Camptothecin derivatives

Abstract

Disclosed herein are novel cytotoxic compounds, and cytotoxic conjugates comprising these cytotoxic compounds and cell-binding agents. More specifically, this disclosure relates to novel camptothecin derivatives thereof, intermediates thereof, conjugates thereof, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents (anticancer agents).

Description

0001] This application claims the benefit of and priority from U.S. Provisional Patent Applications 62 / 839,440, filed April 26, 2019, 62 / 875,169, filed July 17, 2019, and 62 / 978,159, filed February 18, 2020. Each of the foregoing applications is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 27, 2020, is named 000219-0002-WO1_- _Sequence_Listing.txt and is 61,926 bytes in size.FIELD OF THE APPLICATION

[0003] Disclosed herein are novel compounds, and conjugates thereof. More specifically, this disclosure relates to novel camptothecin derivatives, intermediates, metabolites and conjugates thereof, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents (anticancer agents).BACKGROUND

[0004] Cell binding agent-drug conjugates, including antibody-drug conjugates (ADC) are emerging as a powerful class of agents with efficacy across a range of abnormal cell growth or proliferative diseases (e.g., cancers). Cell binding agent-drug conjugates (such as ADCs) are commonly composed of three distinct elements: a cell-binding agent (e.g., an antibody); a linker; and a cytotoxic moiety.

[0005] Camptothecin (CPT) is a pentacyclic alkaloid isolated from the bark and stem of Camptotheca acuminata (Camptotheca, Happy tree), a tree native to China. Camptothecin inhibits topoisomerase I, which leads to cell death. Because of its cytotoxic mechanism and broad-spectrum antitumor activity, there have been substantial efforts towards developing clinical analogues of camptothecin. Poor solubility and inactivity at physiological conditions, however, have limited the clinical development of suitable camptothecin analogues.Camptothecin and most of its derivatives are not soluble in aqueous buffers. Further, camptothecin is in equilibrium in an active lactone form and inactive hydrolyzed carboxylate form, thereby limiting its therapeutic efficacy.

[0006] There exists a need for therapeutically effective camptothecin derivatives that have increased solubility, potency, lactone stability, and bioavailability.SUMMARY

[0007] In one aspect, the invention provides a compound of Formula I, or apharmaceutically acceptable salt, thereof:Z—L1—D (Formula I)wherein:D is represented by the following structural formula:R1 is -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring;R3 is H or C1-C6 alkyl;R4 is C1-C6 alkyl;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z;X1 is -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NR5-, -NR5C(=O)-, or -C(=O)NR5-;X1’ is -O-, -S-, -S(O)-, or -S(O)2-;L2 is phenylene;each R5 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;Z is -H or -X2;X2 is -OR6, -SR6, -S(O)R6, -S(O)2R6, -SSR6, or -N(R6)2;each R6 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;L1 and L2 are each independently optionally substituted with 1-4 substituents selected from halogen, -CN, -OR7, -SR7, -N(R7)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl; andeach R7 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;with the proviso that if R1 is F, then L1 is -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1- (C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z; and Z is -X2; andwith the proviso that if R1 is F and R2 is–OMe, then–L1-Z cannot be–NH2.

[0008] In some embodiments, the compound of Formula I has the further proviso that if R1 is F and R2 is–Me, then–L1-Z cannot be–CH2OH.

[0009] In some embodiments, R1 is -H or -F. In some embodiments, R1 is -F. In some embodiments, R2 is -H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, -S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl. In some embodiments, R2 is -F. In some embodiments, R2 is -OMe, -SMe, -S(O)Me, or methyl. In some embodiments, R2 is methyl. In some embodiments, R1 is -F and R2 is -F. In some embodiments, R1 is methyl and R2 is -F. In some embodiments, R1 is -F and R2 is -methyl.

[0010] In some embodiments, -L1-Z is -H. In some embodiments, -L1-Z is -(C1-C6 alkylene)-H, or -(C1-C6 alkylene)-X2. In some embodiments, -L1-Z is -(C1-C6 alkylene)-H. In some embodiments, -L1-Z is -(C1-C6 alkylene)-X2. In some embodiments, -L1-Z is -(C1-C6 alkylene)-X2. In some embodiments, -L1-Z is methyl, ethyl, propyl, or butyl.

[0011] In some embodiments, -L1-Z is -(C1-C4 alkylene)-OR6, -(C1-C4 alkylene)-SR6, or -(C1-C4 alkylene)-N(R6)2. In some embodiments, -L1-Z is -(C1-C4 alkylene)-OR6. In some embodiments, -L1-Z is -(C1-C4 alkylene)-SR6. In some embodiments, -L1-Z is -(C1-C4 alkylene)-N(R6)2.

[0012] In some embodiments, -L1-Z is -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH2OMe, -(CH2)2OMe, -(CH2)3OMe, -(CH2)4OMe, -CH2SH, -(CH2)2SH, -(CH2)3SH, -(CH2)4SH, -CH2SMe, -(CH2)2SMe, -(CH2)3SMe, -(CH2)4SMe, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, or-(CH2)4NH2.

[0013] In some embodiments, -L1-Z is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-OR6, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-SR6, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SR6, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SSR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-OR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-SR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SSR6.

[0014] In some embodiments, -L1-Z is -CH2NHC(=O)CH2OH, -CH2NHC(=O)(CH2)2OH, -CH2NHC(=O)(CH2)3OH, -CH2NHC(=O)(CH2)4OH, -CH2NHC(=O)(CH2)5OH, -CH2NHC(=O)CH2OMe, -CH2NHC(=O)(CH2)2OMe, -CH2NHC(=O)(CH2)3OMe, -CH2NHC(=O)(CH2)4OMe, -CH2NHC(=O)(CH2)5OMe, -CH2NHC(=O)CH2SH, -CH2NHC(=O)(CH2)2SH, -CH2NHC(=O)(CH2)3SH, -CH2NHC(=O)(CH2)4SH, -CH2NHC(=O)(CH2)5SH, -CH2NHC(=O)CH2SMe, -CH2NHC(=O)(CH2)2SMe, -CH2NHC(=O)(CH2)3SMe, -CH2NHC(=O)(CH2)4SMe, -CH2NHC(=O)(CH2)5SMe, -CH2SCH2OH, -CH2S(CH2)2OH, -CH2S(CH2)3OH, -CH2S(CH2)4OH, -CH2S(CH2)5OH, -CH2SCH2OMe,-CH2S(CH2)2OMe, -CH2S(CH2)3OMe, -CH2S(CH2)4OMe, -CH2S(CH2)5OMe,-CH2SCH2SH, -CH2S(CH2)2SH, -CH2S(CH2)3SH, -CH2S(CH2)4SH, -CH2S(CH2)5SH, -CH2SCH2SMe, -CH2S(CH2)2SMe, -CH2S(CH2)3SMe, -CH2S(CH2)4SMe, or -CH2S(CH2)5SMe.

[0015] In some embodiments, each R5 is independently -H, methyl, or benzyl. In some embodiments, each R5 is independently -H. In some embodiments, each R5 is methyl. In some embodiments, each R5 is benzyl.

[0016] In some embodiments, each R6 is independently -H, methyl, or benzyl. In some embodiments, each R6 is independently -H. In some embodiments, each R6 is methyl. In some embodiments, each R6 is benzyl.

[0017] In some embodiments, -L1-Z is -X1’-(C1-C4 alkylene)-X2. In some embodiments, -L1-Z is -OCH2OH, -O(CH2)2OH, -O(CH2)3OH, -O(CH2)4OH, -SCH2OH, -S(CH2)2OH, -S(CH2)3OH, -S(CH2)4OH, -S(O)CH2OH, -S(O)(CH2)2OH, -S(O)(CH2)3OH, -S(O)(CH2)4OH, -S(O)2CH2OH, -S(O)2(CH2)2OH, -S(O)2(CH2)3OH, -S(O)2(CH2)4OH, -OCH2SMe, -O(CH2)2SMe, - O(CH2)3SMe, -O(CH2)4SMe, -SCH2SMe, - S(CH2)2SMe, -S(CH2)3SMe, -S(CH2)4SMe, -S(O)CH2SMe, -S(O)(CH2)2SMe, -S(O)(CH2)3SMe, -S(O)(CH2)4SMe, -S(O)2CH2SMe, -S(O)2(CH2)2SMe, -S(O)2(CH2)3SMe, or -S(O)2(CH2)4SMe.

[0018] In some embodiments, -L1-Z is -(C1-C6 alkylene)-X1-L2-X2. In some embodiments, -. some embodiments, -L1-Z is. , .

[0019] In some embodiments, the compound is any one of the compounds selected from the following: .

[0020] In some embodiments, the compound is any one of the compounds selected from the following: .

[0021] In some embodiments, the compound is any one of the compounds selected from Table 1B.

[0022] In another aspect, the invention provides a compound of Formula II, or a pharmaceutically acceptable salt thereof:E—A—Z’—L1—D (Formula II)wherein:D is represented by the following structural formula:R1 is -H, -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring; with the proviso that both R1 and R2 cannot be -H;R3 is H or C1-C6 alkyl;R4 is C1-C6 alkyl;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, X1’-(C1-C6 alkylene)-* or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z’;X1 is -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NR5-, -NR5C(=O)-, or -C(=O)NR5-;X1’ is -O-, -S-, -S(O)-, or -S(O)2-;L2 is phenylene;each R5 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;Z’ is -O-CH2-NR8-*, -S-CH2-NR8-*, -NR8-*; where * is the site covalently attached to A;each R8 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;L1 and L2 are each independently optionally substituted with 1-4 substituents selected from halogen, -CN, -OR7, -SR7, -N(R7)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl; andeach R7 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;A is a peptide comprising 2 to 10 amino acids; wherein A is optionally substituted with one or more polyol; andE is -C(=O)-L3-X3;L3 is -(C1-C10 alkylene)- or -Y1-(C1-C10 alkylene)-X4-Y2-(C1-C10 alkylene)-*; where * is the site covalently attached to X3;Y1 is absent, -(CRaRbO)n-, or -(CRaRbCRa’Rb’O)m-;X4 is -NR9C(=O)- or -C(=O)NR9-;Y2 is absent, -(CRcRdO)o-, or -(CRcRdCRc’Rd’O)p-;n, m, o, and p are each independently 1-10;each Ra, Rb, Ra’, Rb’, Rc, Rd, Rc’, and Rd’ are independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;wherein L3 is optionally substituted with 0-4 substituents selected from halogen, -CN, -OR11, -SR11, -N(R11)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, heteroaryl, and polyol;each R11 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;each W’ is independently -H, -N(Rgg)2, C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -(CH2CH2O)q-Rff;q is 1 to 24;each Raa, Rbb, Rcc, Ree, and Rff are independently -H or optionally substituted C1-C6 alkyl;each RYY and RXX are independently -H or C1-C6 alkyl;Rgg are each independently -H or C1-C6 alkyl; andR9 and R10 are each independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.

[0023] In some embodiments, R1 is -H or -F. In some embodiments, R1 is -F. In some embodiments, R2 is–H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, -S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl. In some embodiments, R2 is -F. In some embodiments, R2 is -OMe, -SMe, -S(O)Me, or methyl. In some embodiments, R2 is methyl. In some embodiments, R1 is -F and R2 is -F. In some embodiments, R1 is methyl and R2 is -F. In some embodiments, R1 is -F and R2 is -methyl.

[0024] In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-O-CH2-NR8-*, -(C1-C4 alkylene)-S-CH2-NR8-*, or -(C1-C4 alkylene)-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-O-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-NR8-*.

