Optically active crosslinked cyclic secondary amine derivative

Patent metadata

Field	Value
Publication number	US-11325921-B2
Application number	US-201917042479-A
Country	US
Kind code	B2
Filing date	Mar 29, 2019
Priority date	Mar 30, 2018
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

The present invention relates to the compound of formula (I) wherein p is 1 or 2, R1 is —CF3 or the like, R2a, R2b, R3a, and R3b are hydrogen atom or the like, X is —C(═O)—or the like, 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 (1):

or a pharmaceutically acceptable salt thereof, wherein
p is 1 or 2,
R 1 is —CF 3 , —CHF 2 , or cyano,
R 2a , R 2b , R 3a , and R 3b are each independently hydrogen atom, halogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —OR 4 , 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, or 5- to 12-membered heteroaryl (wherein the alkyl may be substituted with 1-3 fluorine atoms; the cycloalkyl and the saturated heterocyclyl are each independently substituted with the same or different 1-5 substituents selected from the group consisting of fluorine atom and C 1-3 alkyl; and the aryl and the heteroaryl are each independently substituted with the same or different 1-5 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, and C 1-3 alkyl); or R 2a and R 2b may be combined together to form ═O, and R 3a and R 3b may be combined together to form ═O,
R 4 is, each independently if there are plural, hydrogen atom, C 1-6 alkyl, 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 alkyl may be substituted with the same or different 1-5 substituents selected from the group consisting of C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C 6-10 aryl, and 5- to 12-membered heteroaryl; the cycloalkyl and the saturated heterocyclyl may be each independently substituted with the same or different 1-5 substituents selected from the group consisting of fluorine atom and C 1-3 alkyl; and the aryl and the heteroaryl may be each independently substituted with the same or different 1-5 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, and C 1-3 alkyl), and
X is C(═O)— or C 1-6 alkylene.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is —C(═O)—, and R 1 is —CF 3 .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 2a , R 2b , R 3a , and R 3b are each independently hydrogen atom, fluorine atom, C 1-6 alkyl, or —OR 4 ; or R 2a and R 2b may be combined together to form ═0, and R 3a and R 3b may be combined together to form ═0, and
R 4 is, each independently if there are plural, hydrogen atom, C 2-6 alkenyl, or C 1-6 alkyl (wherein the alkyl may be substituted with C 6-10 aryl).

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (1) is the following formula (1-A):

wherein
p is 1 or 2,
R 2a and R 2b are each independently hydrogen atom, fluorine atom, or —OR 4 ,
R 3a and R 3b are each independently hydrogen atom or fluorine atom, or R 3a and R 3b may be combined together to form ═0, and
R 4 is, each independently if there are plural, hydrogen atom, C 2-4 alkenyl, or C 1-3 alkyl (wherein the alkyl may be substituted with phenyl).

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 2a and R 2b are hydrogen atom, and
R 3a and R 3b are each independently hydrogen atom or fluorine atom.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen atom, and R 3b is fluorine atom.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:
{(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.2]octan-3-yl}{6-[2- (2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
[(1R,3S,4S)-2-azabicyclo [2.2.1]heptan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
[(3S)-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
[(1S,3S,4S)-5, 5-difluoro-2-azabicyclo[2.2.2]octan-3-yl]{6-[2(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2, 3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl)methanone,
[1S,3S,4R,6S)-6-hydroxy-2-azabicyclo [2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2, 6-diazaspiro [3.3]heptan-2-yl}methanone,
(1S,3S,4S)-3-{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carbonyl}-2-azabicyclo[2.2.2]octan-5-one,
[(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-yl]{6[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
[(1S,3S,4R,6R)-6-fluoro-2-azabicyclo[2.2.2]octan-3-yl]{6[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
{(1S,3S,4R,6S)-6-[(prop-2-en-1-yl)oxy]-2-azabicyclo[2.2.2]octan-3-yl}{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
[(1S,3S,4R,6S)-6-(benzyloxy)-2-azabicyclo [2.2.2]octan-3-yl]}6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
4-{6-[3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
4-{6-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
4-{6-[(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
4-{6-[(1S,3S,4S)-5,5-difluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl{-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
4-{6-[(1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,6-diazaspiro[3.3]heptan-2-yl-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
[(3S)-2-azabicyclo[2.2.2]octan-3-yl]{6-[5-(difluoromethyl)-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone, and
[(1R,3S 4S)-2-azabicyclo [2.2.1]heptan-3-yl]{6-[5-(difluoromethyl)-2-(2,2,2-trifluoroethyl)thieno [2,3-b]pyridin-4-yl]-2, 6-diazaspiro [3.3]heptan-2-yl}methanone.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:
{(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.2]octan-3-yl}{6(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
[(1R,3S,4S)-2-azabicyclo [2.2.1]heptan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
[(3S)-2-azabicyclo[2.2.2]octan-3-yl]}6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
[(1S,3S,4S)-5,5-difluoro-2-azabicyclo[2.2.2]octan-3-yl]{6-[2(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
[1S,3S,4R,6S)-6-hydroxy-2-azabicyclo [2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
(1S,3S,4S)-3-{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carbonyl}-2-azabicyclo[2.2.2]octan-5-one,
[(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro [3.3]heptan-2-yl}methanone,
[(1S,3S,4R,6R)-6-fluoro-2-azabic

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

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

Classifications

• A61K45/06 Primary

  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

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• C07D519/00 Primary

  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