Methotrexate analogs and methods of use

A compound having a structure according to Formula I

• or a pharmaceutically acceptable salt, N-oxide, or hydrate thereof, wherein:
• each of Z1 and Z2 independently is N or CH;
• each R1 independently is optionally substituted C1-6alkyl, C1-6haloalkyl, halogen, OH, cyano, amino, SH, S(═O)Rb, or
• each Ra is H, C1-6alkyl, or two Ras together form a 5-membered heterocycloaliphatic ring, optionally substituted with 1-4 alkyl groups;
• Rb is H, C1-6alkyl, or C1-6haloalkyl;
• m is 0, 1, 2, 3 or 4;
• n is 1, 2, 3, 4, or 5;
• ring A is heterocyclyl or aryl;
• X1 is —CH═N—, —CH2NY3—, or —CH2CHR2—;
• R2 is H, optionally substituted aliphatic, or R2 together with the atoms to which it is attached, forms a 5-membered optionally substituted heterocyclic ring that is fused to ring A;
• X2 is S, O or CH═CR3;
• each X3 independently is NR4 or CHR4;
• each X6 independently is CH2, CHF, or
• each of Y1 and Y2 independently is OH, OC1-6alkyl or -Linker-E3 Ligand;
• Y3 is —X7-Linker-E3 Ligand or R2, where X7 is C4-8alkyl;
• with the provision that at least one of Y1, Y2 or Y3 is or comprises -Linker-E3 Ligand;
• R3 is H or halogen;
• each R4 independently is H or optionally substituted C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl;
• or R3 and R4 together with the atoms to which they are attached, form an optionally substituted heterocyclic ring;
• E3 Ligand is selected from
• wherein each of Z3, Z4, and Z5 independently is CH or N;
• Z6 is CH2 or C═O;
• R5 is H, D, C1-6alkyl or halogen;
• and
• R6 is H, C1-6alkyl,
• and
• Linker has a formula
• wherein G is a bond, NR7, —NR7C(═O)—, or CH2;
• R7 is H, or optionally substituted C1-4alkyl;
• K is a bond, O, optionally substituted C1-4alkyl, NR8, C(O)NR8, NHC(O), NHCO2CH2, CH2C(O)NH, NHC(O)CH2O, NHC(O)CH2NH, C(O)CH2O, C≡C, S, or S(═O);
• R8 is H, or optionally substituted C1-6alkyl;
• and
• J is optionally substituted C1-12alkyl, (CH2)n—O—(CH2)p where n is 1-6 and p is 1-6, (—CH2CH2O—)q, (—CH2CH2O—)qCH2—, (—CH2CH2O—)qCH2CH2— where q is 1-6, (CH2CH2)r—O—(CH2CH2)s where r is 2-6 and s is 1-6, or —(CH2)x-M-(CH2)y— where M is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocyclyl, where x is 0-8 and y is 0-8.