[0025] In some embodiments, -L1-Z’-* is -CH2O-CH2NH-*, -(CH2)2O-CH2NH-*, -(CH2)3O-CH2NH-*, -(CH2)4O-CH2NH-*, -CH2S-CH2NH-*, -(CH2)2S-CH2NH-*, -(CH2)3S-CH2NH-*, -(CH2)4S-CH2NH-*, -CH2NH-*, -(CH2)2NH-*, -(CH2)3NH-*, or -(CH2)4NH-*.

[0026] In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*.

[0027] In some embodiments, -L1-Z’-* is -CH2NHC(=O)CH2O-CH2-NH-*, -CH2NHC(=O)(CH2)2O-CH2-NH-*, -CH2NHC(=O)(CH2)3O-CH2-NH-*, -CH2NHC(=O)(CH2)4O-CH2-NH-*, -CH2NHC(=O)(CH2)5O-CH2-NH-*, -CH2NHC(=O)CH2S-CH2-NH-*, -CH2NHC(=O)(CH2)2S-CH2-NH-*, -CH2NHC(=O)(CH2)3S-CH2-NH-*, -CH2NHC(=O)(CH2)4S-CH2-NH-*, -CH2NHC(=O)(CH2)5S-CH2-NH-*, -CH2SCH2O-CH2-NH-*, -CH2S(CH2)2O-CH2-NH-*, -CH2S(CH2)3O-CH2-NH-*, -CH2S(CH2)4O-CH2-NH-*, -CH2S(CH2)5O-CH2-NH-*, -CH2SCH2S-CH2-NH-*, -CH2S(CH2)2S-CH2-NH-*, -CH2S(CH2)3S-CH2-NH-*, -CH2S(CH2)4S-CH2-NH-*, or -CH2S(CH2)5S-CH2-NH-*.

[0028] In some embodiments, each R5 is independently -H, methyl, or benzyl. In some embodiments, each R5 is independently -H. In some embodiments, each R5 is methyl. In some embodiments, each R5 is benzyl. In some embodiments, each R8 is independently -H, methyl, or benzyl. In some embodiments, each R8 is independently -H. In someembodiments, each R8 is methyl. In some embodiments, each R8 is benzyl.

[0029] In some embodiments, -L1-Z’-* is -X1’-(C1-C4 alkylene)-O-CH2-NR8-*, -X1’-(C1-C4 alkylene)-S-CH2-NR8-*, or -X1’-(C1-C4 alkylene)-NR8-*. In some embodiments, -L1-Z’-* is -X1’-(C1-C4 alkylene)-O-CH2-NR8-*. In some embodiments, -L1-Z’-* is -X1’-(C1-C4 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -X1’-(C1-C4 alkylene)-NR8-*.

[0030] In some embodiments, -L1-Z’-* is -OCH2O-CH2-NH-*, - O(CH2)2O-CH2-NH-*, -O(CH2)3O-CH2-NH-*, -O(CH2)4O-CH2-NH-*, -SCH2O-CH2-NH-*, - S(CH2)2O-CH2-NH-*, -S(CH2)3O-CH2-NH-*, -S(CH2)4O-CH2-NH-*, -S(O)CH2O-CH2-NH-*, -S(O)(CH2)2O-CH2-NH-*, -S(O)(CH2)3O-CH2-NH-*, -S(O)(CH2)4O-CH2-NH-*, -S(O)2CH2O-CH2-NH-*, -S(O)2(CH2)2O-CH2-NH-*, -S(O)2(CH2)3O-CH2-NH-*, -S(O)2(CH2)4O-CH2-NH-*, -OCH2S-CH2-NH-*, -O(CH2)2S-CH2-NH-*, -O(CH2)3S-CH2-NH-*, -O(CH2)4S-CH2-NH-*, -SCH2S-CH2-NH-*, - S(CH2)2S-CH2-NH-*, -S(CH2)3S-CH2-NH-*, -S(CH2)4S-CH2-NH-*, -S(O)CH2S-CH2-NH-*, -S(O)(CH2)2S-CH2-NH-*, -S(O)(CH2)3S-CH2-NH-*, -S(O)(CH2)4S-CH2-NH-*, -S(O)2CH2S-CH2-NH-*, -S(O)2(CH2)2S-CH2-NH-*, -S(O)2(CH2)3S-CH2-NH-*, -S(O)2(CH2)4S-CH2-NH-*, -OCH2-NH-*, -O(CH2)2-NH-*, - O(CH2)3-NH-*, -O(CH2)4S-NH-*, -SCH2-NH-*, - S(CH2)2-NH-*, -S(CH2)3-NH-*, -S(CH2)4-NH-*, -S(O)CH2-NH-*, -S(O)(CH2)2-NH-*, -S(O)(CH2)3-NH-*, -S(O)(CH2)4-NH-*, -S(O)2CH2-NH-*, -S(O)2(CH2)2-NH-*, -S(O)2(CH2)3-NH-*, or -S(O)2(CH2)4-NH-*.

[0031] In some embodiments, -L1-Z’-* is -(C1-C6 alkylene)-X1-L2-Z’-*. In someembodiments, -L1-Z’-* is . In someembodiments, -L1-Z’-* is In some embodiments, -L1-Z’-* is.

[0032] In the various embodiments disclosing -L1-Z’-* herein, * is the site covalently attached to A.

[0033] In some embodiments, A is a peptide comprising 2 to 8 amino acids. In some embodiments, A is a peptide comprising 2 to 4 amino acids. In some embodiments, at least one amino acid in said peptide is a L amino acid. In some embodiments, each amino acid in said peptide is a L amino acid. In some embodiments, at least one amino acid in said peptide is a D amino acid.

[0034] In some embodiments, A is -(AA1)-(AA2)a1-*, where * is the site covalently attached to E; AA1 and AA2 are each independently an amino acid residue; and a1 is an integer from 1-9.

[0035] In some embodiments, -AA1-(AA2)a1-* is -Gly-Gly-Gly-*, -Ala-Val-*, -Val-Ala-*, - Val-Cit-*, -Val-Lys-*, -Lys-Val-*, -Phe-Lys-*,-Lys-Phe-*, -Lys-Lys-*, -Ala-Lys-*, -Lys- Ala-*, -Phe-Cit-*,-Cit-Phe-*, -Leu-Cit-*,- Cit-Leu-* -Ile-Cit-*, -Phe-Ala-*,-Ala-Phe-*, -Phe- N9-tosyl-Arg-*, -N9-tosyl-Arg-Phe-*, -Phe-N9-nitro-Arg-*, -N9-nitro-Arg-Phe *, -Phe-Phe- Lys-*, -Lys-Phe-Phe-*, -Gly-Phe-Lys-*, Lys-Phe-Gly-*, -Leu-Ala-Leu-*, -Ile-Ala-Leu-*, - Leu-Ala-Ile-*, -Val-Ala-Val-*, -Ala-Leu-Ala-Leu-*,-Leu-Ala-Leu-Ala-*, - ^-Ala-Leu-Ala- Leu-*, -Gly-Phe-Leu-Gly-*,-Gly-Leu-Phe-Gly-*, -Val-Arg-*, -Arg-Val-*, -Arg-Arg-*, -Ala- Ala-*, -Ala-Met-*, -Met-Ala-*, -Thr-Thr-*, -Thr-Met-*, -Met-Thr-*, -Leu-Ala-*, -Ala-Leu- *, -Cit-Val-*, -Gln-Val-*, -Val-Gln-*, -Ser-Val-*, -Val-Ser-*, -Ser-Ala-*, -Ser-Gly-*, -Ala-Ser-*, -Gly-Ser-*, -Leu-Gln-*, -Gln-Leu-*, -Phe-Arg-*, -Arg-Phe-*, -Tyr-Arg-*, -Arg-Tyr-*, -Phe-Gln-*, -Gln-Phe-*, -Val-Thr-*, -Thr-Val-*, -Met-Tyr-*, and -Tyr-Met-*.

[0036] In some embodiments, -AA1-(AA2)a1-* is -Val-D-Lys-*, -Val-D-Arg-*, -L-Val-Cit-*, -L-Val-Lys-*, -L-Val-Arg-*, -L-Val-D-Cit-*, -L-Phe-Phe-Lys-*, -L-Val-D-Lys-*, -L-Val-D-Arg-*, -L-Arg-D-Arg-*, -L-Ala-Ala-*, -L-Ala-D-Ala-*, -Ala-D-Ala-*, -Val-D-Cit-*, -L-Ala-L-Ala-*, -L-Ala-L-Val-*, -L-Gln-L-Val-*, -L-Gln-L-Leu-*, or -L-Ser-L-Val-*.

[0037] In some embodiments, -AA1-(AA2)a1-* is: -Ala-Ala-*, -Ala-Val-*, -Val-Ala-*, -Gln-Leu-*, -Leu-Gln-*, -Ala-Ala-Ala-*, -Ala-Ala-Ala-Ala-*, -Gly-Ala-Gly-Gly-*, -Gly-Gly-Ala-Gly-*, -Gly-Val-Gly-Gly-*, -Gly-Gly-Val-Gly-*, -Gly-Phe-Gly-Gly-*, or -Gly-Gly-Phe-Gly-*.

[0038] In some embodiments, -AA1-(AA2)a1-* is: -L-Ala-L-Ala-*, -L-Ala-D-Ala-*, -L-Ala-L-Val-*, -L-Ala-D-Val-*, -L-Val-L-Ala-*, -L-Val-D-Ala-*, -L-Gln-L-Leu-*, -L-Gln-D-Leu-*, -L-Leu-L-Gln-*, -L-Leu-D-Gln-*, -L-Ala-L-Ala-L-Ala-*, -L-Ala-D-Ala-L-Ala-*, -L-Ala-L-Ala-D-Ala-*, -L-Ala-L-Ala-L-Ala-L-Ala-*, -L-Ala-D-Ala-L-Ala-L-Ala-*, -L-Ala-L-Ala-D-Ala-L-Ala-*, -L-Ala-L-Ala-L-Ala-D-Ala-*, -Gly-L-Ala-Gly-Gly-*, -Gly-Gly-L-Ala-Gly-*, -Gly-D-Ala-Gly-Gly-*, Gly-Gly-D-Ala-Gly-*, -Gly-L-Val-Gly-Gly-*, Gly-Gly-L-Val-Gly-*, -Gly-D-Val-Gly-Gly-*, Gly-Gly-D-Val-Gly-*, -Gly-L-Phe-Gly-Gly-*, or Gly-Gly-L-Phe-Gly-*.

[0039] In some embodiments, -AA1-(AA2)a1-* is: -L-Ala-L-Ala-*, -L-Ala-D-Ala-LAla-*, -L-Ala-L-Ala-L-Ala-*, or -L-Ala-L-Ala-L-Ala-L-Ala-*.

[0040] In the various embodiments disclosing -AA1-(AA2)a1-* herein, * is the site covalently attached to E.

[0041] In some embodiments, A is substituted with one or more polyol. In someembodiments, E is substituted with one or more polyol. In some embodiments, polyol is -(C1-C6 alkylene)-X5-Y3; wherein: X5 is -NR12C(=O)- or -C(=O)NR12-; Y3 is -C1-C10 alkyl, where Y3 is substituted with 0-10 OH groups; and R12 is -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.

[0042] In some embodiments, wherein polyol wherein R12 is H or methyl.

[0043] In some embodiments, E is -C(=O)-(C1-C10 alkylene)-X3. In some embodiments, E is,

[0044] In some embodiments, E is -C(=O)-Y1-(C1-C10 alkylene)-X4-(C1-C10 alkylene)-X3;Y1 is -(CRaRbO)n-, or -(CRaRbCRa’Rb’O)m-;X4 is -NR9C(=O)-; and, -C(=O)-CRbbRcc-W’, NRee-C(=O)-CRbbRcc-W’, or -SR10.

