IP Library › Granted Patent US 12,215,116

Granted Patent B2

US 12,215,116 · App. 16/977,253 · Granted Feb 4, 2025

Arginase inhibitors and methods of use

Inventors: Abdelghani Abe Achab (Melrose, MA); Matthew L. Childers (Medfield, MA); Jared N. Cumming (Winchester, MA); Christian Fischer (Natick, MA); Symon Gathiaka (Waltham, MA); Hakan Gunaydin (Somerville, MA); Charles A. Lesburg (Newton, MA); Derun Li (West Roxbury, MA); Min Lu (Brookline, MA); Anandan Palani (Needham, MA); Rachel L. Palte (Melrose, MA); Qinglin Pu (Needham, MA); David L. Sloman (Brookline, MA); Sung-Sau So (Verona, NJ); Chunrui Sun (Westfield, NJ); Hongjun Zhang (Boston, MA)

Assignee: Merck Sharp & Dohme LLC

C07F5/025 C07K16/2818

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Quick Facts

Patent No.: US 12,215,116
App. No.: 16/977,253
Granted: Feb 4, 2025
Kind: B2

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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 (164)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is selected from the group consisting of straight or branched (C 2 -C 5 ) alkylene, wherein one or more —CH 2 — groups in W are optionally and independently replaced with a moiety selected from the group consisting of —O—, —S— or —NH—;

V is selected from the group consisting of a bond, O, S, CR 6 R 7 or NR 8 ;

X is selected from the group consisting of a bond, O, S, CR 9 R 10 or NR 11 ;

Y is selected from the group consisting of a bond, O, S, CR 12 R 13 or NR 14 ,

is selected from the group consisting of a bond, O, S, CR 15 R 16 or NR 17 , R 1 is selected from the group consisting of 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 optionally substituted with one to four substituents selected from the group consisting of halogen, —C 1 -C 6 alkyl or —OH;

R 2 is selected from the group consisting of 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 optionally substituted with one to four substituents selected from the group consisting of halogen, —C 1 -C 6 alkyl or —OH;

R 3 is —COOH;

R 4 is hydrogen, halogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —COOH, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, heteroaryl, —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C 1 -C 6 alkylCOOH, —COOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, -haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —C 1 -C 6 alkylheteroaryl, —CON(R 18 )(R 19 ), —N(R 18 )(R 19 ) or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 6 is selected from the group consisting of hydrogen, halogen, —OH, C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, -haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 7 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 8 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 9 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, -haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 10 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 11 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 12 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 13 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 14 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 15 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 16 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 17 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, and —C 1 -C 6 alkylN(R 18 )(R 19 );

R 18 is independently selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylNH 2 , —COheterocycle, and —COC 1 -C 6 alkyl, wherein the —COC 1 -C 6 alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R 19 )(R 19 ), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R 18 taken with R 19 forms a 3-7 membered nitrogen containing ring; and

R 19 is independently selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl and —C 1 -C 6 alkyl, or R 19 taken with R 18 forms a 3-7 membered nitrogen containing ring;

wherein R 6 and R 7 , R 9 and R 10 , R 12 and R 13 , and R 15 and R 16 cannot be: —COOH and —N (R 18 )(R 19 ), or —N(R 18 )(R 19 ) and —COOH.

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

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

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently hydrogen or methyl.

5. The compound of claim 1 having Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

V is selected from the group consisting of a bond, O, S, CR 6 R 7 or NR 8 ;

Y is selected from the group consisting of a bond, O, S, CR 12 R 13 or NR 14 ,

Z is selected from the group consisting of a bond, O, S, CR 15 R 16 or NR 17 ,

R 1 is selected from the group consisting of 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 optionally substituted with one to four substituents selected from the group consisting of halogen, —C 1 -C 6 alkyl or —OH;

R 2 is selected from the group consisting of 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 6 cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C 1 -C 6 alkyl or —OH;

R 3 is —COOH;

R 4 is hydrogen, halogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, —COOH, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, heteroaryl, —C 1 -C 6 alkoxy and —COOC 1 -C 6 alkyl;

R 5 is selected from the group consisting of hydrogen, halogen —CN, —OH, —C 1 -C 6 alkylCOOH, —COOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —C 1 -C 6 alkylheteroaryl, —CON (R 18 )(R 19 ), —N(R 18 )(R 19 ) or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 6 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 8 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 14 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 17 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, and —C 1 -C 6 alkylN(R 18 )(R 19 );

R 18 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylNH 2 , —COheterocycle and —COC 1 -C 6 alkyl, wherein the —COC 1 -C 6 alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R 19 )(R 19 ), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R 18 taken with R 19 forms a 3-7 membered nitrogen containing ring; and

R 19 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl and —C 1 -C 6 alkyl, or R 19 taken with R 18 forms a 3-7 membered nitrogen containing ring;

wherein R 6 and R 7 , R 12 and R 13 , and R 15 and R 16 cannot be —COOH and —N(R 18 )(R 19 ) or —N(R 18 )(R 19 ) and —COOH.

