3 and R 4 may be combined to form each independently ═O or ═CR 12A R 13A ;
M is, each independently if there are plural, C 1-6 alkylene, which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, chlorine atom, bromine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano) C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, 3- to 10-membered saturated heterocyclyl, C 6-10 arylene, or 5- to 12-membered heteroarylene, wherein the alkenylene, the alkynylene, the cycloalkylene, the saturated heterocyclyl, the arylene, and the heteroarylene may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, chlorine atom, bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
Q is, each independently if there are plural, a hydrogen atom, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
R 7 is, each independently if there are plural, a hydrogen atom, C 1-6 alkyl, which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, phenyl, 5- to 6-membered heteroaryl, C 2-4 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered saturated heterocyclyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
R 12A and R 13A are each independently a hydrogen atom, a halogen atom, C 1-6 alkyl, which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, and if there are plural R 12A or R 13A , each R 12A or R 13A may be the same or different, or when R 12A and R 13A are both C 1-6 alkyl, they may be combined with the carbon atom to which they are attached to form 3- to 8-membered saturated carbocycle;
R 35A is, each independently if there are plural, C 1-6 alkyl;
R 36A and R 37A are each independently a hydrogen atom or C 1-6 alkyl, and if there are plural R 36A or R 37A , each R 36A or R 37A may be the same or different, or when R 36A and R 37A are both C 1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
a, b, c, and d are each independently 1 or 2;
P 0 is each independently a hydrogen atom or P 1 ; and
P 1 is each independently an amino-protecting group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, a halogen atom, —OR 7 , or M-Q; or R 1 and R 2 and/or R 3 and R 4 may be combined together to form each independently ═O or ═CR 12A R 13A ;
M is, each independently if there are plural, C 1-6 alkylene, which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
Q is, each independently if there are plural, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano;
R 7 is, each independently if there are plural, a hydrogen atom, C 1-6 alkyl, or C 2-6 alkenyl, wherein the alkyl and the alkenyl may be substituted with one phenyl;
R 12A and R 13A are each independently hydrogen atom, C 1-6 alkyl, which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 35A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 36A R 37A , and cyano, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, —CONR 36A R 37A , —NR 36A R 37A , —NR 36A COR 37A , —NR 36A SO 2 R 35A , —SO 2 R 35A , —SO 2 NR 37A R 37A , and cyano, and if there are plural R 12A or R 13A , each R 12A or R 13A are the same or different, or when R 12A and R 13A are both C 1-6 alkyl, they may be combined with the carbon atom to which they are attached to form 3- to 8-membered saturated carbocycle;
R 35A is, each independently if there are plural, C 1-6 alkyl;
R 36A and R 37A are each independently hydrogen atom or C 1-6 alkyl, and if there are plural R 36A or R 37A , each R 36A or R 37A may be the same or different, or when R 36A and R 37A are both C 1-6 alkyl, they ma

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Kamioka Seiji
• Ban Hitoshi
• Shimada Naoaki
• Hirose Wataru
• Arakawa Akihiko
• Yamazaki Kazuto
• Hira Kenjiro

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

• A61K45/06

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

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title