Plasma kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-12528786-B2
Application number	US-202118014787-A
Country	US
Kind code	B2
Filing date	Jul 6, 2021
Priority date	Jul 10, 2020
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

The present invention provides a compound of Formula I

and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.

First claim

What is claimed is:

1 . A compound of the formula:

wherein X is CR 2 or N;
Y is

wherein

 is selected from

 is a 5 membered heteroaryl ring which is optionally substituted with one or two substituents independently selected from the group consisting of halo, cyano, R x and OR x ;
G is N or CR 7 ;
J is N or CR 8 ;
L is N or CR 7 ;
M is absent, N or CR 8 ;
each R 1 is independently selected from the group consisting of halo, cyano, R x and OR x ;
R 2 is hydrogen, halo, cyano, R x , OR x , CONH 2 or heteroaryl, wherein said heteroaryl is optionally substituted with halo;
R 3 is hydrogen, deuterium, halo or methyl;
R 4 is hydrogen, deuterium, halo, hydroxyl or methyl;
or R 3 and R 4 can be taken with the carbon atoms between them to form a C 3-6 membered cycloalkyl group;
R 5 is hydrogen or C 1-3 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo and hydroxyl;
or R 5 and L can be taken with the carbon atoms between them to form a C 3-6 membered cycloalkyl group;
R 6 is hydrogen, hydroxyl or C 1-3 alkyl;
or R 5 and R 6 can be taken together with the carbon atom between them to form a C 3-6 cycloalkyl group;
each R 7 is independently selected from the group consisting of hydrogen, halo, R x and OR x ;
each R 8 is independently selected from the group consisting of hydrogen, halo, R x , OR x and NH 2 ;
R 9 is hydrogen or C 1-3 alkyl;
R x is hydrogen or C 1-6 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, methoxy and ethoxy;
m is one or two;
n is an integer from zero to three;
or a pharmaceutically salt thereof.

2 . The compound of claim 1 wherein

is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl and oxazolyl, wherein said pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl and oxazolyl groups are optionally substituted with one or two substituents independently selected from the group consisting of halo, cyano, R x and OR x ; or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 wherein

is selected from the group consisting of pyrazolyl, triazolyl or isoxazolyl, wherein said pyrazolyl group is optionally substituted with R x or OR x ; or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 wherein X is CR 2 ; R 2 is cyano, CONH 2 , fluoropyrazolyl, R x or OR x ; or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 wherein R 1 is chloro, fluoro, methyl or cyano; n is one or two; or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 wherein Y is

or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 1 wherein

is

and R 9 is hydrogen; or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 1 wherein J is N; or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 1 selected from any one of
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide:
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazole-4-carboxamide carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-psyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((R or S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((S or R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(5-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(5-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-methyl-1-((R or S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-methyl-1-((S or R)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-cyano-1-((R or S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-cyano-1-((S or R)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-methyl-1-((R or S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-methyl-1-((S or R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;
N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Hicks Jacqueline D
• Kuang Rongze
• Sinz Christopher J
• Lombardo Matthew J
• Lopez Jovan Alexander
• Merchant Rohan Rajiv
• Sharp Phillip Patrick
• Wu Zhicai
• Zhao Zhiqiang
• Cheng Alan C
• Yang Song
• Bao Jianming
• Tian Maoqun
• Shearn-Nance Galen Paul

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61K45/06 Primary

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