Trpml modulators

A compound of Formula II′:

• or a pharmaceutically acceptable salt thereof, wherein
• X1′, X2′, X3′, and X4′ are each independently selected from N, C, CRa, wherein X1′, X2′, X3′, and X4′ are C or N when bound to Cy-L1-Z or L2-V, and are CRa when not bound to Cy-L1-Z or L2-V;
• Y1′ and Y2′ are selected from each C, N, and CRa, or one of Y1′ or Y2′ is absent and the other of Y1′ or Y2′ is selected from C, N, and CRa;
• Cy is absent, or a bivalent moiety selected from C1-6 aliphatic, 4- to 14-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C6-12 aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
• L1 is absent, S—, —C(O)—NR3—, —NR3—C(O)—, or an optionally substituted group selected from C1-6 alkylenyl, C2-6 alkynylenyl, —NR3—C0-6 alkylenyl, —O—C0-6 alkylenyl, —C(O)—C0-6 alkylenyl, —C1-6 alkylenyl-C(O)—, —C(O)O—C0-6 alkylenyl, —C1-6 alkylenyl-O—C(O)—, —C3-6 cycloalkyl, and —NR3—C(O)—C0-6 alkylenyl-O—;
• L2 is —(NR3)s—S(O)—(NR3)—, —(NR3)s—S(O)2—NR3—, —(NR3)s—P(O)(R3)—, —C(O)—(NR3)s—, —NR3—C(O)—, or an optionally substituted bivalent moiety selected from —(NR3)s—S(O)—C0-6 alkylenyl-, —(NR3)s—S(O)2—C0-6 alkylenyl-, —(NR3)s—S(O)—NR3—C0-6 alkylenyl, —(NR3)s—S(O)2—NR3—C0-6 alkylenyl, —(NR3)s—S(O)2—C3-6 cycloalkyl, —NR3—C0-6 alkylenyl, —C1-6 alkylenyl-S(O)—(NR3)s—, —C1-6 alkylenyl-S(O)2—(NR3)s—, 2- to 6-membered heteroaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
• V is selected from C1-6 aliphatic, C6-12 aryl, C3-12 cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein V is substituted with (R6)m;
• Z is selected from P(O)(R3)2, C(O)N(R3)2, C1-6 aliphatic, C6-12 aryl, C3-12 cycloaliphatic, 2- to 10-atom heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q;
• each Ra is independently H, halo, —CN, oxo, or an optionally substituted group selected from C1-6 aliphatic, C3-6 cycloaliphatic, and O—C1-6 aliphatic, or two Ra together when on adjacent atoms form a fused optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or a fused optionally substituted heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S;
• each R1 is independently selected from halo, oxo, —N(R3)2, —OH, —CN, —C(O)N(R3)2, and an optionally substituted group selected from C1-6 aliphatic and N(R3)—C(O)—C1-6 aliphatic;
• each R2 is independently selected from halo, oxo, —CN, —OH, O—R2a, —C(O)—R2a, —C(O)O—R2a, and an optionally group selected from C1-6 aliphatic, C6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
• each R2a is independently H or an optionally substituted group selected from C1-6 aliphatic, C3-12 cycloaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
• each R3 is independently selected from H and optionally substituted C1-6 aliphatic;
• each R5 is —N(R3)2 or an optionally substituted group selected from C1-6 aliphatic, P(O)(C1-6 aliphatic)2, C3-12 cycloaliphatic, and 5- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
• each R6 is independently selected from halo, oxo, —SF5, —S(O)—R5, S(O)2-R5, —S(O)(NH)—R5, —S(O)2—(NH)—R5, —S(O)—N(R5)2, —S(O)2—N(R5)2, —CN, —C(O)—NH(R5), —C(O)—N(R5)2, —P(O)(R5)2, —O—R5, or an optionally substituted group selected from C1-6 aliphatic, S—C1-6 aliphatic, 2- to 12-membered heteroaliphatic, —C0-6 alkylenyl-C(O)—R5, —C0-6 alkylenyl-C(O)O—R5, C6-12 aryl, C3-12 cycloaliphatic, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
• m is 0, 1, 2, 3, or 4;
• q is 0, 1, 2, 3, 4, 5, or 6;
• and
• each s is independently 0 or 1.