Arginase Inhibitors and Their Therapeutic Applications

A compound represented by Formula (I):

• wherein:
• L is —CO2H, —C(O)O((C1-C6)alkyl), —CO2CH2—O-pivaloyl, —CO2CH2OCO2-isopropyl, —C(O)NHOH, —C(O)NHCN, —C(O)NH2, —C(O)NH((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, —C(O)NH(aryl), —C(O)N(aryl)((C1-C6)alkyl), —C(O)N(aryl)2, —C(O)NH((C1-C6)haloalkyl),
• —S(O)2NH2, —S(O)2NH((C1-C6)alkyl), —S(O)2NH((C1i-C6)haloalkyl), —S(O)2NH(aryl), —S(O)2NHC(O)((C1-C6)alkyl), —S(O)2NHC(O)((C1-C6)haloalkyl),
• —S(O)2NHC(O)(aryl),
• —N(H)S(O)2((C1-C6)alkyl), —N(H)S(O)2(aryl), N(H)S(O)2((C1-C6)haloalkyl), —NHC(O)((C1-C6)alkyl), —NHC(O)((C1-C6)haloalkyl), —NHC(O)(aryl), —NHC(O)NH((C1-C6)alkyl), —NHC(O)NH(aryl), —C(O)N(H)S(O)2((C1-C6)alkyl), —C(O)N(H)S(O)2(aryl), —C(O)N(H)S(O)2((C1-C6)haloalkyl), —P(O)(OH)2, —CF3,
• R1 is selected from the group consisting of H, straight or branched (C1-C6) alkyl, and (C1-C6)alkyl-C(O)—;
• X, Y, and Z are each independently selected from the group consisting of a bond, —C(R′)(R′″)—, —C(R′″)2—, ═CR″′—, —CHF—, —CF2—, —NR″′—, ═N—, —O—, —C(O)—, —S—, —S(O)— and —SO2—, wherein
• any two adjacent —CH2— groups optionally represent two members of a (C3-C14)-cycloalkylenyl group or a (C3-C14)-heterocycloalkylenyl group,
• no more than two of X, Y, and Z simultaneously represent a bond;
• and no two adjacent members of X, Y, and Z are simultaneously —O—, —S—, ═N—, or —NR′″—;
• either X and Y or Y and Z optionally represent a fused aryl or heteroaryl ring having from 3 to 7 ring member atoms,
• or Z and L optionally form a fused lactone ring having 4 to 7 ring member atoms including one or two O ring atoms;
• m, n, p independently are integers between 0 and 2 inclusive, wherein at least one of m, n, p is not 0;
• optionally represents one or more double bonds;
• R2 and R3 are each independently selected from hydrogen, straight or branched (C1-C6)alkyl, or C(O)—R′,
• or R2 and R3 taken together with the boron atom and oxygen atoms to which they are bound form a 4-, 5-, 6- or 7-membered ring that is fully saturated, or partially saturated,
• or R2 and R3 taken together with the boron atom and oxygen atoms to which they are bound form a diester of the boronic acid and pinanediol,
• or R2 and R3 taken together with the boron atom and oxygen atoms to which they are bound form an anhydride of the boronic acid and N-methyliminodiacetic acid;
• V is selected from —C(R′)(R″)—, —NR′—, —C(F)(R′)— or —CHF—;
• W is selected from —C(R′)(R′″)—, —C(R′″)2—, —CHF—, —CF2—, —NR″′—, or —C(O)—;
• D is selected from the straight or branched (C1-C5)alkylene, straight or branched (C2-C5)-alkenylene, straight or branched (C2-C8)alkynylene, (C3-C14)arylene, or (C3-C14)cycloalkylene,
• wherein one or more —CH2— groups in D are optionally and independently replaced with a moiety selected from —O—, —NR′—, —S—, —S(O)—, —S(O)2, or —C(R′)(R″)—;
• —CHF— or —CF2—, or
• wherein any two adjacent —CH2— groups optionally represent two members of a (C3-C14)-cycloalkylenyl group;
• and
• wherein no two adjacent —CH2— groups are simultaneously replaced with O, NR′, S, SO, or SO2;
• R′, R″ and R″′ are each independently selected from H, OH, S(O)Rd, S(O)2Rd, (C1-C8)alkyl, (C3-C6)aryl, —NH2, —NH(C1-C6)alkyl, —N[(C1-C6)alkyl]2, —NRdSO2N(Re)2, —NRdC(NRe)N(Rg)2, —C(O)NRdRe, —C(O)(C1-C6)alkyl, —C(O)(C3-C14)aryl, —C(O)O(C1-C6)alkyl, —C(O)O(C3-C14)aryl, (C3-C6)cycloalkyl, (C3-C14)heterocycloalkyl, —C(O)(C3-C14)heterocycloalkyl, (C3-C14)heteroaryl, (C3-C14)aryl-(C1-C6)alkylene-, —C(O) (C3-C14)aryl-(C1-C6)alkylene-, —C(O)(C3-C14)aryl, (C3-C6)cycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene-, (C3-C14)heterocyclyl-(C1-C6)alkylene-;
• and wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more selected from the group consisting of halogen, (C1-C3)alkyl, —COOH, —CN, —NO2, —OH, —NRdRe, —NRgS(O)2Rh, (C1-C6)alkoxy, (C3-C14)aryl, heterocyclyl having from 3 to 7 ring member atoms, (C1-C8)haloalkyl or (C3-C14)aryloxy;
• wherein Rd, Re, Rg, and Rh are each independently selected from H, straight or branched (C1-C6)alkyl, optionally substituted (C3-C14)aryl(C1-C6)alkylene-, optionally substituted (C3-C14)aryl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, H2N(C1-C6)alkylene-, optionally substituted (C3-C6)cycloalkyl, optionally substituted (C3-C14)heterocycloalkyl, optionally substituted (C3-C14)heteroaryl, optionally substituted (C3-C14)aryl-(C1-C6)alkylene-, NR′R″C(O)—, or (C3-C6)aryl-(C3-C14)-cycloalkylene-,
• or R′ and R″′ taken together represent —(C1-C3)alkylene-N(Me)-(C1-C3)alkylene-,
• or a tautomer, stereoisomer, racemate, pharmaceutically acceptable salt, ester, solvate, polymorph, active metabolite, or prodrug thereof;
• with the proviso that the compound is not
• 1-amino-3-(4-boronobutyl)cyclobutane-1-carboxylic acid,
• 1-amino-3-(2-boronoethyl)cyclobutane-1-carboxylic acid,
• 1-amino-3-(boronomethyl)cyclobutane-1-carboxylic acid,
• 1-amino-3-(3-boronopropyl)cyclopentane-1-carboxylic acid, or
• 1-amino-3-(3-boronopropyl)cyclohexane-1-carboxylic acid.