[0045] In some embodiments, E is -C(=O)-Y1-(CH2)2-X4-(CH2)2-X3;Y1 is -(CH2O)n- or -(CH2CH2O)m-;X4 is -NHC(=O)-;n is 2; m is 2 to 6;, -C(=O)-CRbbRcc-W’, NRee-C(=O)-CRbbRcc-W’, or -SR10.

[0046] In some embodiments, the compound is any one of the compounds selected from Table 2.

[0047] In another aspect, the invention provides a compound of Formula III, or a pharmaceutically acceptable salt thereof:CBA—E’—A—Z’—L1—D (Formula III)wherein:D is represented by the following structural formula:R1 is -H, -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring; with the proviso that both R1 and R2 cannot be -H;R3 is H or C1-C6 alkyl;R4 is C1-C6 alkyl;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z’;X1 is -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NR5-, -NR5C(=O)-, or -C(=O)NR5-;X1’ is -O-, -S-, -S(O)-, or -S(O)2-;L2 is phenylene;each R5 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;Z’ is -O-CH2-NR8-*, -S-CH2-NR8-*, -NR8-*; where * is the site covalently attached to A;each R8 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;L1 and L2 are each independently optionally substituted with 1-4 substituents selected from halogen, -CN, -OR7, -SR7, -N(R7)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl; andeach R7 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;A is a peptide comprising 2 to 10 amino acids; wherein A is optionally substituted with one or more polyol;E’ is -C(=O)-L3-X6-*; where * is the site covalently linked to CBA;L3 is -(C1-C10 alkylene)- or -Y1-(C1-C10 alkylene)-X4-Y2-(C1-C10 alkylene)-*; where * is the site covalently attached to X6;Y1 is absent, -(CRaRbO)n- or -(CRaRbCRa’Rb’O)m-;X4 is -NR9C(=O)- or -C(=O)NR9-;Y2 is absent, -(CRcRdO)o-, or -(CRcRdCRc’Rd’O)p-;n, m, o, and p are each independently 1-10;each Ra, Rb, Ra’, Rb’, Rc, Rd, Rc’, and Rd’ are independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;wherein L3 is optionally substituted with 0-4 substituents selected from halogen, -CN, -OR11, -SR11, -N(R11)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, heteroaryl, and polyol;each R11 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;CRbbRcc-*; where * is the site covalently attached to CBA;each Raa, Rbb, Rcc, and Ree are independently -H or optionally substituted C1-C6 alkyl; each RYY and RXX are independently -H or C1-C6 alkyl;R9 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl; andCBA is a cell binding agent.

[0048] In some embodiments, R1 is -H or -F. In some embodiments, R1 is -F. In some embodiments, R2 is–H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, -S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl. In some embodiments, R2 is -F. In some embodiments, R2 is -OMe, -SMe, -S(O)Me, or methyl. In some embodiments, R2 is methyl. In some embodiments, R1 is -F and R2 is -F. In some embodiments, R1 is methyl and R2 is -F. In some embodiments, R1 is -F and R2 is -methyl.

[0049] In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-O-CH2-NR8-*, -(C1-C4 alkylene)-S-CH2-NR8-*, or -(C1-C4 alkylene)-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-O-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-NR8-*.

[0050] In some embodiments, -L1-Z’-* is -CH2O-CH2NH-*, -(CH2)2O-CH2NH-*, -(CH2)3O-CH2NH-*, -(CH2)4O-CH2NH-*, -CH2S-CH2NH-*, -(CH2)2S-CH2NH-*, -(CH2)3S-CH2NH-*, -(CH2)4S-CH2NH-*, -CH2NH-*, -(CH2)2NH-*, -(CH2)3NH-*, or -(CH2)4NH-.

[0051] In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*.

[0052] In some embodiments, -L1-Z’-* is -CH2NHC(=O)CH2O-CH2-NH-*, -CH2NHC(=O)(CH2)2O-CH2-NH-*, -CH2NHC(=O)(CH2)3O-CH2-NH-*, -CH2NHC(=O)(CH2)4O-CH2-NH-*, -CH2NHC(=O)(CH2)5O-CH2-NH-*, -CH2NHC(=O)CH2S-CH2-NH-*, -CH2NHC(=O)(CH2)2S-CH2-NH-*, -CH2NHC(=O)(CH2)3S-CH2-NH-*, -CH2NHC(=O)(CH2)4S-CH2-NH-*, -CH2NHC(=O)(CH2)5S-CH2-NH-*, -CH2SCH2O-CH2-NH-*, -CH2S(CH2)2O-CH2-NH-*, -CH2S(CH2)3O-CH2-NH-*, -CH2S(CH2)4O-CH2-NH-*, -CH2S(CH2)5O-CH2-NH-*, -CH2SCH2S-CH2-NH-*, -CH2S(CH2)2S-CH2-NH-*, -CH2S(CH2)3S-CH2-NH-*, -CH2S(CH2)4S-CH2-NH-*, or -CH2S(CH2)5S-CH2-NH-*.

[0053] In some embodiments, each R5 is independently -H, methyl, or benzyl. In some embodiments, each R5 is independently–H. In some embodiments, each R5 is methyl. In some embodiments, each R5 is benzyl. In some embodiments, each R8 is independently -H, methyl, or benzyl. In some embodiments, each R8 is independently–H. In someembodiments, each R8 is methyl. In some embodiments, each R8 is benzyl.

[0054] In some embodiments -L1-Z’-* is -X1’-(C1-C4 alkylene)-O-CH2-NR8-*, -X1’-(C1-C4 alkylene)-S-CH2-NR8-*, or -X1’-(C1-C4 alkylene)-NR8-*. In some embodiments -L1-Z’-* is -X1’-(C1-C4 alkylene)-O-CH2-NR8-*. In some embodiments -L1-Z’-* is -X1’-(C1-C4 alkylene)-S-CH2-NR8-*. In some embodiments -L1-Z’-* is -X1’-(C1-C4 alkylene)-NR8-*.

[0055] In some embodiments -L1-Z’-* is -OCH2O-CH2-NH-*, - O(CH2)2O-CH2-NH-*, - O(CH2)3O-CH2-NH-*, -O(CH2)4O-CH2-NH-*, -SCH2O-CH2-NH-*, -S(CH2)2O-CH2-NH-*, - S(CH2)3O-CH2-NH-*, -S(CH2)4O-CH2-NH-*, -S(O)CH2O-CH2-NH-*, -S(O)(CH2)2O-CH2- NH-*, -S(O)(CH2)3O-CH2-NH-*, -S(O)(CH2)4O-CH2-NH-*, -S(O)2CH2O-CH2-NH-*, - S(O)2(CH2)2O-CH2-NH-*, -S(O)2(CH2)3O-CH2-NH-*, -S(O)2(CH2)4O-CH2-NH-*, -OCH2S- CH2-NH-*, -O(CH2)2S-CH2-NH-*, -O(CH2)3S-CH2-NH-*, -O(CH2)4S-CH2-NH-*, -SCH2S- CH2-NH-*, - S(CH2)2S-CH2-NH-*, -S(CH2)3S-CH2-NH-*, -S(CH2)4S-CH2-NH-*, - S(O)CH2S-CH2-NH-*, -S(O)(CH2)2S-CH2-NH-*, -S(O)(CH2)3S-CH2-NH-*, -S(O)(CH2)4S- CH2-NH-*, -S(O)2CH2S-CH2-NH-*, -S(O)2(CH2)2S-CH2-NH-*, -S(O)2(CH2)3S-CH2-NH-*, - S(O)2(CH2)4S-CH2-NH-*, -OCH2-NH-*, -O(CH2)2-NH-*, -O(CH2)3-NH-*, -O(CH2)4S-NH-*, -SCH2-NH-*, -S(CH2)2-NH-*, -S(CH2)3-NH-*, -S(CH2)4-NH-*, -S(O)CH2-NH-*, - S(O)(CH2)2-NH-*, -S(O)(CH2)3-NH-*, -S(O)(CH2)4-NH-*, -S(O)2CH2-NH-*, -S(O)2(CH2)2- NH-*, -S(O)2(CH2)3-NH-*, or -S(O)2(CH2)4-NH-*.

[0056] In some embodiments, -L1-Z’-* is -(C1-C6 alkylene)-X1-L2-Z’-*. In someembodiments, -L1-Z’-* is In someembodiments, -L1-Z’-* is In some embodiments, -L1-Z’-* is

[0057] In the various embodiments disclosing -L1-Z’-* herein, * is the site covalently attached to A.

[0058] In some embodiments, A is a peptide comprising 2 to 8 amino acids. In some embodiments, A is a peptide comprising 2 to 4 amino acids. In some embodiments, at least one amino acid in said peptide is a L amino acid. In some embodiments, each amino acid in said peptide is a L amino acid. In some embodiments, at least one amino acid in said peptide is a D amino acid.

[0059] In some embodiments, A is -(AA1)-(AA2)a1-*, where * is the point of attachment to E’, AA1 and AA2 are each independently an amino acid residue; and a1 is an integer from 1-9.

[0060] In some embodiments, -AA1-(AA2)a1-* is -Gly-Gly-Gly-*, -Ala-Val-*, -Val-Ala-*, -Val-Cit-*, -Val-Lys-*, -Lys-Val-*, -Phe-Lys-*,-Lys-Phe-*, -Lys-Lys-*, -Ala-Lys-*, -Lys-Ala-*, -Phe-Cit-*,-Cit-Phe-*, -Leu-Cit-*,- Cit-Leu-* - Ile -Cit-*, -Phe-Ala-*,-Ala-Phe-*, -Phe-N9-tosyl-Arg-*, -N9-tosyl-Arg-Phe-*, -Phe-N9-nitro-Arg-*, -N9-nitro-Arg-Phe *, -Phe-Phe-Lys-*, -Lys-Phe-Phe-*, -Gly-Phe-Lys-*, Lys-Phe-Gly-*, -Leu-Ala-Leu-*, -Ile-Ala-Leu-*, -Leu-Ala-Ile-*, -Val-Ala-Val-*, -Ala-Leu-Ala-Leu-*,-Leu-Ala-Leu-Ala-*, - ^-Ala-Leu-Ala-Leu-*, -Gly-Phe-Leu-Gly-*,-Gly-Leu-Phe-Gly-*, -Val-Arg-*, -Arg-Val-*, -Arg-Arg-*, -Ala-Ala-*, -Ala-Met-*, -Met-Ala-*, -Thr-Thr-*, -Thr-Met-*, -Met-Thr-*, -Leu-Ala-*, -Ala-Leu-*, -Cit-Val-*, -Gln-Val-*, -Val-Gln-*, -Ser-Val-*, -Val-Ser-*, -Ser-Ala-*, -Ser-Gly-*, -Ala-Ser-*, -Gly-Ser-*, -Leu-Gln-*, -Gln-Leu-*, -Phe-Arg-*, -Arg-Phe-*, -Tyr-Arg-*, -Arg-Tyr-*, -Phe-Gln-*, -Gln-Phe-*, -Val-Thr-*, -Thr-Val-*, -Met-Tyr-*, and -Tyr-Met-*.

[0061] In some embodiments, -AA1-(AA2)a1-* is -Val-D-Lys-*, -Val-D-Arg-*, -L-Val-Cit-*, -L-Val-Lys-*, -L-Val-Arg-*, -L-Val-D-Cit-*, -L-Phe-Phe-Lys-*, -L-Val-D-Lys-*, -L-Val-D-Arg-*, -L-Arg-D-Arg-*, -L-Ala-Ala-*, -L-Ala-D-Ala-*, -Ala-D-Ala-*, -Val-D-Cit-*, -L-Ala-L-Ala-*, -L-Ala-L-Val-*, -L-Gln-L-Val-*, -L-Gln-L-Leu-*, or -L-Ser-L-Val-*.

