Crosslinked optically active secondary amine derivative

Patent metadata

Field	Value
Publication number	US-12559487-B2
Application number	US-202017763265-A
Country	US
Kind code	B2
Filing date	Sep 25, 2020
Priority date	Sep 27, 2019
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

The present invention relates to the compound of formula (1a) wherein p is 1 or 2, R 1 -R 4 are hydrogen atom or the like, Ring A is cycloalkylene or the like, L is single bond or the like, and R is methyl or the like, or a pharmaceutically acceptable salt thereof, which has an anticancer effect by inhibiting the binding between a MLL fusion protein that is fused 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 (1a):

or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2;
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen atom, halogen, —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 5 the same or different substituents selected from the group consisting of 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 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, 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 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;
R 7 is, each independently if there are plural, 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 fluorine atom, chlorine atom, 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 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;
R 12A and R 13A are each independently hydrogen atom, halogen, C 1-6 alkyl (which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of 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 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 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, 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 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;
Ring A is (A-1), (A-2), (A-3), or (A-4):

wherein * is a bonding site to L, ** is a bonding site to the carbonyl group, and the dot-line in the ring means that there may be optionally a unsaturated bond in the ring;
R A1 and R A2 are each independently hydrogen atom or C 1-3 alkyl, or R A1 and R A2 may be combined with each carbon atom to which they are attached to form a bridged structure with C 1-3 alkylene;
a, b, c, and d are each independently 1, 2, or 3;
L is single bond or —CH 2 —; and
R is methyl or isopropyl.

2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
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 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.

3 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
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 5 the same or different substituents selected from the group consisting of 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.

4 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 7 is, each independently if there are plural, 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 fluorine atom, phenyl, C 3-7 cycloalkyl, and 3- to 7-membered saturated heterocyclyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl (wherein the cycloalkyl and the saturated heterocyclyl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom and C 1-3 alkyl), C 6-10 aryl, or 5- to 12-membered heteroaryl, wherein 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 fluorine atom, chlorine atom, bromine atom, and C 1-3 alkyl.

5 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 12A and R 13A are each independently 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 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

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Kamioka Seiji
• Shimada Naoaki
• Hirose Wataru
• Ban Hitoshi

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

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title