Arginase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-12240867-B2
Application number	US-201917312480-A
Country	US
Kind code	B2
Filing date	Dec 13, 2019
Priority date	Dec 18, 2018
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

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:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Y is a straight or branched (C 2 -C 5 ) alkylenyl, 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 CR 7 R 8 or O;
X is a bond or CR 9 R 10 ;
Z is a bond or CR 11 R 12 ;
R is hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH or C 1 -C 6 alkylOC 1 -C 6 alkyl;
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, oxo and 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, oxo and OH;
R 3 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylNH 2 or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with the carbon to which it is attached and the adjacent hydrogen forms C═O;
R 4 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with the carbon to which it is attached and the adjacent hydrogen forms C═O;
R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylNH 2 ;

R 6 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH or C 1 -C 6 alkylOC 1 -C 6 alkyl;
R 7 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, NH 2 , or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with R 8 forms ═O;
R 8 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, NH 2 , or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with R 7 forms ═O;
R 9 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 23 )(R 24 ) or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with R 10 forms ═O;
R 10 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 23 )(R 24 ) or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with R 9 forms ═O;
R 11 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 23 )(R 24 ) or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with R 12 forms ═O;
R 12 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 23 )(R 24 ) or C 1 -C 6 alkylOC 1 -C 6 alkyl, or when taken with R 11 forms ═O;
R 13 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkylN(R 21 )(R 22 ), or C 1 -C 6 alkylOC 1 -C 6 alkyl or when taken with R 14 forms a nitrogen containing heterocycle or when taken with R 15 or R 16 forms a nitrogen containing heteroaryl or heterocycle;
R 14 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkylN(R 21 )(R 22 ), or C 1 -C 6 alkylOC 1 -C 6 alkyl or when taken with R 13 forms a nitrogen containing heterocycle or when taken with R 15 or R 16 forms a nitrogen containing heteroaryl or heterocycle;
R 15 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 21 )(R 22 ), C 1 -C 6 alkylCOOR 21 , C 1 -C 6 alkylCON(R 21 )(R 22 ), C 1 -C 6 alkylSH, C 1 -C 6 alkylSC 1 -C 6 alkyl or C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylaryl, C 1 -C 6 alkylheteroaryl, C 1 -C 6 alkylheterocycle or when taken with R 13 or R 14 forms a nitrogen containing heterocycle, or when taken with R 16 forms a C 3 -C 7 cycloalkyl or heterocycle;
R 16 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 21 )(R 22 ), C 1 -C 6 alkylCOOR 21 , C 1 -C 6 alkylCON(R 21 )(R 22 ), C 1 -C 6 alkylSH, C 1 -C 6 alkylSC 1 -C 6 alkyl or C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylaryl, C 1 -C 6 alkylheteroaryl, C 1 -C 6 alkylheterocycle or when taken with R 13 or R 14 forms a nitrogen containing heterocycle, or when taken with R 15 forms a C 3 -C 7 cycloalkyl or heterocycle;
R 17 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, or C 1 -C 6 alkylOC 1 -C 6 alkyl or when taken with R 18 forms a nitrogen containing heterocycle;
R 18 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, OH, C 1 -C 6 alkylOH, or C 1 -C 6 alkylOC 1 -C 6 alkyl or when taken with R 17 forms a nitrogen containing heterocycle;
R 19 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylS C 1 -C 6 alkyl or C 1 -C 6 alkylOC 1 -C 6 alkyl;
R 20 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylS C 1 -C 6 alkyl or C 1 -C 6 alkylOC 1 -C 6 alkyl;
each occurrence of R 21 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;
each occurrence of R 22 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;
each occurrence of R 23 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 21 )(R 22 ), C 1 -C 6 alkylCOOR 21 , C 1 -C 6 alkylCON(R 21 )(R 22 ), C 1 -C 6 alkylSH, C 1 -C 6 alkylSC 1 -C 6 alkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylaryl, C 1 -C 6 alkylheteroaryl or C 1 -C 6 alkylheterocycle; and
each occurrence of R 24 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylN(R 21 )(R 22 ), C 1 -C 6 alkylCOOR 21 , C 1 -C 6 alkylCON(R 21 )(R 22 ), C 1 -C 6 alkylSH, C 1 -C 6 alkylSC 1 -C 6 alkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylaryl, C 1 -C 6 alkylheteroaryl or C 1 -C 6 alkylheterocycle.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both hydrogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is propylenyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, CH 2 NH 2 or methyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a bond.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 9 R 10 and Z is a bond.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.

10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen, ethanol or methyl.

11. The compound of claim 1 , or a pharmaceutically acceptable sa

Assignees

• Merck Sharp & Dohme Llc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title