[0062] In some embodiments, -AA1-(AA2)a1-* is: -Ala-Ala-*, -Ala-Val-*, -Val-Ala-* -Gln-Leu-*, -Leu-Gln-*, -Ala-Ala-Ala-*, -Ala-Ala-Ala-Ala-*, -Gly-Ala-Gly-Gly-*, -Gly-Gly-Ala-Gly-*, -Gly-Val-Gly-Gly-*, -Gly-Gly-Val-Gly-*, -Gly-Phe-Gly-Gly-*, or -Gly-Gly-Phe-Gly-*.

[0063] In some embodiments, -AA1-(AA2)a1-* is: -L-Ala-L-Ala-*, -L-Ala-D-Ala-*, -L-Ala-L-Val-*, -L-Ala-D-Val-*, -L-Val-L-Ala-*, -L-Val-D-Ala-*, -L-Gln-L-Leu-*, -L-Gln-D-Leu-*, -L-Leu-L-Gln-*, -L-Leu-D-Gln-*, -L-Ala-L-Ala-L-Ala-*, -L-Ala-D-Ala-L-Ala-*, -L-Ala-L-Ala-D-Ala-*, -L-Ala-L-Ala-L-Ala-L-Ala-*, -L-Ala-D-Ala-L-Ala-L-Ala-*, -L-Ala-L-Ala-D-Ala-L-Ala-*, -L-Ala-L-Ala-L-Ala-D-Ala-*, -Gly-L-Ala-Gly-Gly-*, -Gly-Gly-L-Ala-Gly-*,-Gly-D-Ala-Gly-Gly-*, Gly-Gly-D-Ala-Gly-*, -Gly-L-Val-Gly-Gly-*, Gly-Gly-L-Val-Gly-*, -Gly-D-Val-Gly-Gly-*, Gly-Gly-D-Val-Gly-*, -Gly-L-Phe-Gly-Gly-*, or Gly-Gly-L-Phe-Gly-*.

[0064] In some embodiments, -AA1-(AA2)a1-* is: -L-Ala-L-Ala-*, -L-Ala-D-Ala-L-Ala-*, -L-Ala-L-Ala-L-Ala-*, or -L-Ala-L-Ala-L-Ala-L-Ala-*.

[0065] In the various embodiments disclosing -AA1-(AA2)a1-* herein, * is the site covalently attached to E’.

[0066] In some embodiments, A is substituted with one or more polyol. In someembodiments, E’ is substituted with one or more polyol. In some embodiments, polyol is -(C1-C6 alkylene)-X5-Y3; wherein: X5 is -NR12C(=O)- or -C(=O)NR12-; Y3 is -C1-C10 alkyl, where Y3 is substituted with 0-10 OH groups; and R12 is -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.

[0067] In some embodiments, polyol wherein R12 is H or methyl.

[0068] In some embodiments, E’ is -C(=O)-(C1-C10 alkylene)-X6-*. In some embodiments, E’ is, -C(=O)CH2CH2-C(=O)-CRbbRcc-*, or -C(=O)CH2CH2-NRee-C(=O)- CRbbRcc-*; where * is the site covalently attached to CBA.

[0069] In some embodiments, E’ is -C(=O)-Y1-(C1-C10 alkylene)-X4-(C1-C10 alkylene)-X6- *;Y1 is -(CRaRbO)n-, or -(CRaRbCRa’Rb’O)m-;X4 is -NR9C(=O)-; and, , , , ,, -C(=O)-CRbbRcc-*, or -NRee-C(=O)- CRbbRcc-*; where * is the site covalently attached to CBA.

[0070] In some embodiments, E’ is -C(=O)-Y1-(CH2)2-X4-(CH2)2-X6-*;Y1 is -(CH2O)n-, or -(CH2CH2O)m-;X4 is -NHC(=O)-;n is 2; m is 2 to 6;-C(=O)-CRbbRcc-*, or -NRee-C(=O)- CRbbRcc-*; where * is the site covalently attached to the CBA.

[0071] In some embodiments, the CBA comprises a -SH group that covalently links with E’to provide -C(=O)-CRbbRcc-S-CBA, or -NRee-C(=O)- CRbbRcc-S-CBA.

[0072] In some embodiments, the CBA is an antibody and—E’—A—Z’—L1— D is a drug- linker structure, the average number of drug-linker structures conjugated per antibody is in the range of from 2 to 10.

[0073] In some embodiments, the average number of drug-linker structures conjugated per antibody is in the range of from 2 to 10. In some embodiments, the average number of drug- linker structures conjugated per antibody is in the range of from 6 to 8. In someembodiments, the average number of drug-linker structures conjugated per antibody is 8.

[0074] In some embodiments, the CBA is an antibody, a single chain antibody, an antibody fragment that specifically binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that specifically binds to a target cell, a chimeric antibody, a chimeric antibody fragment that specifically binds to the target cell, a domain antibody, a domain antibody fragment that specifically binds to the target cell, a probody, a nanobody, a hexabody, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule.

[0075] In some embodiments, the CBA binds to target cells selected from tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes; cells expressing any one or more of 5T4, ADAM-9, ALK, AMHRII, ASCT2, Axl, B7-H3, BCMA, C4.4a, CA6, CA9, CanAg, CD123, CD138, CD142, CD166, CD184, CD19, CD20, CD205, CD22, CD248, CD25, CD3, CD30, CD33, CD352, CD37, CD38, CD40L, CD44v6, CD45, CD46, CD48, CD51, CD56, CD7, CD70, CD71, CD74, CD79b, CDH6, CEACAM5, CEACAM6, cKIT, CLDN18.2, CLDN6, CLL-1, c-MET, Cripto, CSP-1, CXCR5, DLK-1, DLL3, DPEP3, Dysadherin, EFNA4 , EGFR, EGFRviii, ENPP3, EpCAM, EphA2, EphA3, ETBR, FGFR2, FGFR3, FLT3, FOLR-alpha, FSH, GCC, GD2, GD3, Globo H, GPC-1, GPC3, gpNMB,HER-2, HER-3, HLA-DR, HSP90, IGF-1R, IL-13R, IL1RAP, IL7R, Interleukin-4 Receptor (IL4R), KAAG-1, LAMP-1, Lewis Y antigen, LGALS3BP, LGR5, LH / hCG, LHRH, LIV-1, LRP-1, LRRC15, Ly6E, MAGE, Mesothelin (MSLN), MET, MHC class I chain-related protein A and B (MICA and MICB), MT1-MMP, MTX3, MTX5, MUC1, MUC16, NaPi2b, Nectin-4, NOTCH3, OAcGD2, OX001L, p-Cadherin, PD-L1, Phosphatidylserine (PS), Polymorphic epithelial mucin (PEM), Prolactin Receptor (PRLR), PSMA, PTK7, RNF43, ROR1, ROR2, SAIL, SLAMF7, SLC44A4, SLITRK6, SSTR2, STEAP-1, STING, STn, TIM-1, TM4SF1, TNF- alpha, TRA, TROP-2, Tumor-associated glycoprotein 72 (TAG-72), tumor-specific epitope of mucin-1 (TA-MUC1), CD5, TIM-3, UPK2, or UPK1b antigen.

[0076] In some embodiments, the cell-binding agent is an anti-folate receptor antibody or an antibody fragment thereof, an anti-EGFR antibody or an antibody fragment thereof, an anti-CD33 antibody or an antibody fragment thereof, an anti-EpCAM antibody or an antibody fragment thereof, an anti-CD19 antibody or an antibody fragment thereof, an anti-Muc1 antibody or an antibody fragment thereof, or an anti-CD37 antibody or an antibody fragment thereof.

[0077] The present invention also includes a composition (e.g., a pharmaceutical composition) comprising a cytotoxic compound or a conjugate of the present invention described herein, and a carrier (a pharmaceutically acceptable carrier). The present compounds, conjugates or compositions are useful for inhibiting abnormal cell growth or treating a proliferative disorder (e.g., cancer), an autoimmune disorder, destructive bone disorder, infectious disease, viral disease, fibrotic disease, neurodegenerative disorder, pancreatitis or kidney disease in a mammal (e.g., human).

[0078] The present compounds, conjugates or compositions are useful for treating cancer in a subject in need thereof. In some embodiments, the cancer is a lymphoma or a leukemia. In some embodiments, the cancer is acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), acute B lymphoblastic leukemia or B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), acute promyelocytic leukemia (APL), B-cell chronic lymphoproliferative disease (B-CLPD), atypical chronic lymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), non-Hodgkin lymphomas (NHL), mantel cell leukemia (MCL), small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, and Burkitt's lymphoma. In some embodiments, the cancer is endometrial cancer, lung cancer, colorectal cancer, bladder cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, prostate cancer, esophageal cancer, breast cancer, head and neck cancer, uterine cancer, ovarian cancer, liver cancer, cervical cancer, thyroid cancer, testicular cancer, myeloid cancer, melanoma, and lymphoid cancer. In some embodiments, the lung cancer is non-small cell lung cancer or small-cell lung cancer.

[0079] Also included in the present invention is the use of a cytotoxic compound, a conjugate, or a composition of the present invention for the manufacture of a medicament for inhibiting abnormal cell growth or treating a proliferative disorder (e.g., cancer), an autoimmune disorder, destructive bone disorder, infectious disease, viral disease, fibrotic disease, neurodegenerative disorder, pancreatitis or kidney disease in a mammal (e.g., human).

[0080] The present compounds, conjugates or compositions are useful for the manufacture of a medicament for treating cancer in a subject in need thereof. In some embodiments, the cancer is a lymphoma or a leukemia. In some embodiments, the cancer is acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), acute B lymphoblastic leukemia or B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), acute promyelocytic leukemia (APL), B-cell chronic lymphoproliferative disease (B-CLPD), atypical chronic lymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), non-Hodgkin lymphomas (NHL), mantel cell leukemia (MCL), small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, and Burkitt's lymphoma. In some embodiments, the cancer is endometrial cancer, lung cancer, colorectal cancer, bladder cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, prostate cancer, esophageal cancer, breast cancer, head and neck cancer, uterine cancer, ovarian cancer, liver cancer, cervical cancer, thyroid cancer, testicular cancer, myeloid cancer, melanoma, and lymphoid cancer. In some embodiments, the lung cancer is non-small cell lung cancer or small-cell lung cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0081] FIG.1 depicts the first part of the synthesis of camptothecin building blocks.

[0082] FIG.2 depicts the second part of the synthesis of camptothecin building blocks.

[0083] FIG.3 depicts the first part of the synthesis of the side chains.

[0084] FIG.4 depicts the second part of the synthesis of the side chains.

[0085] FIG.5 depicts the first part of coupling the camptothecin building blocks to the side chains.

[0086] FIG.6 depicts the second part of coupling the camptothecin building blocks to the side chains.

[0087] FIG.7 depicts the third part of coupling the camptothecin building blocks to of the side chains.

[0088] FIG.8 depicts the synthesis of additional camptothecin metabolites.

[0089] FIG.9 depicts the coupling of camptothecin building blocks to side chains.

[0090] FIG.10 depicts the synthesis of additional camptothecin compounds.

[0091] FIG.11 depicts compounds used for comparison, which include a generic Ab-999 structure of an ADC bearing the 999 moiety linked through reduced inter-chain disulfides of an antibody.

