Arginase inhibitors as therapeutics

A method for the treatment or prevention of a disease or condition associated with expression or activity of arginase I, arginase II, or a combination thereof in a subject, comprising administering to the subject therapeutically effective amount of at least one compound according to Formula I,

• wherein
• R1 is selected from —OH, ORa, and NRbR;
• Ra is selected from hydrogen, straight or branched chain (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C14)aryl, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene-, and (C3-C14)aryl(C1-C6)alkylene-;
• Rb and Rc are each independently selected from H, —OH, straight or branched (C1-C6)alkyl, —SO2—(C1-C6)alkyl, (C3-C14)aryl-SO2—, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, and (C3-C14)heteroaryl-(C1-C6)alkylene-;
• R2 is selected from H, straight or branched (C1-C6) alkyl, and (C1-C6)alkyl-C(O)—;
• W, X, Y, and Z are each independently selected from —C(R′)(R′″)—, —C(R′″)2—, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, and —S—, wherein no more than three of W, X, Y, and Z simultaneously represent a bond;
• at least one of W, X, Y, or Z is selected from —NR′″—, —N—, —O—, and —S—;
• and no two adjacent members of W, X, Y, and Z are simultaneously —O—, —S—, —N—, or —NR′″—;
• l, m, n and p are each independently 0 or 1 or 2;
• optionally represents one or more double bonds;
• R3 and R4 are each independently selected from hydrogen, straight or branched (C1-C6)alkyl, and C(O)—R′,
• or R3 and R4 together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated, or partially saturated;
• D is selected from straight or branched (C3-C5)alkylene, straight or branched (C2-C8)alkenylene, straight or branched (C2-C8)alkynylene, (C3-C14)arylene, and (C3-C14)cycloalkylene,
• wherein one or more —CH2— groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO2, and CR′R″;
• or
• wherein any two adjacent —CH2— groups optionally are replaced by two members of a (C3-C14)-cycloalkylenyl group;
• and
• provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and 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, —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-, and (C3-C14)heterocycle-(C1-C6)alkylene-;
• and
• wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO2, —OH, —NRdRe, —NRgS(O)2Rh, (C1-C6)alkoxy, (C3-C14)aryl, (C1-C6)haloalkyl and (C3-C14)aryloxy;
• wherein Rd, Re, Rg, and Rh are each independently selected from of 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)—, and (C3-C6)aryl-(C3-C14)-cycloalkylene-,
• or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

A method for the treatment or prevention of a disease or condition associated with expression or activity of arginase I, arginase II, or a combination thereof in a subject, comprising administering to the subject therapeutically effective amount of at least one compound according to Formula II,

• wherein
• R1 is selected from —OH, ORa, and NRbRc;
• Ra is selected from hydrogen, straight or branched chain (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C14)aryl, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene-, and (C3-C14)aryl(C1-C6)alkylene-;
• Rb and Rc are each independently selected from H, —OH, straight or branched (C1-C6)alkyl, —SO2—(C1-C6)alkyl, (C3-C14)aryl-SO2—, (C3-C14)heterocycloalkyl-(C1-C6)alkylene-, and (C3-C14)heteroaryl-(C1-C6)alkylene-;
• R2 is selected from H, straight or branched (C1-C6) alkyl, and (C1-C6)alkyl-C(O)—;
• W, X, Y, and Z are each independently selected from —C(R′)(R′″)—, —C(R′″)2—, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, and —S—, wherein no two adjacent members of W, X, Y, and Z are simultaneously —O—, —S—, —N—, or —NR′″—;
• l, m, n and p are each independently 0 or 1 or 2,
• optionally represents one or more double bonds;
• R3 and R4 are each independently selected from hydrogen, straight or branched (C1-C6)alkyl, and C(O)—R′,
• or R3 and R4 together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated, or partially saturated;
• D is selected from straight or branched (C3-C5)alkylene, straight or branched (C2-C8)alkenylene, straight or branched (C2-C8)alkynylene, (C3-C14)arylene, and (C3-C14)cycloalkylene,
• wherein one or more —CH2— groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO2, and CR′R″;
• or
• wherein any two adjacent —CH2— groups optionally are replaced by two members of a (C3-C14)-cycloalkylenyl group;
• and
• provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and 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, —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-, and (C3-C14)heterocycle-(C1-C6)alkylene-;
• provided that at least one occurrence of R′″ is not H;
• and
• wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO2, —OH, —NRdRe, —NRgS(O)2Rh, (C1-C6)alkoxy, (C3-C14)aryl, (C1-C6)haloalkyl and (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)—, and (C3-C6)aryl-(C3-C14)-cycloalkylene-,
• or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.