Selective GRP94 inhibitors and uses thereof

A compound of the Formula (V):

• or a pharmaceutically acceptable salt thereof, wherein:
• (a) Y is —C(RY)2—, —S—, —NR—, —O—,
• wherein each RY is independently hydrogen, —OH, or halo;
• (b) each of Z and Z3 are independently —CH— or —N—;
• (c) Z2 is —N— or —CR10—, wherein R10 is H or unsubstituted or substituted —(C1-C6)aliphatic;
• (d) each of Z4, Z5, Z6, Z7 and Z8 are independently —C— or —N—, with the proviso that no three consecutive Z4 through Z8 are N;
• (e) X1 is —H, -halo, —N(R)2, —OR, —CN, or unsubstituted or substituted —(C1-C6)aliphatic;
• (f) each of X4, X5, and X6 are independently —H, -halo, —SR, —N(R)2, —OR, —CN, —NO2, —CN, —C(O)R, —C(O)2R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)SO2R, —OC(O)N(R)2, unsubstituted or substituted —(C1-C6)aliphatic, or an unsubstituted or substituted group selected from (5- or 6-membered)aryl, (5- or 6-membered)arylalkyl, and (5- or 6-membered)heterocyclic aromatic or heterocyclic non-aromatic group;
• with the provisos that at least one of X2, X4 and X5 is —H and that X2 is absent when Z4 is —N—, X3 is absent when Z5 is —N—, X4 is absent when Z6 is —N— and X5 is absent when Z7 is —N—;
• (g) each of X2 and X3 are independently selected from
• (1) —H, -halo, —SR, —N(R)2, —OR, —CN, —NO2, —CN, —C(O)R, —C(O)2R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)SO2R, —OC(O)N(R)2, unsubstituted or substituted —(C1-C6)aliphatic, or an unsubstituted or substituted group selected from (5- or 6-membered)aryl, (5- or 6-membered)arylalkyl, and (5- or 6-membered)heterocyclic aromatic or heterocyclic non-aromatic group;
• or
• (2) X2 and X3 taken together form a fused benzo or fused (5- or 6-membered) heteroaryl that may be substituted with one or more R8groups;
• (h) R7 is —(C1-C6)aliphatic-N+—(R2)(R3)(R4), —(C1-C6)aliphatic-N—R3R4, —(C1-C6)aliphatic- C(═O)N—R3R4, —(C1-C6)aliphatic-R3R4, —(C1-C6)aliphatic-R2R3R4, —(C1-C6)aliphatic-N—CR2R3R4, —(C1-C6)aliphatic-C(halo)3, —(C1-C6)aliphatic-alkynyl, —(C1-C6)aliphatic-(C3-C8)cycloalkyl, —(C1-C6)aliphatic-(C3-C8)heterocycloalkyl, —(C1-C6)aliphatic-phenyl, —(C1-C6)aliphatic-(5 or 6-membered)heteroaryl, —(C1-C6)aliphatic-cyano, with the proviso that when all of R2—R4 are present the compound further comprises a pharmaceutically acceptable counter ion;
• (i) R2 and R3 are independently hydrogen, —N(R)2, —CH2CH(OH)R4, —CH(OH)CH2R4, —CH2SO2NHR4, —CH2NHSO2R4, or unsubstituted or substituted —(C1-C6)aliphatic, or R3 and R4 form an unsubstituted or substituted 3- to 7-membered heterocyclic ring when taken together with the nitrogen to which they are attached;
• (j) R8 is —H, -halo, —SR, —N(R)2, —OR, —CN, —NO2, —CN, —C(O)R, —C(O)2R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)SO2R, —OC(O)N(R)2, unsubstituted or substituted —(C1-C6)aliphatic, or an unsubstituted or substituted group selected from (5- or 6-membered)aryl, (5- or 6-membered)arylalkyl, and (5- or 6-membered)heterocyclic aromatic or heterocyclic non-aromatic group;
• (k) R4 is hydrogen, halogen, or unsubstituted or substituted —(C1-C6)aliphatic;
• and
• (l) each R is independently hydrogen, unsubstituted C1-6 aliphatic, or C1-6 aliphatic substituted with halo, —OH, —CN, or —NH2;
• wherein each substituted group is substituted with one or more groups selected from halo, —N(R)2, —OR, —CN, oxo, unsubstituted C1-6 aliphatic, or C1-6 aliphatic substituted with halo, —OH, —CN, or —NH2.