6. The compound of claim 5 , or a pharmaceutically salt thereof, wherein R 1 and R 2 are both hydrogen.

7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein W is propylenyl.

8. The compound of claim 1 , having Formula III

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —COOH;

R 4 is hydrogen, halogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —COOH, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, heteroaryl, —C 1 -C 6 alkoxy and —COOC 1 -C 6 alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C 1 -C 6 alkylCOOH, —COOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —C 1 -C 6 alkylheteroaryl, CON (R 18 )(R 19 ), —N(R 18 )(R 19 ) or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 18 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylNH 2 , and —COC 1 -C 6 alkyl, wherein the —COC 1 -C 6 alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R 19 )(R 19 ), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R 18 taken with R 19 forms a 3-7 membered nitrogen containing ring; and

R 19 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl and —C 1 -C 6 alkyl, or R 19 taken with R 18 forms a 3-7 membered nitrogen containing ring.

9. The compound of claim 8 , or a pharmaceutically salt thereof, wherein R 1 and R 2 are both hydrogen.

10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein W is propylenyl.

11. The compound of claim 1 , having Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from the group consisting of a bond, O, S, CR 12 R 13 or NR 14 ,

X is selected from the group consisting of a bond, O, S, CR 9 R 10 or NR 11 ,

Z is selected from the group consisting of a bond, O, S, CR 15 R 16 or NR 17 ;

R 1 is selected from the group consisting of 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 6 cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C 1 -C 6 alkyl or —OH;

R 3 is —COOH;

R 5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C 1 -C 6 alkylCOOH, —COOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —C 1 -C 6 alkylheteroaryl, —CON(R 18 )(R 19 ), —N(R 18 )(R 19 ) or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 9 is selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 11 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 14 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 16 is selected from the group consisting of hydrogen, halogen, —OH, —C 6 alkylOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —COOH, —N(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 17 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylheteroaryl, and —C 1 -C 6 alkylN(R 18 )(R 19 );

R 18 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylNH 2 , —COheterocycle and —COC 1 -C 6 alkyl, wherein the COC 1 -C 6 alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R 19 )(R 19 ), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R 18 taken with R 19 forms a 3-7 membered nitrogen containing ring; and

R 19 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl and —C 1 -C 6 alkyl, or R 19 taken with R 18 forms a 3-7 membered nitrogen containing ring;

wherein R 9 and R 10 , R 12 and R 13 and R 15 and R 16 cannot be —COOH and —N(R 18 )(R 19 ) or —N(R 18 )(R 19 ) and —COOH.

12. The compound of claim 1 , having Formula V:

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —COOH;

R 4 is hydrogen, halogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —COOH, —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, heteroaryl, —C 1 -C 6 alkoxy and —COOC 1 -C 6 alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C 1 -C 6 alkylCOOH, COOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —C 1 -C 6 alkylheteroaryl, —CON (R 18 )(R 19 ), —N(R 18 )(R 19 ) or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 19 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl and —C 1 -C 6 alkyl, or R 19 taken with R 18 forms a 3-7 membered nitrogen containing ring.

13. The compound of claim 1 , having Formula VI:

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —COOH;

R 5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C 1 -C 6 alkylCOOH, —COOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —C 1 -C 6 alkylheteroaryl, CON (R 18 )(R 19 ),>—N(R 18 )(R 19 ) or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 19 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl and —C 1 -C 6 alkyl, or R 19 taken with R 18 forms a 3-7 membered nitrogen containing ring.

14. The compound of claim 1 , having Formula VII:

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —COOH;

R 4 is hydrogen, halogen, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —COOH, N (R 18 )(R 19 ), —C 1 -C 6 alkylN(R 18 )(R 19 ), —C 1 -C 6 alkylheteroaryl, heteroaryl, —C 1 -C 6 alkoxy or —COOC 1 -C 6 alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C 1 -C 6 alkylCOOH, —COOH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkylOH, —C 1 -C 6 alkylheteroaryl, —CON(R 18 )(R 19 ), —N(R 18 )(R 19 ) or —C 1 -C 6 alkylN(R 18 )(R 19 );

R 18 is selected from the group consisting of hydrogen, —haloC 1 -C 6 alkyl, —C 1 -C 6 alkyl, —C 1 -C 6 alkylNH 2 , —COheterocycle and —COC 1 -C 6 alkyl, wherein the —COC 1 -C 6 alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R 19 )(R 19 ), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R 18 taken with R 19 forms a 3-7 membered nitrogen containing ring; and

R 19 is selected from the group consisting of hydrogen, —C 3 -C 6 cycloalkyl, —haloC 1 -C 6 alkyl and —C 1 -C 6 alkyl, or R 19 taken with R 18 forms a 3-7 membered nitrogen containing ring.

15. A compound which is: