Tubulysins and protein-tubulysin conjugates

A compound having the structure of Formula I

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is hydrogen, C1-C10 alkyl, a first N-terminal amino acid residue, —C1-C10 alkyl-NR3aR3b, or —C1-C10 alkyl-OH;
• R3 is hydroxyl, —O—C1-C5 alkyl, —OC(O)C1-C5 alkyl, —OC(O)N(H)C1-C10 alkyl, —OC(O)N(H)C1-C10 alkyl-NR3aR3b, —NHC(O)C1-C5 alkyl, or —OC(O)N(H)(CH2CH2O)nC1-C10 alkyl-NR3aR3b,
• wherein R3a and R3b are independently in each instance, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl;
• wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted;
• R4 and R5 are, independently in each instance, hydrogen or C1-C5 alkyl;
• R6 is —OH, —NHNH2, —NHSO2(CH2)a1-aryl-(CH2)a2NR6aR6b,
• wherein aryl is substituted or unsubstituted;
• and
• R6a and R6b are independently in each instance, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl;
• wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted;
• R7 is, independently in each instance, hydrogen, —OH, halogen, or —NR7aR7b,
• wherein R7a and R7b are, independently in each instance, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, —C(O)CH2OH, a first N-terminal amino acid residue, a first N-terminal peptide residue, and —CH2CH2NH2;
• wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted;
• R8 is, independently in each instance, hydrogen, —NHR9, or halogen,
• wherein R9 is hydrogen, —C1-C5 alkyl, or —C(O)C1-C5 alkyl;
• and
• m is one or two;
• R10, when present, is —C1-C5 alkyl;
• Q is —CH2— or —O— wherein
• R2 is alkyl, alkynyl, or a regioisomeric triazole;
• wherein said regioisomeric triazole is unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl;
• wherein n is an integer from one to ten;
• wherein r is an integer from one to six;
• wherein a, a1, and, a2 are, independently, zero or one;
• and
• wherein T is not compound IVa, IVa′, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, IVk, IVl, IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVvA, IVvB, IVw, IVx, IVy, Va, Va′, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk, VIa, IVb, VIc, VId, VIe, VIf, VIg, VIh, VI, VIi, VII, VIII, IX, X, D-5a, D-5c, Tubulysin A-I, U-X, or Z, Pretubulysin D, or N14-desacetoxytubulysin H.

A linker-payload having the formula

• L-T
• or a pharmaceutically acceptable salt thereof, wherein
• L is a linker covalently bound to T;
• T is
• wherein
• R1 is a bond, hydrogen, C1-C10 alkyl, a first N-terminal amino acid residue, a first amino acid residue, —C1-C10 alkyl-NR3aR3b, or —C1-C10 alkyl-OH;
• R3 is hydroxyl, —O—, —O—C1-C5 alkyl, —OC(O)C1-C5 alkyl, —OC(O)N(H)C1-C10 alkyl, —OC(O)N(H)C1-C10 alkyl-NR3aR3b, —NHC(O)C1-C5 alkyl, or —OC(O)N(H)(CH2CH2O)nC1-C10 alkyl-NR3aR3b,
• wherein R3a and R3b are independently in each instance, a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl;
• wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted;
• R4 and R5 are, independently in each instance, hydrogen or C1-C5 alkyl;
• R6 is —OH, —O—, —NHNH2, —NHNH—, —NHSO2(CH2)a1-aryl-(CH2)a2NR6aR6b,
• wherein aryl is substituted or unsubstituted;
• and
• R6a and R6b are independently in each instance, a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl;
• wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted;
• R7 is, independently in each instance, hydrogen, —OH, —O—, halogen, or —NR7aR7b,
• wherein R7a and R7b are, independently in each instance, a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, —C(O)CH2OH, —C(O)CH2O—, a first N-terminal amino acid residue, a first amino acid residue, a first N-terminal peptide residue, a first peptide residue, —CH2CH2NH2, and —CH2CH2NH—;
• wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted;
• R8 is, independently in each instance, hydrogen, —NHR9, or halogen,
• wherein R9 is hydrogen, —C1-C5 alkyl, or —C(O)C1-C5 alkyl;
• and
• m is one or two;
• R10, when present, is —C1-C5 alkyl;
• Q is —CH2— or —O— wherein
• R2 is alkyl, alkylene, alkynyl, alkynylene, a regioisomeric triazole, a regioisomeric triazolylene;
• wherein said regioisomeric triazole or regioisomeric triazolylene is unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl;
• wherein n is an integer from one to ten;
• wherein r is an integer from one to six;
• wherein a, a1, and, a2 are, independently, zero or one;
• and
• wherein the linker-payload is not LP1-IVa, LP2-Va, LP3-IVd, LP4-Ve, LP5-IVd, LP6-Vb, LP7-IVd, LP9-IVvB, LP10-VIh, LP11-IVvB, LP12-VIi, LP13-Ve, LP14-Ve, LP15-VIh, LP16-Ve, LP17-Ve, LP18-Ve, LP19-Ve, LP20-Ve, LP21-Ve, LP22-Ve, LP23-Vb, LP24-Vb, LP25-Ve, and LP26-Ve, or a pharmaceutically acceptable salt thereof.