IP Library › Granted Patent US 12,528,786
Granted Patent B2
US 12,528,786 · App. 18/014,787 · Granted Jan 20, 2026

Plasma kallikrein inhibitors

Inventors: Jacqueline D. Hicks (Watchung, NJ); Rongze Kuang (Green Brook, NJ); Christopher J. Sinz (Walnut Creek, CA); Matthew J. Lombardo (Flemington, NJ); Jovan Alexander Lopez (New Haven, CT); Rohan Rajiv Merchant (Burlingame, CA); Phillip Patrick Sharp (San Francisco, CA); Zhicai Wu (Montvale, NJ); Zhiqiang Zhao (Little Neck, NY); Alan C. Cheng (San Francisco, CA); Song Yang (San Francisco, CA); Jianming Bao (Princeton, NJ); Maoqun Tian (Forster, CA); Galen Paul Shearn-Nance (Tiburon, CA)
Assignee: Merck Sharp & Dohme LLC
C07D401/14A61K45/06A61P27/02A61P35/00C07D403/14C07D413/14C07B2200/05
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Quick Facts
Patent No.
US 12,528,786
App. No.
18/014,787
Granted
Jan 20, 2026
Kind
B2
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.

Claims (222)

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)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)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-((R or S)-1-(3-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(3-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(3-fluoro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(3-fluoro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(5-fluoro-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-(5-fluoro-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-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;

1-((R or S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(4-methylpyridin-2-yl)cyclobutyl)-1H-pyrazole-4-carboxamide;

1-((S or R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(4-methylpyridin-2-yl)cyclobutyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-fluorophenyl)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-(2-cyano-5-fluorophenyl)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-(2-cyano-5-methylphenyl)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-((4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-(difluoromethyl)-1-((4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(4,5-dimethyl-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-(4,5-dimethyl-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-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(5-methoxy-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-(5-methoxy-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-(2-cyano-5-methylphenyl)cyclobutyl)-1-((R or S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)-1-((S or R)-1-(4,5-dimethyl-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-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-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)pyridazin-3-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-(methoxymethyl)-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-(methoxymethyl)-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-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((R or S)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazole-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)pyridazin-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)pyridazin-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-1,2,3-triazole-4-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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-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-1,2,3-triazole-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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(2-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)propan-2-yl)-1H-1,2,3-triazole-4-carboxamide;

N-((1R,3S)-3-(5-chloro-2-cyanophenyl)cyclopentyl)-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-1,2,3-triazole-4-carboxamide;

N-((1R,3S)-3-(5-chloro-2-cyanophenyl)cyclopentyl)-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-1,2,3-triazole-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-1,2,3-triazole-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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-(difluoromethoxy)phenyl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-(difluoromethoxy)phenyl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-(difluoromethyl)phenyl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-(difluoromethyl)phenyl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(4-chloropyridin-2-yl)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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(4-chloropyridin-2-yl)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-1,2,3-triazole-4-carboxamide;

N-(cis)-3-(5-chloro-2-cyanophenyl)-3-fluorocyclobutyl)-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-1,2,3-triazole-4-carboxamide;

N-(cis)-3-(5-chloro-2-cyanophenyl)-3-fluorocyclobutyl)-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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((R or S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((S or R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(3-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(3-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(3-fluoro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(3-fluoro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(2-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(2-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((R or S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R and S)-1-(5-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-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-1,2,3-triazole-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-1,2,3-triazole-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)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-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-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-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-1,2,3-triazole-4-carboxamide;

1-((R or S)-1-(5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-1,2,3-triazole-4-carboxamide;

1-((S or R)-1-(5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((R or S)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)-1-((R or S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)-1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((R or S)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-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)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-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)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)-1-((R or S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)-1-((S or R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(6-methoxy-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(6-methoxy-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1R,2R,3R or 1S,2S,3S)-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((R or S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1S,2S,3S or 1R,2R,3R)-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((R or S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1R,2R,3R or 1S,2S,3S)-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((S or R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1S,2S,3S or 1R,2R,3R)-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((S or R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((R or S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1R,2R,3R or 1S,2S,3S))-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((R or S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1S,2S,3S or 1R,2R,3R))-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((R or S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1R,2R,3R or 1S,2S,3S))-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1S,2S,3S or 1R,2R,3R))-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)-1-((R or S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)-1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((R or S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)-1-((S or R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R or S)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-cyano-5-methylphenyl)-3-methylcyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(2-carbamoyl-5-chlorophenyl)-3-methylcyclobutyl)-1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis or trans)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl-1-d)-1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((trans or cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl-1-d)-1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl-3-d)-1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl-1-d)-1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-(4-fluoro-1H-pyrazol-1-yl)phenyl)cyclobutyl)-1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-(5-(5-chloro-2-cyanophenyl)bicyclo[3.1.1]heptan-1-yl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1R,2R,3R or 1S,2S,3S))-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((1S,2S,3S or 1R,2R,3R))-3-(3-chlorophenyl)-2-hydroxycyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-3-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-3-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-2-hydroxy-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-2-hydroxy-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-((R)-1-hydroxy-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)isoxazole-3-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-((S)-1-hydroxy-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)isoxazole-3-carboxamide;

N-(cis)-3-(2-carbamoyl-5-chlorophenyl)cyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)cyclopropyl)-1H-pyrazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(1,5-dimethyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(1,5-dimethyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-hydroxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-hydroxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide;

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(4-fluoro-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-((S)-1-(4-fluoro-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-chloro-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-(5-chloro-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-((S)-1-hydroxyethyl)-1-((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)-3-((R)-1-hydroxyethyl)-1-((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)-3-((R)-1-hydroxyethyl)-1-((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-((S)-1-hydroxyethyl)-1-((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-methyl-3-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-5-carboxamide; and

N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-methyl-3-((R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-5-carboxamide

or a pharmaceutically acceptable salt thereof.

10 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11 . The composition of claim 10 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.

12 . A method for treating impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, or bleeding from postoperative surgery in a mammal, comprising administering a composition of claim 10 to a mammal in need of thereof.

13 . The method of claim 12 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.

14 . A method for treating hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.

15 . A method of treating diabetic retinopathy in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.

16 . A method of treating diabetic macular edema in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.

Assignments (2)
MERGER Recorded Jan 6, 2023
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 062304/0060 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 6, 2023
From: HICKS, JACQUELINE D.; KUANG, RONGZE; SINZ, CHRISTOPHER J.; LOMBARDO, MATTHEW J.; LOPEZ, JOVAN ALEXANDER; MERCHANT, ROHAN; SHARP, PHILLIP PATRICK; WU, ZHICAI; ZHAO, ZHIQIANG; CHENG, ALAN C.; YANG, SONG; BAO, JIANMING; TIAN, MAOQUN; SHEARN-NANCE, GALEN PAUL
To: MERCK SHARP & DOHME CORP.
Reel/Frame 062310/0462 →
Continuity (2)
Provisional Application 63050220 · Jul 10, 2020
Related Publication 20230348428A1 · Nov 2, 2023
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