Therapeutic conjugates

A therapeutic conjugate having a structure of

• or a pharmaceutically acceptable salt thereof,
• wherein X is any of the CLMs disclosed herein;
• R1 and R2 are independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, cyano, halo, hydroxy, azido, imino, amido, phosphoryl, sulfonyl, silyl groups, alkylthios, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, and optionally substituted carbamimidoyl;
• R3 is selected from the group consisting of
• R4 is selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, cyano, halo, hydroxy, azido, imino, amido, phosphoryl, sulfonyl, silyl groups, alkylthios, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, and optionally substituted carbamimidoyl;
• X—Ar1 is selected from the group consisting of
• R5, R6, R7 and R8 are independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, cyano, halo, hydroxy, azido, imino, amido, phosphoryl, sulfonyl, silyl groups, alkylthios, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, and optionally substituted carbamimidoyl;
• L is either absent or X-L is selected from the group consisting of
• R9 and R10 are independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, cyano, halo, hydroxy, azido, imino, amido, phosphoryl, sulfonyl, silyl groups, alkylthios, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, and optionally substituted carbamimidoyl;
• R11, R12, R13 and R14 are independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, cyano, halo, hydroxy, azido, imino, amido, phosphoryl, sulfonyl, silyl groups, alkylthios, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, and optionally substituted carbamimidoyl;
• wherein each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C8 alkyl, aryl, heteroaryl, aryl-C1-C8 alkyl-, heteroaryl-C1-C8 alkyl-, C1-C8 haloalkyl, —OC1-C8 alkyl, —OC1-C8 alkylphenyl, alkyl-OH, OC1-C8 haloalkyl, halo, —OH, —NH2, —C1-C8 alkyl-NH2, —N(C1-C8 alkyl)(C1-C8 alkyl), —NH(C1-C8 alkyl), —N(C1-C8 alkyl)(C1-C8 alkylphenyl), —NH(C1-C8 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), —CO2H, —C(O)OC1-C8 alkyl, —CON(C1-C8 alkyl)(C1-C8 alkyl), —CONH(C1-C8 alkyl), —CONH2, —NHC(O)(C1-C8 alkyl), —NHC(O)(phenyl), —N(C1-C8 alkyl)C(O)(C1-C8 alkyl), —N(C1-C8 alkyl)C(O)(phenyl), —C(O)C1-C8 alkyl, —C(O)C1-C8 phenyl, —C(O)C1-C8 haloalkyl, —OC(O)C1-C8 alkyl, SO2(C1-C8 alkyl), —SO2(phenyl), —SO2(C1-C8 haloalkyl), —SO2NH2, SO2NH(C1-C8 alkyl), —SO2NH(phenyl), —NHSO2(C1-C8 alkyl), NHSO2(phenyl), or —NHSO2(C1-C8 haloalkyl).

A therapeutic conjugate having a structure of Formula 4-203,

• wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, CN, alkyl, CF3 and N(R4)(R5);
• R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, C(O)-alkyl, C(O)-Nalkyl, C(O)-alkenyl and C(O)-aryl;
• W, X, Y and Z are independently selected from the group consisting of CH, C-alkyl, CF3 and N;
• and T and V are independently CH, C-alkyl, C-halogen, C—CF3, C—CN or N.

A therapeutic conjugate having a structure of Formula 4-205,

• wherein R1 is selected from the group consisting of
• R2 is
• R is H or an alkyl group;
• and X is CH or N.

A therapeutic conjugate having a structure of Formula 4-206,

• wherein R4 is selected from the group consisting of hydrogen,
• CF3 and halogen;
• R5 is selected from the group consisting of hydrogen,
• CF3, NH2 and halogen;
• R3 is selected from the group consisting of hydrogen,
• CF3, NH2, CN and halogen;
• R is H or an alkyl group;
• and X, Y1, Y2, or Y3 is independently CH, C-alkyl or N.