US 12,215,116 B2
Arginase inhibitors and methods of use
Abdelghani Abe Achab, Melrose, MA (US); Matthew L. Childers, Medfield, MA (US); Jared N. Cumming, Winchester, MA (US); Christian Fischer, Natick, MA (US); Symon Gathiaka, Waltham, MA (US); Hakan Gunaydin, Somerville, MA (US); Charles A. Lesburg, Newton, MA (US); Derun Li, West Roxbury, MA (US); Min Lu, Brookline, MA (US); Anandan Palani, Needham, MA (US); Rachel L. Palte, Melrose, MA (US); Qinglin Pu, Needham, MA (US); David L. Sloman, Brookline, MA (US); Sung-Sau So, Verona, NJ (US); Chunrui Sun, Westfield, NJ (US); and Hongjun Zhang, Boston, MA (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Appl. No. 16/977,253
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
PCT Filed Mar. 8, 2019, PCT No. PCT/US2019/021247
§ 371(c)(1), (2) Date Sep. 1, 2020,
PCT Pub. No. WO2019/177873, PCT Pub. Date Sep. 19, 2019.
Claims priority of provisional application 62/642,098, filed on Mar. 13, 2018.
Prior Publication US 2021/0040127 A1, Feb. 11, 2021
Int. Cl. C07F 5/02 (2006.01); C07K 16/28 (2006.01)
CPC C07F 5/025 (2013.01) [C07K 16/2818 (2013.01)] 46 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of straight or branched (C2-C5) alkylene, wherein one or more —CH2— 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, CR6R7 or NR8;
X is selected from the group consisting of a bond, O, S, CR9R10 or NR11;
Y is selected from the group consisting of a bond, O, S, CR12R13 or NR14,
is selected from the group consisting of a bond, O, S, CR15R16 or NR17, R1 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R2 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl or —C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of halogen, —C1-C6alkyl or —OH;
R3 is —COOH;
R4 is hydrogen, halogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylOH, —COOH, —C1-C6alkylN(R18)(R19), —C1-C6alkylheteroaryl, heteroaryl, —C1-C6alkoxy or —COOC1-C6alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —CN, —OH, —C1-C6alkylCOOH, —COOH, —C3-C6cycloalkyl, —C1-C6alkyl, -haloC1-C6alkyl, —C1-C6alkylOH, —C1-C6alkylheteroaryl, —CON(R18)(R19), —N(R18)(R19) or —C1-C6alkylN(R18)(R19);
R6 is selected from the group consisting of hydrogen, halogen, —OH, C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, -haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R7 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R8 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R9 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, -haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R10 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R11 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R12 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R13 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R14 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, or —C1-C6alkylN(R18)(R19);
R15 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R16 is selected from the group consisting of hydrogen, halogen, —OH, —C1-C6alkylOH, —C3-C6cycloalkyl, —C1-C6alkyl, —haloC1-C6alkyl, —COOH, —N(R18)(R19), —C1-C6alkylheteroaryl, —C1-C6alkylN(R18)(R19), —C1-C6alkoxy or —COOC1-C6alkyl;
R17 is selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —C1-C6alkyl, —C1-C6alkylheteroaryl, and —C1-C6alkylN(R18)(R19);
R18 is independently selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl, —C1-C6alkyl, —C1-C6alkylNH2, —COheterocycle, and —COC1-C6alkyl, wherein the —COC1-C6alkyl can be optionally substituted with one or two substituents selected from the group consisting of —N(R19)(R19), —OH, cycloalkyl, or a 3-7 membered nitrogen containing ring or R18 taken with R19 forms a 3-7 membered nitrogen containing ring; and
R19 is independently selected from the group consisting of hydrogen, —C3-C6cycloalkyl, —haloC1-C6alkyl and —C1-C6alkyl, or R19 taken with R18 forms a 3-7 membered nitrogen containing ring;
wherein R6 and R7, R9 and R10, R12 and R13, and R15 and R16 cannot be: —COOH and —N (R18)(R19), or —N(R18)(R19) and —COOH.