[0092] FIG.12 depicts the cytotoxicity of the sulfide-bearing compound 8c and its sulfoxide 34a and sulfone 34b.

[0093] FIG.13 depicts the pharmacokinetics of ML66-999 in mice. Top panel depicts plots of concentration (µg / mL) vs time of the mAb component (average), and payload component, at 2 min, 1 day and 3 day time points post administration in mice. Bottom panel depicts plots of concentration (µg / mL) vs time of the mAb component (average), and retained Bioactivity (pooled samples), of ADCs at 2 min, 1 day and 3 day time points post administration in mice.

[0094] FIG.14 depicts the pharmacokinetics of ML66-22a in mice. Top panel depicts plots of concentration (µg / mL) vs time of the mAb component (average), and payload component, at 2 min, 1 day and 3 day time points post administration in mice. Bottom panel depicts plots of concentration (µg / mL) vs time of the mAb component (average), and retained Bioactivity (pooled samples), of ADCs at 2 min, 1 day and 3 day time points post administration in mice.

[0095] FIG.15 depicts the in vitro cytotoxicities of ADCs against Ag+ and Ag- cells. ADC standard in formulation (Standard) or blood serum (pooled) containing ADC taken at 2 min, 1 day or 3 days post administration into mice for ML66-999.

[0096] FIG.16 depicts the in vitro cytotoxicities of ADCs against Ag+ and Ag- cells. ADC standard in formulation (Standard) or blood serum (pooled) containing ADC taken at 2 min, 1 day or 3 days post administration into mice for ML66-22a.

[0097] FIG.17 depicts the efficacy of ADCs in a HSC-2 xenograft model. Dosing is based on payload (75 µg / kg and 250 µg / kg are ~ 3 mg / kg and ~10 mg / kg based on antibody).

[0098] FIG.18 depicts the efficacy of ADCs in a FaDu xenograft models. Dosing is based on payload (75 µg / kg and 250 µg / kg are ~ 3 mg / kg and ~10 mg / kg based on antibody).

[0099] FIG.19 depicts the mouse tolerability to ML66-999, ML66-22a and ML66-28a ADCs.

[00100] FIG.20 depicts the anti-tumor activity of ADCs in a H1703 mouse xenograft model. Dosing is based on payload (75 µg / kg and 250 µg / kg are ~ 3 mg / kg and ~10 mg / kg based on antibody).

[00101] FIG.21 depicts the mouse tolerability of non-cross-reactive ADCs at 5000 µg / kg payload dose (~200 mg / kg based on the Ab component). AbF = humanized anti-folate receptor antibody.DETAILED DESCRIPTION

[00102] In order that the invention described herein may be fully understood, the following detailed description is set forth. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents that can be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention.

[00103] The term“herein” means the entire application.

[00104] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this invention belongs. Generally, nomenclature used in connection with the compounds, composition and methods described herein, are those well-known and commonly used in the art.

[00105] It should be understood that any of the embodiments described herein, including those described under different aspects of the invention and different parts of thespecification (including embodiments described only in the Examples) can be combined with one or more other embodiments of the invention, unless explicitly disclaimed or improper. Combination of embodiments are not limited to those specific combinations claimed via the multiple dependent claims.

[00106] Chemistry terms used herein are used according to conventional usage in the art, as exemplified by“The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[00107] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. Any information in any material that has been incorporated by reference herein, is only incorporated by reference to the extent that no conflict exists between such information and the other statements and drawings set forth herein. In the event of such conflict, any such conflicting information in such incorporated by reference material is specifically not incorporated by reference herein, and the present specification, including its specific definitions, will control.

[00108] Throughout this specification, the word“comprise” or variations such as“comprises” or“comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components).

[00109] Throughout the specification, where compositions are described as having, including, or comprising (or variations thereof), specific components, it is contemplated thatcompositions also may consist essentially of, or consist of, the recited components.Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also may consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[00110] The term“including” is used to mean“including but not limited to.”“Including” and“including but not limited to” are used interchangeably.

[00111] As used herein,“about” or“approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[00112] The use of the terms“a” and“an” and“the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[00113] The term“or” as used herein should be understood to mean“and / or,” unless the context clearly indicates otherwise.

[00114] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.Definitions

[00115] The term“alkyl’ or“linear or branched alkyl” as used herein refers to a saturated linear or branched monovalent hydrocarbon radical. In preferred embodiments, a straight chain or branched chain alkyl has thirty or fewer carbon atoms (e.g., C1-C30 for straight chain alkyl group and C3-C30 for branched alkyl), and more preferably twenty or fewer carbon atoms. Even more preferably, the straight chain or branched chain alkyl has ten or fewer carbon atoms (i.e., C1-C10 for straight chain alkyl group and C3-C10 for branched alkyl). In other embodiments, the straight chain or branched chain alkyl has six or fewer carbon atoms (i.e., C1-C6 for straight chain alkyl group or C3-C6 for branched chain alkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, -CH2CH(CH3)2), 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl), 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like. Moreover, the term "alkyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. As used herein, (Cx-Cxx)alkyl or Cx-xxalkyl means a linear or branched alkyl having x-xx number of carbon atoms.

[00116] The term“alkylene” as used herein refers to a saturated linear or branched divalent hydrocarbon radical. In preferred embodiments, a straight chain or branched chain alkylene has thirty or fewer carbon atoms (e.g., C1-C30 for straight chain alkylene group and C3-C30 for branched alkylene), and more preferably twenty or fewer carbon atoms. Even more preferably, the straight chain or branched chain alkylene has ten or fewer carbon atoms (i.e., C1-C10 for straight chain alkylene group and C3-C10 for branched alkylene). In other embodiments, the straight chain or branched chain alkylene has six or fewer carbon atoms (i.e., C1-C6 for straight chain alkylene group or C3-C6 for branched chain alkylene). As used herein, (Cx-Cxx)alkylene or Cx-xxalkylene means a linear or branched alkylene having x-xx number of carbon atoms.

[00117] The term“alkenyl” or“linear or branched alkenyl” refers to linear or branched-chain monovalent hydrocarbon radical of two to twenty carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical includes radicals having“cis” and“trans” orientations, or alternatively,“E” and“Z” orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like. Preferably, the alkenyl has two to ten carbon atoms. More preferably, the alkyl has two to four carbon atoms.

[00118] The term“alkynyl” or“linear or branched alkynyl” refers to a linear or branched monovalent hydrocarbon radical of two to twenty carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, triple bond. Examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, hexynyl, and the like. Preferably, the alkynyl has two to ten carbon atoms. More preferably, the alkynyl has two to four carbon atoms.

[00119] The terms“cyclic alkyl” and“cycloalkyl” can be used interchangeably. As used herein, the term refers to the radical of a saturated carbocyclic ring. In preferred embodiments, cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably from 5 to 7 carbon atoms in the ring structure. In some embodiments, the two cyclic rings can have two or more atoms in common, e.g., the rings are "fused rings." Suitable cycloalkyls include, but are not limited to cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. In someembodiments, the cycloalkyl is a monocyclic group. In some embodiments, the cycloalkyl is a bicyclic group. In some embodiments, the cycloalkyl is a tricyclic group.

[00120] The term“cycloalklalkyl” refers to an alkyl group described above that is substituted with a cycloalkyl group.

[00121] The term“cyclic alkenyl” refers to a carbocyclic ring radical having at least one double bond in the ring structure.

[00122] The term“cyclic alkynyl” refers to a carbocyclic ring radical having at least one triple bond in the ring structure.

[00123] The term“aryl” or“aromatic ring” as used herein, include substituted orunsubstituted single-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. Aryl groups include, but are not limited to, phenyl, phenol, aniline, and the like. The terms "aryl" also includes "polycyclyl", "polycycle", and "polycyclic" ring systems having two or more rings in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings," wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, or aromatic rings. In some preferred embodiments, polycycles have 2-3 rings. In certain preferred embodiments, polycyclic ring systems have two cyclic rings in which both of the rings are aromatic. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 carbon atoms in the ring, preferably from 5 to 7. For example, aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl, and the like. In some embodiments, the aryl is a single-ring aromatic group. In some embodiments, the aryl is a two-ring aromatic group. In some embodiments, the aryl is a three-ring aromatic group.

[00124] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., O, S, N (e.g., -NH, -N(alkyl)-), or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C30heteroalkyl. A C1-C30heteroalkyl refers to an alkyl group having 1 to 30 carbon atoms and 1 to 15 heteroatoms. Examples of C1-C30heteroalkyl groups include, but are not limited to, ethers (e.g., -CH2-O-CH3, -(CH2)2-O-CH3, -(CH2)3-O-(CH2)2-O-CH3, -(CH2)2-O-(CH2)3CH3, CH2-O-CH2-O-CH3, -CH2-O-(CH2)3-O-CH3), polyethylene glycol (PEG) derivatives (e.g., -[(CH2)2O]10CH2CH3), thiothers (e.g., -CH2-S-CH3, -(CH2)2-S-CH3, -(CH2)3-S-(CH2)2CH3, -((CH2)2S)10CH2CH3), -CH2-S-S-CH2, -(CH2)2-S-(CH2)3CH3, CH2-S-CH2-S-CH3, -CH2-S-(CH2)3-S-CH3), amines (e.g., -CH2-NH-CH3, -(CH2)2-N(alkyl)-CH3, -(CH2)3-NH-(CH2)2CH3, -(CH2)2-N(alkyl)-(CH2)3CH3, CH2-NH-CH2-NH-CH3, -CH2-NH-(CH2)3-NH-CH3), or combinations thereof. This disclosure also contemplates C1-C30heteroalkyl groups wherein one of the 1 to 15 heteroatoms occupies the terminal position of the alkyl group, resulting in, for example, an alcohol (i.e., OH), thiol (i.e., SH), or amine (e.g., -NH2) in the terminal position of the moiety.

[00125] The term "heteroalkenyl" refers to an alkenyl group as defined herein, in which one or more of the carbon atoms have been replaced by a heteroatom, e.g., O, S, N (e.g., -NH, -N(alkyl)-). A heteroalkenyl is attached to the rest of the molecule at a carbon atom of the heteroalkenyl. In one aspect, a heteroalkenyl is a C1-C30heteroalkenyl. A C1-C30heteroalkenyl refers to an alkenyl group having 1 to 30 carbon atoms and 1 to 15 heteroatoms, for example, 1 to 10 heteroatoms or 1 to 5 heteroatoms. This disclosure also contemplates C1-C30heteroalkenyl groups wherein one of the 1 to 15 heteroatoms occupies the terminal position of the alkenyl group, resulting in, for example, an alcohol (i.e., OH), thiol (i.e., SH), amine (e.g., -NH2), or imine (-C=N) in the terminal position of the moiety.

[00126] The term "heteroalkynyl" refers to an alkenyl group as defined herein, in which one or more of the carbon atoms have been replaced by a heteroatom, e.g., O, S, N (e.g., -NH, -N(alkyl)-). A heteroalkynyl is attached to the rest of the molecule at a carbon atom of the heteroalkynyl. In one aspect, a heteroalkynyl is a C1-C30heteroalkynyl. A C1-C30heteroalkenyl refers to an alkynyl group having 1 to 30 carbon atoms and 1 to 15 heteroatoms, for example, 1 to 10 heteroatoms or 1 to 5 heteroatoms. This disclosure also contemplates C1-C30heteroalkynyl groups wherein one of the 1 to 15 heteroatoms occupies the terminal position of the alkynyl group, resulting in, for example, an alcohol (i.e., OH), thiol (i.e., SH), amine (e.g., -NH2), or nitrile (-C ^N) in the terminal position of the moiety.

