US 12,240,867 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); Symon Gathiaka, Waltham, MA (US); Charles A. Lesburg, Waban, MA (US); Derun Li, West Roxbury, MA (US); Min Lu, Brookline, MA (US); Matthew J. Mitcheltree, Jamaica Plain, MA (US); Anandan Palani, Needham, MA (US); Rachel L. Palte, Melrose, MA (US); and Hongjun Zhang, Boston, MA (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Appl. No. 17/312,480
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
PCT Filed Dec. 13, 2019, PCT No. PCT/US2019/066128
§ 371(c)(1), (2) Date Jun. 10, 2021,
PCT Pub. No. WO2020/131598, PCT Pub. Date Jun. 25, 2020.
Claims priority of provisional application 62/780,990, filed on Dec. 18, 2018.
Prior Publication US 2022/0056051 A1, Feb. 24, 2022
Int. Cl. C07F 5/02 (2006.01)
CPC C07F 5/025 (2013.01) 23 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
Y is a straight or branched (C2-C5) alkylenyl, wherein one or more —CH2— groups in Y are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH;
U is CR7R8 or O;
X is a bond or CR9R10;
Z is a bond or CR11R12;
R is hydrogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH or C1-C6alkylOC1-C6alkyl;
R1 is hydrogen, C3-C6cycloalkyl or C1-C6alkyl or, taken with R2 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting of halogen, C1-C6alkyl, oxo and OH;
R2 is hydrogen, C3-C6cycloalkyl or C1-C6alkyl or, taken with R1 forms a C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting of halogen, C1-C6alkyl, oxo and OH;
R3 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylNH2 or C1-C6alkylOC1-C6alkyl, or when taken with the carbon to which it is attached and the adjacent hydrogen forms C═O;
R4 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, or C1-C6alkylOC1-C6alkyl, or when taken with the carbon to which it is attached and the adjacent hydrogen forms C═O;
R5 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylNH2;

OG Complex Work Unit Chemistry
R6 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH or C1-C6alkylOC1-C6alkyl;
R7 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, OH, C1-C6alkylOH, NH2, or C1-C6alkylOC1-C6alkyl, or when taken with R8 forms ═O;
R8 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, OH, C1-C6alkylOH, NH2, or C1-C6alkylOC1-C6alkyl, or when taken with R7 forms ═O;
R9 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, OH, C1-C6alkylOH, C1-C6alkylN(R23)(R24) or C1-C6alkylOC1-C6alkyl, or when taken with R10 forms ═O;
R10 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, OH, C1-C6alkylOH, C1-C6alkylN(R23)(R24) or C1-C6alkylOC1-C6alkyl, or when taken with R9 forms ═O;
R11 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylN(R23)(R24) or C1-C6alkylOC1-C6alkyl, or when taken with R12 forms ═O;
R12 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylN(R23)(R24) or C1-C6alkylOC1-C6alkyl, or when taken with R11 forms ═O;
R13 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkylN(R21)(R22), or C1-C6alkylOC1-C6alkyl or when taken with R14 forms a nitrogen containing heterocycle or when taken with R15 or R16 forms a nitrogen containing heteroaryl or heterocycle;
R14 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkylN(R21)(R22), or C1-C6alkylOC1-C6alkyl or when taken with R13 forms a nitrogen containing heterocycle or when taken with R15 or R16 forms a nitrogen containing heteroaryl or heterocycle;
R15 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylN(R21)(R22), C1-C6alkylCOOR21, C1-C6alkylCON(R21)(R22), C1-C6alkylSH, C1-C6alkylSC1-C6alkyl or C1-C6alkylOC1-C6alkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl, C1-C6alkylheterocycle or when taken with R13 or R14 forms a nitrogen containing heterocycle, or when taken with R16 forms a C3-C7cycloalkyl or heterocycle;
R16 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylN(R21)(R22), C1-C6alkylCOOR21, C1-C6alkylCON(R21)(R22), C1-C6alkylSH, C1-C6alkylSC1-C6alkyl or C1-C6alkylOC1-C6alkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl, C1-C6alkylheterocycle or when taken with R13 or R14 forms a nitrogen containing heterocycle, or when taken with R15 forms a C3-C7cycloalkyl or heterocycle;
R17 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, OH, C1-C6alkylOH, or C1-C6alkylOC1-C6alkyl or when taken with R18 forms a nitrogen containing heterocycle;
R18 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, OH, C1-C6alkylOH, or C1-C6alkylOC1-C6alkyl or when taken with R17 forms a nitrogen containing heterocycle;
R19 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylS C1-C6alkyl or C1-C6alkylOC1-C6alkyl;
R20 is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylS C1-C6alkyl or C1-C6alkylOC1-C6alkyl;
each occurrence of R21 is independently selected from the group consisting of hydrogen, C1-C6alkyl and C3-C6cycloalkyl;
each occurrence of R22 is independently selected from the group consisting of hydrogen, C1-C6alkyl and C3-C6cycloalkyl;
each occurrence of R23 is independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylN(R21)(R22), C1-C6alkylCOOR21, C1-C6alkylCON(R21)(R22), C1-C6alkylSH, C1-C6alkylSC1-C6alkyl, C1-C6alkylOC1-C6alkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl or C1-C6alkylheterocycle; and
each occurrence of R24 is independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkylOH, C1-C6alkylN(R21)(R22), C1-C6alkylCOOR21, C1-C6alkylCON(R21)(R22), C1-C6alkylSH, C1-C6alkylSC1-C6alkyl, C1-C6alkylOC1-C6alkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl or C1-C6alkylheterocycle.