Methods and Compositions for Targeting Tregs using CCR8 Inhibitors

A compound of Formula (I):

• wherein A is 6-, 9-, 10- or 11-membered carbocycle or heterocycle,
• wherein A may be optionally substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C1-6 alkyl, halo substituted C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, —COOH, —NH2, —CN, —NHCO(C1-6 alkyl), —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —CONH2, —COO(C1-6 alkyl), —OCO(C1-6 alkyl), —CONH(C1-6 alkyl), CON(C1-6 alkyl)2;
• m is 0 or 1;
• p is 0 or 1;
• t is 0, 1, 2, or 3;
• n is 0 or 1;
• R5 is O or NH;
• R1 is H or C1-6 alkyl;
• each of R2 and R3 is independently selected from H, C1-6 alkyl, —CH2OH, —COOCH3, C3-6 cycloalkyl, phenyl, heterocyclic or heteroaromatic ring;
• R4 is C1-6 alkyl, phenyl, 4-, 5-, 6-, 7- or 8-membered cycloalkyl, 5-membered heteroaromatic ring, bridged (C5-12)cycloalkyl ring,
• each of B1 and B2 is 4-, 5-, 6-, 7- or 8-membered cycloalkyl, each of B3 is 5-, 6-membered carbocycle with saturated or unsaturated hydrocarbon,
• wherein carbon atoms in the phenyl may be replaced by 0, 1 or 2 of N, carbon atoms in the 4-, 5-, 6-, 7- or 8 membered cycloalkyl, 5-membered heteroaromatic ring, bridged (C5-12)cycloalkyl, B1, or B2, may be replaced by 0, 1 or 2 heteroatoms independently selected from N, O or S, carbon atoms in the B3 may be replaced by 0, 1, 2 or 3 heteroatoms independently selected from N, O or S,
• the phenyl, the 4-, 5-, 6-, 7- or 8 membered cycloalkyl, bridged (C5-12)cycloalkyl,
• is optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-6 alkyl, halo substituted C1-6 alkyl, C3-8 cycloalkyl, —O(C1-6 alkyl), —OH, —NH2, —N(C1-6 alkyl)2, —NHCO(C1-6 alkyl), —NHBoc, —COOH, —COO(C1-6 alkyl), —COOC(C1-6 alkyl)3, —CO(C1-6 alkyl), —CH2COO(C1-6 alkyl), —CO(CH2)qN(C1-6 alkyl)2, —COCH2NH2, —CH2CON(C1-6 alkyl)2, —CH2CONH(C1-6 alkyl), —(C1-6 alkyl)OH, —COCH2NHBoc, —COCH(CH3)(NHBoc), —(C1-6 alkyl)N(C1-6 alkyl)2, —CH2CF3, —(C1-6 alkyl)O(C1-6 alkyl), α-amino acid group,
• wherein the carbon atoms in the C3-8 cycloalkyl may be replaced by 0, 1 or 2 heteroatoms independently selected from O, N, S;
• or R4 is
• wherein q is 0 or 1,
• Y1 is CH, or N,
• Y2 is CH2, O, or NR6, and R6 is H or C1-6 alkyl,
• Y3 is —CH2OH, —COO(C1-6 alkyl), —(C1-6 alkyl)N(C1-6 alkyl)2, —N(C1-6 alkyl)2;
• X is selected from
• —NHCOC(C1-6 alkyl)3,
• wherein r is 0, 1, 2, 3, 4, R7 is H or C1-6 alkyl,
• the
• is optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of —OH, C1-6 alkyl, C3-6 cycloalkyl, halo, halo substituted C1-6 alkyl, C1-6 alkoxy,
• D is 4-, 5-, 6-7- or 8-membered cycloalkyl except phenyl, or bridged (C5-12)cycloalkyl, carbon atoms in the D may be replaced by 0, 1 or 2 heteroatoms independently selected from N or O, the D is optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of C1-3 alkyl, halo, —COOH, C1-6 alkoxy,
• E1 is C3-7 cycloalkyl, and E2 is CF3 or C3-6 cycloalkyl,
• wherein the carbon atoms in E2 may be replaced by 0 or 1 heteroatoms independently selected from N, O or S;
• carbon atoms in the ring of
• may be replaced by 0, 1 or 2 heteroatoms independently selected from N, O or S;
• or a pharmaceutically acceptable salt, ester, isotope, stereoisomer, tautomer, solvate, prodrug, or combination thereof.