[00127] The terms“heterocycle,”“heterocyclyl,” and“heterocyclic ring” as used herein, refers to substituted or unsubstituted non-aromatic ring structures of 3- to 18-membered rings, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. In certain embodiments, the ring structure can have two cyclic rings. In some embodiments, the two cyclic rings can have two or more atoms in common, e.g., the rings are "fused rings." Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. Heterocycles are described in Paquette, Leo A.;“Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocyclic rings include, but are not limited to, tetrahydrofurane, dihydrofuran, tetrahydrothiene, tetrahydropyran, dihydropyran, tetrahydrothiopyran, thiomorpholine, thioxane, homopiperazine, azetidine, oxetane, thietane, homopiperidine, piperidine, piperazine, pyrrolidine, morpholine, oxepane, thiepane, oxazepine, diazepine, thiazepine, 2-pyrroline, 3-pyrroline, indoline, 2H-pyrane, 4H-pyrane, dioxane, 1,3-dioxolane, pyrazoline, dithiane, dithiolane, dihydropyrane, dihydrothiene, dihydrofurane,pyrazolidinylimidazoline, imidazolidine, 3-azabicyco[3.1.0]hexane, 3-azabicyclo[4.1.0]heptane, and azabicyclo[2.2.2]hexane. Spiro moieties are also included within the scope of this definition. Examples of a heterocyclic group wherein ring atoms are substituted with oxo (=O) moieties are pyrimidinone and 1,1-dioxo-thiomorpholine.

[00128] The term“heteroaryl” or“heteroaromatic ring” as used herein, refers to substituted or unsubstituted aromatic single ring structures, preferably 6- to 18-member rings, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom (e.g., O, N, or S), preferably one to four or one to threeheteroatoms, more preferably one or two heteroatoms. When two or more heteroatoms are present in a heteroaryl ring, they may be the same or different. The term "heteroaryl" also includes "polycyclyl", "polycycle", and "polycyclic" ring systems having two or more cyclic rings in which two or more ring atoms are common to two adjoining rings, e.g., the rings are "fused rings," wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaromatics, and / orheterocyclyls. In some preferred embodiments, polycyclic heteroaryls have 2-3 rings. In certain embodiments, preferred polycyclic heteroaryls have two cyclic rings in which both of the rings are aromatic. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7 atoms in the ring. For examples, heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, quinoline, pyrimidine, indolizine, indole, indazole, benzimidazole, benzothiazole, benzofuran, benzothiophene, cinnoline, phthalazine, quinazoline, carbazole, phenoxazine, quinoline, purine and the like. In some embodiments, the heteroaryl is a single-ring aromatic group. In some embodiments, the heteroaryl is a two-ring aromatic group. In some embodiments, the heteroaryl is a three-ring aromatic group.

[00129] The heterocycle or heteroaryl groups can be carbon (carbon-linked) or nitrogen (nitrogen-linked) attached where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

[00130] By way of example and not limitation, nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or O-carboline.

[00131] The heteroatoms present in heteroaryl or heterocyclyl include the oxidized forms such as NO, SO, and SO2.

[00132] In some embodiments, the heteroaromatic ring is a 5- to 18-membered ring.

[00133] The term“halo” or“halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). In some embodiments, the halogen is fluorine. In some embodiments, the halogen is chlorine. In some embodiments, the halogen is bromine. In some embodiments, the halogen is iodine. As used herein, the term“haloalkyl” refers to an alkyl, as defined herein, that is substituted by one or more halo groups as defined herein. The haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl. A monohaloalkyl can have one fluoro, chloro, bromo, or iodo substituent. Dihaloalkyl or polyhaloalkyl can be substituted with two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl include, but are not limited to, flouromethyl, difluoromethyl, trifluoromethyl, chloroamethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, diflurochloromethyl, dichlorofluoromethyl, difluoroehthyl, diflosoropropyl, dichloroethyl and dichloropropyl.

[00134] The term“alkoxy” used herein refers to alkyl-O-, wherein alkyl is defined herein above. Examples of alkoxy include, not are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[00135] The alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cyclic alkyl, cyclic alkenyl, cyclic alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl described above can be optionally substituted with one or more (e.g., 2, 3, 4, 5, 6 or more) substituents.

[00136] Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to also include substituted variants. For example, reference to an "alkyl" group or moiety implicitly includes both substituted and unsubstituted variants. Examples of substituents on chemical moieties includes but is not limited to, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, alkylthio, acyloxy, phosphoryl, phosphate, phosphonate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aryl or heteroaryl moiety.

[00137] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the application includes instances where the circumstance occurs and instances where it does not. For example, the phrase“optionally substituted" means that a nonhydrogen substituent may or may not be present on a given atom, and, thus, the application includes structures wherein a non-hydrogen substituent is present and structures wherein a nonhydrogen substituent is not present.

[00138] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons, nitrogens, oxygens or sulfurs atoms. It will be understood that"substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of the invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated).

[00139] If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) can separately and / or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) can each be replaced with an independently selected optional substituent. One exemplary substituent can be depicted as -NR’R’’, wherein R’ and R’’ together with the nitrogen atom to which they are attached, can form a heterocyclic ring. The heterocyclic ring formed from R’ and R’’ together with the nitrogen atom to which they are attached can be partially or fully saturated. In some embodiments, the heterocyclic ring consists of 3 to 7 atoms. In other embodiments, the heterocyclic ring is selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridyl and thiazolyl.

[00140] This specification uses the terms“substituent,”“radical,” and“group”interchangeably.

[00141] If a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group can include: (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and / or (3) substitutable substituents that are substituted by one or more of the optional substituents.

[00142] If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions. Such substituents, in non-limiting examples, can be selected from a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, aryl, heteroaryl, heterocyclyl, halogen, guanidinium [-NH(C=NH)NH2], -OR100, NR101R102, -NO2, -NR101COR102, -SR100, a sulfoxide represented by -SOR101, a sulfone represented by -SO2R101, a sulfonate -SO3M, a sulfate -OSO3M, a sulfonamide represented by -SO2NR101R102, cyano, an azido, -COR101, -OCOR101, -OCONR101R102 and a polyethylene glycol unit (-OCH2CH2)nR101 wherein M is H or a cation (such as Na+ or K+); R101, R102 and R103 are each independently selected from H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit (-OCH2CH2)n-R104, wherein n is an integer from 1 to 24, an aryl having from 6 to 10 carbon atoms, a heterocyclic ring having from 3 to 10 carbon atoms and a heteroaryl having 5 to 10 carbon atoms; and R104 is H or a linear or branched alkyl having 1 to 4 carbon atoms, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl in the groups represented by R100, R101, R102, R103 and R104 are optionally substituted with one or more (e.g., 2, 3, 4, 5, 6 or more) substituents independently selected from halogen, -OH, -CN, -NO2 and unsubstituted linear or branched alkyl having 1 to 4 carbon atoms. Preferably, the substituents for the optionally substituted alkyl, alkenyl, alkynyl, cyclic alkyl, cyclic alkenyl, cyclic alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl described above include halogen, -CN, -NR102R103, -CF3, -OR101, aryl, heteroaryl, heterocyclyl, -SR101, -SOR101, -SO2R101 and -SO3M.

[00143] For sulfoxides, represented by -SOR101 as indicated in the preceding paragraph, both optical isomers (R and S configurations at the sulfur atom of the sulfoxide group) are encompassed.

[00144] The number of carbon atoms in a group can be specified herein by the prefix“Cx-xx” or“Cx-Cxx”, wherein x and xx are integers. For example,“C1-4alkyl” or“C1-C4 alkyl” is an alkyl group having from 1 to 4 carbon atoms.

[00145] The term“compound” or“cytotoxic compound,”“cytotoxic dimer” and“cytotoxic dimer compound” are used interchangeably. They are intended to include compounds for which a structure or formula or any derivative thereof has been disclosed in the present invention or a structure or formula or any derivative thereof that has been incorporated by reference. The term also includes, stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts (e.g., pharmaceutically acceptable salts) and prodrugs, and prodrug salts of a compound of all the formulae disclosed in the present invention. The term also includes any solvates, hydrates, and polymorphs of any of the foregoing. The specific recitation of “stereoisomers,”“geometric isomers,”“tautomers,”“solvates,”“metabolites,”“salt” “prodrug,”“prodrug salt,”“conjugates,”“conjugates salt,”“solvate,”“hydrate,” or “polymorph” in certain aspects of the invention described in this application shall not be interpreted as an intended omission of these forms in other aspects of the invention where the term“compound” is used without recitation of these other forms.

[00146] The term“conjugate” as used herein refers to a compound described herein or a derivative thereof that is linked to a cell binding agent.

[00147] The term“chiral” refers to molecules that have the property of non-superimposability of the mirror image partner, while the term“achiral” refers to molecules that are superimposable on their mirror image partner.

[00148] The term“stereoisomer” refers to compounds that have identical chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds.

[00149] The term“diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as crystallization, electrophoresis and chromatography.

[00150] The term“enantiomers” refer to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[00151] Stereochemical definitions and conventions used herein generally follow S. P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill BookCompany, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms“racemic mixture” and“racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[00152] The term“tautomer” or“tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

[00153] The term“pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound of the invention.Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate“mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt can involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion can be any organic orinorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt can have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[00154] If the compound of the invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[00155] If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[00156] As used herein, the term“solvate” means a compound that further includes a stoichiometric or non-stoichiometric amount of solvent such as water, isopropanol, acetone, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces. Solvates or hydrates of the compounds are readily prepared by addition of at least one molar equivalent of a hydroxylic solvent such as methanol, ethanol, 1-propanol, 2-propanol or water to the compound to result in solvation or hydration of the imine moiety.

[00157] The phrase“pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[00158] The term“leaving group” refers to a group of charged or uncharged moiety that departs during a substitution or displacement. Such leaving groups are well known in the art and include, but not limited to, halogens, esters, alkoxy, hydroxyl, tosylates, triflates, mesylates, nitriles, azide, carbamate, disulfides, thioesters, thioethers and diazonium compounds.

[00159] The term“reactive ester” refers to an ester having an easily displaceable leaving group that can readily react with an amine group to form an amide bond. Examples of reactive esters include, but are not limited to, N-hydroxysuccinimide ester, N-hydroxy sulfosuccinimide ester, nitrophenyl (e.g., 2 or 4-nitrophenyl) ester, dinitrophenyl (e.g., 2,4-dinitrophenyl) ester, sulfo-tetraflurophenyl (e.g., 4 sulfo-2,3,5,6-tetrafluorophenyl) ester, or pentafluorophenyl ester.

[00160] The term“reactive group” refers to a group that can react with a moiety located on another molecule, such as the cell-binding agent or the cytotoxic compound, to form a covalent bond. The reactive group includes, but is not limited to an amine reactive group and a thiol reactive group.

[00161] The term“amine reactive group” refers to a group that can react with an amine group to form a covalent bond. Exemplary amine reactive groups include, but are not limited to, reactive ester groups, acyl halides, sulfonyl halide, imidoester, or a reactive thioester groups. In certain embodiments, the amine reactive group is a reactive ester group. In one embodiment, the amine reactive group is a N-hydroxysuccinimide ester or a N-hydroxy sulfo-succinimide ester.

[00162] The term“thiol-reactive group” refers to a group that can react with a thiol (-SH) group to form a covalent bond. Exemplary thiol-reactive groups include, but are not limited to, maleimide, haloacetyl, aloacetamide, vinyl sulfone, vinyl sulfonamide or vinyl pyridine. In one embodiment, the thiol-reactive group is maleimide.

