IP Library › Granted Patent US 12,240,867
Granted Patent B2
US 12,240,867 · App. 17/312,480 · Granted Mar 4, 2025

Arginase inhibitors and methods of use

Inventors: Abdelghani Abe Achab (Melrose, MA); Matthew L. Childers (Medfield, MA); Jared N. Cumming (Winchester, MA); Symon Gathiaka (Waltham, MA); Charles A. Lesburg (Waban, MA); Derun Li (West Roxbury, MA); Min Lu (Brookline, MA); Matthew J. Mitcheltree (Jamaica Plain, MA); Anandan Palani (Needham, MA); Rachel L. Palte (Melrose, MA); Hongjun Zhang (Boston, MA)
Assignee: Merck Sharp & Dohme LLC
C07F5/025
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Quick Facts
Patent No.
US 12,240,867
App. No.
17/312,480
Granted
Mar 4, 2025
Kind
B2
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.

Claims (72)

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 salt thereof, wherein R 6 is hydrogen.

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

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is C 1 -C 6 alkyl.

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

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

wherein,

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; and

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.

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

wherein,

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; and

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.

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

wherein,

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; and

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.

18. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

20. A method of treating cancer comprising administering to a patient in need thereof a compound or pharmaceutically acceptable salt of claim 1 , wherein the cancer is selected from the group consisting of renal cell carcinoma, prostate cancer, colorectal, breast cancer, skin cancer, lung cancer, ovarian cancer, and gastric cancer.

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

22. A compound selected from the group consisting of:

23. A compound selected from the group consisting of:

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 10, 2021
From: 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
To: MERCK SHARP & DOHME CORP.
Reel/Frame 056627/0543 →