Arginase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-11274111-B2
Application number	US-201916973623-A
Country	US
Kind code	B2
Filing date	Jun 14, 2019
Priority date	Jun 20, 2018
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

Abstract

Described herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) act as arginase inhibitors and can be useful in preventing, treating or acting as a remedial agent for arginase-related diseases.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Y is a straight or branched (C 2 -C 5 )alkylene, wherein one or more —CH 2 — groups in Y are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH;
U is a bond, O, NR 15 or CR 7 R 8 ;
X is O, NR 15 or CR 9 R 10 , wherein U and X cannot be simultaneously O and NR 15 , respectively;
Z is a bond or CR 11 R 12 ;
R 1 is hydrogen, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl or, taken with R 2 forms a C 3 -C 8 cycloalkyl, wherein the C 3 -C 8 cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting of halogen, C 1 -C 6 alkyl or OH;
R 2 is hydrogen, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl or, taken with R 1 forms a C 3 -C 8 cycloalkyl, wherein the C 3 -C 8 cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting of halogen, C 1 -C 6 alkyl or OH;
R 3 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl;
R 4 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl;
R 5 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl or when taken with R 6 forms a C 3 -C 6 cycloalkyl or heterocycle, wherein the C 3 -C 6 cycloalkyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkylOH, C 3 -C 6 cycloalkyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COC 1 -C 6 alkyl, COC 1 -C 6 alkylN(R 13 )(R 14 ), COC 1 -C 6 alkyl(OH)N(R 13 )(R 14 ), C 1 -C 6 alkylCON(R 13 )(R 14 ), CON(R 13 )(R 14 ), SO 2 C 1 -C 6 alkyl, SO 2 N(R 13 )(R 14 ), N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkylaryl, C 1 -C 6 alkylhaloaryl, C(NH)N(R 13 )(R 14 ), heteroaryl, C 1 -C 6 alkoxy and COOC 1 -C 6 alkyl;
R 6 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl or when taken with R 5 forms a C 3 -C 6 cycloalkyl or heterocycle, or taken with R 7 forms a C 1 -C 6 alkyl bridge, or taken with R 10 or R 12 forms an aryl, heteroaryl, C 3 -C 6 cycloalkyl or heterocycle or when taken with R 15 forms a heteroaryl or heterocycle, wherein the aryl, heteroaryl, C 3 -C 6 cycloalkyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkylOH, C 3 -C 6 cycloalkyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COC 1 -C 6 alkyl, COC 1 -C 6 alkylN(R 13 )(R 14 ), COC 1 -C 6 alkyl(OH)N(R 13 )(R 14 ), C 1 -C 6 alkylCON(R 13 )(R 14 ), CON(R 13 )(R 14 ), SO 2 C 1 -C 6 alkyl, SO 2 N(R 13 )(R 14 ), N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkylaryl, C 1 -C 6 alkylhaloaryl, C(NH)N(R 13 )(R 14 ), heteroaryl, C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl;
R 7 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl or when taken with R 6 , R 11 or R 12 forms a C 1 -C 6 alkyl bridge or when taken with R 8 forms a C 3 -C 6 cycloalkyl or heterocycle, wherein the C 3 -C 6 cycloalkyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkylOH, C 3 -C 6 cycloalkyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COC 1 -C 6 alkyl, COC 1 -C 6 alkylN(R 13 )(R 14 ), COC 1 -C 6 alkyl(OH)N(R 13 )(R 14 ), C 1 -C 6 alkylCON(R 13 )(R 14 ), CON(R 13 )(R 14 ), SO 2 C 1 -C 6 alkyl, SO 2 N(R 13 )(R 14 ), N(R 13 )(R 14 ), —C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkylaryl, C 1 -C 6 alkylhaloaryl, C(NH)N(R 13 )(R 14 ), heteroaryl, C 1 -C 6 alkoxy and COOC 1 -C 6 alkyl;
R 8 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl or when taken with R 11 or R 12 forms a C 1 -C 6 alkyl bridge or when taken with R 7 forms a C 3 -C 6 cycloalkyl or heterocycle, or when taken with R 10 forms an aryl, heteroaryl, C 3 -C 6 cycloalkyl or heterocycle or when taken with R 15 forms a heteroaryl or heterocycle, wherein the aryl, heteroaryl, C 3 -C 6 cycloalkyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkylOH, C 3 -C 6 cycloalkyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COC 1 -C 6 alkyl, COC 1 -C 6 alkylN(R 13 )(R 14 ), COC 1 -C 6 alkyl(OH)N(R 13 )(R 14 ), C 1 -C 6 alkylCON(R 13 )(R 14 ), CON(R 13 )(R 14 ), SO 2 C 1 -C 6 alkyl, SO 2 N(R 13 )(R 14 ), N(R 13 )(R 14 ), —C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkylaryl, C 1 -C 6 alkylhaloaryl, C(NH)N(R 13 )(R 14 ), heteroaryl, C 1 -C 6 alkoxy and COOC 1 -C 6 alkyl;
R 9 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl or when taken with R 10 forms a C 3 -C 6 cycloalkyl or heterocycle, wherein the C 3 -C 6 cycloalkyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkylOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COC 1 -C 6 alkyl, COC 1 -C 6 alkylN(R 13 )(R 14 ), COC 1 -C 6 alkyl(OH)N(R 13 )(R 14 ), C 1 -C 6 alkylCON(R 13 )(R 14 ), CON(R 13 )(R 14 ), SO 2 C 1 -C 6 alkyl, SO 2 N(R 13 )(R 14 ), N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), —C 1 -C 6 alkylaryl, —C 1 -C 6 alkylhaloaryl, C(NH)N(R 13 )(R 14 ), heteroaryl, C 1 -C 6 alkoxy and COOC 1 -C 6 alkyl;
R 10 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl or when taken with R 6 or R 8 forms an aryl, heteroaryl, C 3 -C 6 cycloalkyl or heterocycle, or taken with R 9 forms C 3 -C 6 cycloalkyl or heterocycle, or when taken with R 15 forms a heteroaryl or heterocycle, wherein the aryl, heteroaryl, C 3 -C 6 cycloalkyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkylOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, COC 1 -C 6 alkyl, COC 1 -C 6 alkylN(R 13 )(R 14 ), COC 1 -C 6 alkyl(OH)N(R 13 )(R 14 ), C 1 -C 6 alkylCON(R 13 )(R 14 ), CON(R 13 )(R 14 ), SO 2 C 1 -C 6 alkyl, SO 2 N(R 13 )(R 14 ), N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkylaryl, C 1 -C 6 alkylhaloaryl, C(NH)N(R 13 )(R 14 ), C 1 -C 6 alkoxy and COOC 1 -C 6 alkyl;
R 11 is hydrogen, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylOC 1 -C 6 alkyl, COOH, N(R 13 )(R 14 ), C 1 -C 6 alkylN(R 13 )(R 14 ), C 1 -C 6 alkoxy or COOC 1 -C 6 alkyl or when taken with R 7 or R 8

Assignees

• Merck Sharp & Dohme

Inventors

• Achab Abdelghani Abe
• Cumming Jared N
• Fischer Christian
• Gathiaka Symon
• Lesburg Charles A
• Li Derun
• Lu Min
• Mitcheltree Matthew J
• Palani Anandan
• Palte Rachel L
• Sloman David L
• Zhang Hongjun

Classifications

• C07K16/2818

  against CD28 or CD152 · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61K45/06

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