[00163] The term“bifunctional crosslinking agent,”“bifunctional linker” or“crosslinking agents” refers to modifying agents that possess two reactive groups; one of which is capable of reacting with a cell-binding agent while the other one reacts with the cytotoxic compound to link the two moieties together. Such bifunctional crosslinkers are well known in the art (see, for example, Isalm and Dent in Bioconjugation chapter 5, p218-363, GrovesDictionaries Inc. New York, 1999). For example, bifunctional crosslinking agents that enable linkage via a thioether bond include N-succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) to introduce maleimido groups, or with N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB) to introduce iodoacetyl groups. Other bifunctional crosslinking agents that introduce maleimido groups or haloacetyl groups on to a cell binding agent are well known in the art (see US Patent Applications 2008 / 0050310, 20050169933, available from Pierce Biotechnology Inc. P.O. Box 117, Rockland, IL 61105, USA) and include, but not limited to, bis-maleimidopolyethyleneglycol (BMPEO), BM(PEO)2, BM(PEO)3, N-( ^-maleimidopropyloxy)succinimide ester (BMPS), ^-maleimidobutyric acid N-succinimidyl ester (GMBS), ^-maleimidocaproic acid N-hydroxysuccinimide ester (EMCS), 5-maleimidovaleric acid NHS, HBVS, N-succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxy-(6-amidocaproate), which is a“long chain” analog of SMCC (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl)-butyric acid hydrazide or HCl salt (MPBH), N-succinimidyl 3-(bromoacetamido)propionate (SBAP), N-succinimidyl iodoacetate (SIA), ^-maleimidoundecanoic acid N-succinimidyl ester (KMUA), N-succinimidyl 4-(p-maleimidophenyl)-butyrate (SMPB), succinimidyl-6-( ^-maleimidopropionamido)hexanoate (SMPH), succinimidyl-(4-vinylsulfonyl)benzoate (SVSB), dithiobis-maleimidoethane (DTME), 1,4-bis-maleimidobutane (BMB), 1,4 bismaleimidyl-2,3-dihydroxybutane (BMDB), bis-maleimidohexane (BMH), bis-maleimidoethane (BMOE), sulfosuccinimidyl 4-(N-maleimido-methyl)cyclohexane-1-carboxylate (sulfo-SMCC), sulfosuccinimidyl(4-iodo-acetyl)aminobenzoate (sulfo-SIAB), m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sulfo-MBS), N-( ^-maleimidobutryloxy)sulfosuccinimide ester (sulfo-GMBS), N-( ^-maleimidocaproyloxy)sulfosuccimido ester (sulfo-EMCS), N-( ^-maleimidoundecanoyloxy)sulfosuccinimide ester (sulfo-KMUS), and sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate (sulfo-SMPB).

[00164] Heterobifunctional crosslinking agents are bifunctional crosslinking agents having two different reactive groups. Heterobifunctional crosslinking agents containing both an amine-reactive N-hydroxysuccinimide group (NHS group) and a carbonyl-reactive hydrazine group can also be used to link the cytotoxic compounds described herein with a cell-binding agent (e.g., antibody). Examples of such commercially available heterobifunctional crosslinking agents include succinimidyl 6-hydrazinonicotinamide acetone hydrazone (SANH), succinimidyl 4-hydrazidoterephthalate hydrochloride (SHTH) and succinimidyl hydrazinium nicotinate hydrochloride (SHNH). Conjugates bearing an acid-labile linkage can also be prepared using a hydrazine-bearing benzodiazepine derivative of the present invention. Examples of bifunctional crosslinking agents that can be used includesuccinimidyl-p-formyl benzoate (SFB) and succinimidyl-p-formylphenoxyacetate (SFPA).

[00165] Bifunctional crosslinking agents that enable the linkage of cell binding agent with cytotoxic compounds via disulfide bonds are known in the art and include N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl-4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl-4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)2-sulfo butanoate (sulfo-SPDB) to introduce dithiopyridyl groups. Other bifunctional crosslinking agents that can be used to introduce disulfide groups are known in the art and are disclosed in U.S. Patents 6,913,748, 6,716,821 and US Patent Publications 20090274713 and 20100129314, all of which are incorporated herein by reference. Alternatively, crosslinking agents such as 2-iminothiolane, homocysteine thiolactone or S-acetylsuccinic anhydride that introduce thiol groups can also be used.

[00166] The term“linker,”“linker moiety,” or“linking group” as defined herein refers to a moiety that connects two groups, such as a cell binding agent and a cytotoxic compound, together. Typically, the linker is substantially inert under conditions for which the two groups it is connecting are linked. A bifunctional crosslinking agent can comprise two reactive groups, one at each ends of a linker moiety, such that one reactive group can be first reacted with the cytotoxic compound to provide a compound bearing the linker moiety and a second reactive group, which can then react with a cell binding agent. Alternatively, one end of the bifunctional crosslinking agent can be first reacted with the cell binding agent to provide a cell binding agent bearing a linker moiety and a second reactive group, which can then react with a cytotoxic compound. The linking moiety can contain a chemical bond that allows for the release of the cytotoxic moiety at a particular site. Suitable chemical bonds are well known in the art and include disulfide bonds, thioether bonds, acid labile bonds, photolabile bonds, peptidase labile bonds and esterase labile bonds (see for example US Patents 5,208,020; 5,475,092; 6,441,163; 6,716,821; 6,913,748; 7,276,497; 7,276,499;7,368,565; 7,388,026 and 7,414,073). Preferred are disulfide bonds, thioether and peptidase labile bonds. Other linkers that can be used in the present invention include non-cleavable linkers, such as those described in are described in detail in U.S. publication number20050169933, or charged linkers or hydrophilic linkers and are described in US2009 / 0274713, US 2010 / 01293140 and WO 2009 / 134976, each of which is expressly incorporated herein by reference, each of which is expressly incorporated herein by reference.

[00167] The term“self-immolative linker” refers to a linker that will allow for release of the cytotoxic compound when a remote site is activated. In certain embodiments, the linker comprises a p-aminobenzyl unit. In some such embodiments, a p-aminobenzyl alcohol is attached to an amino acid unit via an amide bond, and a carbamate, methylcarbamate, or carbonate is made between the benzyl alcohol and the drug (Hamann et al. (2005) Expert Opin. Ther. Patents (2005) 15:1087-1103). In some embodiments, the linker comprises p-aminobenzyloxycarbonyl (PAB). Other examples of self-immolative linkers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group, such as 2-aminoimidazol-5-methanol derivatives (U.S. Pat. No.7,375,078; Hay et al. (1999) Bioorg. Med. Chem. Lett.9:2237) and ortho- or para-aminobenzylacetals. In some embodiments, spacers can be used that undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al (1995) Chemistry Biology 2:223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al (1972) J. Amer. Chem. Soc.94:5815) and 2-aminophenylpropionic acid amides (Amsberry, et al (1990) J. Org. Chem.55:5867). Linkage of a drug to the a-carbon of a glycine residue is another example of a self-immolative linker that may be useful in ADC (Kingsbury et al (1984) J. Med. Chem.27:1447).

[00168] The term“amino acid” refers to naturally occurring amino acids or non-naturally occurring amino acid. In some embodiments, the amino acid is represented by NH2-C(Raa’Raa)-C(=O)OH, wherein Raa and Raa’ are each independently H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, aryl, heteroaryl or heterocyclyl or Raa and the N-terminal nitrogen atom can together form a heterocyclic ring (e.g., as in proline). The term“amino acid residue” refers to thecorresponding residue when one hydrogen atom is removed from the amine and / or carboxy end of the amino acid, such as -NH-C(Raa’Raa)-C(=O)-.

[00169] The term“peptide” refers to short chains of amino acid monomers linked by peptide (amide) bonds. In some embodiments, the peptides contain 2 to 20 amino acid residues. In other embodiments, the peptides contain 2 to 10 or 2 to 8 amino acid residues. In yet other embodiments, the peptides contain 2 to 5 amino acid residues. As used herein, when a peptide is a portion of a cytotoxic agent or a linker described herein represented by a specific sequence of amino acids, the peptide can be connected to the rest of the cytotoxic agent or the linker in both directions.

[00170] The term“cation” refers to an ion with positive charge. The cation can be monovalent (e.g., Na+, K+, etc.), bi-valent (e.g., Ca2+, Mg2+, etc.) or multi-valent (e.g., Al3+ etc.). Preferably, the cation is monovalent.

[00171] The term“antibody” means an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term“antibody” encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab’, F(ab’)2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies (e.g., bispecific antibodies, biparatopic antibodies, etc.), multivalent antibodies (e.g., trivalent, tetravalent, etc. antibodies that have three, four or more antigen binding sites) chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity. An antibody can be of any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1,IgG2, IgG3, IgG4, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc. As used herein“antibody” also includes is an activatable antibody (e.g., a probody). By activatable is meant that the activatable antibody, exhibits a first level of binding to a target when the activatable antibody, is in an inhibited, masked, intact or uncleaved state (i.e., a first conformation), and a second level of binding to the target in the uninhibited, unmasked and / or cleaved state (i.e., a second conformation), where the second level of target binding is greater than the first level of binding.

[00172] In some embodiments, an antibody is a non-naturally occurring antibody. In some embodiments, an antibody is purified from natural components. In some embodiments, an antibody is recombinantly produced. In some embodiments, an antibody is produced by a hybridoma.

[00173] The term“antibody fragment” refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab’, F(ab’)2, and Fv fragments, linear antibodies, single chain antibodies, and multispecific antibodies (e.g., bispecific, biparatopic) formed from antibody fragments. The term“antigen-binding fragment” of an antibody includes one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by certain fragments of a full-length antibody. Examples of binding fragments encompassed within the term“antigen-binding fragment” of an antibody include (without limitation): (i) an Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains (e.g., an antibody digested by papain yields three fragments: two antigen-binding Fab fragments, and one Fc fragment that does not bind antigen); (ii) a single chain Fab (scFab), a fragment consisting of the VL, VH, CL, and CH1 domains, wherein the CL and VH domains are linked via a linker peptide; (iii) a F(ab’)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region (e.g., an antibody digested by pepsin yields two fragments: a bivalent antigen-binding F(ab’)2 fragment, and a pFc’ fragment that doesnot bind antigen) and its related F(ab’) monovalent unit; (iv) a Fd fragment consisting of the VH and CH1 domains (i.e., that portion of the heavy chain which is included in the Fab); (v) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, and the related disulfide linked Fv; (vi) a dAb (domain antibody) or sdAb (single domain antibody) fragment (Ward et al., Nature 341:544-546, 1989), which consists of a VH domain; (vii) an isolated complementarity determining region (CDR); (viii) a single chain variable fragment (scFv), a fragment consisting of a VH and VL domain, connected via a linker peptide; and (ix) a tetravalent antibody, which may include various formats (structures) whereby the antibody comprises 4 antigen binding sites.

[00174] The term“monoclonal antibody” refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term“monoclonal antibody” encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab’, F(ab’)2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore,“monoclonal antibody” refers to such antibodies made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[00175] The term“humanized antibody” refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability (Jones et al., Nature 321:522-525, 1986; Riechmann et al., Nature 332:323-327, 1988;Verhoeyen et al., Science 239:1534-1536, 1988).

[00176] In some instances, the Fv framework region (FR) residues of a humanimmunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity, and capability. The humanized antibody can be further modified by the substitution of additional residues either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and / or capability. In general, the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pats.5,225,539 and 5,639,641, Roguska et al., Proc. Natl. Acad. Sci. USA 91(3):969-973, 1994; and Roguska et al., Protein Eng.9(10):895-904, 1996 (all incorporated herein by reference). In some embodiments, a“humanized antibody” is a resurfaced antibody. In some embodiments, a“humanized antibody” is a CDR-grafted antibody.

[00177] The term“variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al.Sequences of Proteins of Immunological Interest, 5th ed., 1991, National Institutes of Health, Bethesda Md.); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., J. Molec. Biol.273:927-948, 1997). In addition, combinations of these two approaches are sometimes used in the art to determine CDRs.

[00178] The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[00179] The amino acid position numbering as in Kabat, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991) (incorporated herein by reference). Using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain can include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues can be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a“standard” Kabat numbered sequence. Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol.196:901-917,1987). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop. This is because the Kabat numbering scheme places the insertions at H35A and H35B - if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34. The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software.

[00180] The EU index or EU index as in Kabat or EU numbering scheme refers to the numbering system based on the human IgG1 Eu antibody of Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, incorporated herein by reference.

[00181] The term“human antibody” means an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human made using any technique known in the art. In certain embodiments, the human antibody does not have non-human sequence. This definition of a human antibody includes intact or full-length antibodies, or antigen-binding fragments thereof.

[00182] The term“chimeric antibodies” refers to antibodies wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species. Typically, the variable region of both light and heavy chains corresponds to the variable region of antibodies derived from one species of mammals (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies derived from another (usually human) to avoid or reduce the chance of eliciting an immune response in that species (e.g., human). In certain embodiments, chimeric antibody may include an antibody or antigen-binding fragment thereof comprising at least one human heavy and / or light chain polypeptide, such as, for example, an antibody comprising murine light chain and human heavy chain polypeptides.

[00183] The terms“epitope” or“antigenic determinant” are used interchangeably herein and refer to that portion of an antigen capable of being recognized and specifically bound by a particular antibody. When the antigen is a polypeptide, epitopes can be formed both from contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding are typically lost upon protein denaturing. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.

[00184] “Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein,“binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd) or the half-maximal effective concentration (EC50). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present invention. Specific illustrative embodiments are described herein.

[00185] By“specifically binds,” it is generally meant that an antibody binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain more readily than it would bind to a random, unrelated epitope. The term“specificity” is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope. For example, antibody“A” may be deemed to have a higher specificity for a given epitope than antibody“B,” or antibody“A” may be said to bind to epitope“C” with a higher specificity than it has for related epitope“D.”

[00186] The term“immunoconjugate,”“conjugate,” or“ADC” as used herein refers to a compound or a derivative thereof that is linked to a cell binding agent (e.g., an antibody or antigen-binding fragment thereof).

[00187] The term“cysteine-engineered antibody” includes an antibody with at least one Cys that is not normally present at a given residue of the antibody light chain or heavy chain. Such Cys, which may also be referred to as“engineered Cys,” can be engineered using any conventional molecular biology or recombinant DNA technology (e.g., by replacing the coding sequence for a non-Cys residue at the target residue with a coding sequence for Cys). For example, if the original residue is Ser with a coding sequence of 5’-UCU-3’, the coding sequence can be mutated (e.g., by site-directed mutagenesis) to 5’-UGU-3’, which encodes Cys. In certain embodiments, the Cys engineered antibody of the invention has an engineered Cys in the heavy chain. In certain embodiments, the engineered Cys is in or near the CH3 domain of the heavy chain. In certain embodiments, the engineered Cys is at residue 442 of the heavy chain (EU / OU numbering). The C442 residue can be conjugated with acytotoxic drug / agent through the free thiol group of the C442 residue, such as through reacting with a thiol-reactive agent of the cytotoxic drug (e.g., a maleimido group).

[00188] The terms“cancer” and“cancerous” refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. “Tumor” and“neoplasm” refer to one or more cells that result from excessive cell growth or proliferation, either benign (noncancerous) or malignant (cancerous) including pre-cancerous lesions.

[00189] Examples of cancer include endometrial cancer, lung cancer (e.g., non-small-cell lung cancer), colorectal cancer, bladder cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, prostate cancer, esophageal cancer, breast cancer, head and neck cancer, uterine cancer, ovarian cancer, liver cancer, cervical cancer, thyroid cancer, testicular cancer, myeloid cancer, melanoma, and lymphoid cancer. In certain embodiments, the cancer is non-small-cell lung cancer, colorectal cancer, gastric cancer or pancreatic cancer. In certain embodiments, the cancer is non-small-cell lung cancer (squamous cell, nonsquamous cell, adenocarcinoma, or large-cell undifferentiated carcinoma), colorectal cancer(adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, or squamous cell carcinoma) or breast cancer (e.g., triple negative breast cancer (TNBC)). In certain embodiments, cancer is lymphoma and leukemia. In certain embodiments, examples of cancers include AML, CML, ALL (e.g., B-ALL), CLL, myelodysplastic syndrome, basic plasmacytoid DC neoplasm (BPDCN) leukemia, B-cell lymphomas including non-Hodgkin lymphomas (NHL), precursor B-cell lymphoblastic leukemia / lymphoma and mature B-cell neoplasms, such as B-cell chronic lymphocytic leukemia (B-CLL) / small lymphocytic lymphoma (SLL), B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), including low-grade, intermediate-grade and high-grade FL, cutaneous follicle center lymphoma, marginal zone B-cell lymphoma (MALT type, nodal and splenic type), hairy cell leukemia (HCL), diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma, plasmacytoma, plasma cell myeloma, post-transplant lymphoproliferative disorder, Waldenstrom’s macroglobulinemia, anaplastic large-cell lymphoma (ALCL), andHodgkin’s leukemia (HL). In certain embodiments, the cancer is BPDCN leukemia. In certain embodiments, the cancer is ALL. In other embodiments, the cancer is AML.

[00190] The term“subject” refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms“subject,”“patient,” and“individual” are used interchangeably herein in reference to a human subject.

[00191] The term“pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. Such composition can be sterile.

[00192] A“therapeutically effective amount” as used herein is an amount of a compound or composition sufficient to carry out a specifically stated purpose. The full therapeutic effect may not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. The particular“therapeutically effective amount” will depend upon e.g., the age, weight and medical condition of the subject, as well as on the method of administration and the therapeutic or combination of therapeutics selected for administration. A“therapeutically effective amount” can be determined empirically and in a routine manner, in relation to the stated purpose.

[00193] As used herein, the term“treating,”“treat,” or“treatment” includes reversing, reducing, or arresting the symptoms, clinical signs or underlying pathology of a condition in a manner to improve, or stabilize the subject’s condition. As used herein, and as well understood in the art,“treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired results include, but are not limited to, prevention, alleviation, amelioration, or slowing the progression of one or more symptoms or conditions associated with a condition, diminishment of extent of disease, stabilized state of disease, delay or slowing of disease progression, amelioration or palliation of disease state, and remission (partial or total), whether detectable or undetectable.“Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.Compounds

[00194] In one aspect, the invention provides a compound of Formula I, or apharmaceutically acceptable salt, thereof:Z—L1—D (Formula I)wherein:D is represented by the following structural formula:R1 is -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring;R3 is H or C1-C6 alkyl;R4 is C1-C6 alkyl;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z;X1 is -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NR5-, -NR5C(=O)-, or -C(=O)NR5-;X1’ is -O-, -S-, -S(O)-, or -S(O)2-;L2 is phenylene;each R5 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;Z is -H or -X2;X2 is -OR6, -SR6, -S(O)R6, -S(O)2R6, -SSR6, or -N(R6)2;each R6 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;L1 and L2 are each independently optionally substituted with 1-4 substituents selected from halogen, -CN, -OR7, -SR7, -N(R7)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl; andeach R7 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;with the proviso that if R1 is F, then L1 is -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1- (C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z; and Z is -X2; andwith the proviso that if R1 is F and R2 is–OMe, then–L1-Z cannot be–NH2.

[00195] In some embodiments, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, thereof:Z—L1—D (Formula I)wherein:D is represented by the following structural formula:R1 is -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring;R3 is H or C1-C6 alkyl;R4 is C1-C6 alkyl;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z;X1 is -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NR5-, -NR5C(=O)-, or -C(=O)NR5-;X1’ is -O-, -S-, -S(O)-, or -S(O)2-;L2 is phenylene;each R5 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;Z is -H or -X2;X2 is -OR6, -SR6, -S(O)R6, -S(O)2R6, -SSR6, or -N(R6)2;each R6 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;L1 and L2 are each independently optionally substituted with 1-4 substituents selected from halogen, -CN, -OR7, -SR7, -N(R7)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl; andeach R7 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;with the proviso that if R1 is F, then L1 is -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1- (C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z; and Z is -X2;with the proviso that if R1 is F and R2 is–OMe, then–L1-Z cannot be–NH2; and with the proviso that if R1 is F and R2 is–Me, then–L1-Z cannot be–CH2OH.

[00196] In some embodiments, R1 is F and -L1-Z is -(C1-C6 alkylene)-X2, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-X2, -X1’-(C1-C6 alkylene)-X2, or -(C1-C6 alkylene)-X1-L2-X2. In some embodiments, R1 is F and -L1-Z is -(C1-C6 alkylene)-OR6, -(C1-C6 alkylene)-SR6, -(C1-C6 alkylene)-S(O)R6, -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-SSR6, or -(C1-C6 alkylene)-N(R6)2. In some embodiments, R1 is F and -L1-Z is -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-OR6, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-SR6, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-S(O)R6, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-SSR6, or -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-N(R6)2. In some embodiments, R1 is F and -L1-Z is -X1’-(C1-C6 alkylene)-OR6, -X1’-(C1-C6 alkylene)-SR6, -X1’-(C1-C6 alkylene)-S(O)R6, -X1’-(C1-C6 alkylene)-S(O)2R6, -X1’-(C1-C6 alkylene)-SSR6, or -X1’-(C1-C6 alkylene)-N(R6)2. In some embodiments, R1 is F and -L1-Z is -(C1-C6 alkylene)-X1-L2-OR6, -(C1-C6 alkylene)-X1-L2-SR6, -(C1-C6 alkylene)-X1-L2-S(O)R6, -(C1-C6 alkylene)-X1-L2-S(O)2R6, -(C1-C6 alkylene)-X1-L2-SSR6, or -(C1-C6 alkylene)-X1-L2-N(R6)2.

[00197] In some embodiments, R1 is -H or -F. In some embodiments, R1 is -F. In some embodiments, R2 is -H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, -S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl. In some embodiments, R2 is -F. In some embodiments, R2 is -OMe, -SMe, -S(O)Me, or methyl. In some embodiments, R2 is methyl. In someembodiments, R1 is -F and R2 is -F. In some embodiments, R1 is methyl and R2 is -F. In some embodiments, R1 is -F and R2 is -methyl.

[00198] In some embodiments, -L1-Z is -H. In some embodiments, -L1-Z is -(C1-C6 alkylene)-H, or -(C1-C6 alkylene)-X2. In some embodiments, -L1-Z is -(C1-C6 alkylene)-H. In some embodiments, -L1-Z is -(C1-C6 alkylene)-X2. In some embodiments, -L1-Z is -(C1-C6 alkylene)-X2. In some embodiments, -L1-Z is methyl, ethyl, propyl, or butyl.

[00199] In some embodiments, -L1-Z is -(C1-C4 alkylene)-OR6, -(C1-C4 alkylene)-SR6, or -(C1-C4 alkylene)-N(R6)2. In some embodiments, -L1-Z is -(C1-C4 alkylene)-OR6. In some embodiments, -L1-Z is -(C1-C4 alkylene)-SR6. In some embodiments, -L1-Z is -(C1-C4 alkylene)-N(R6)2.

[00200] In some embodiments, -L1-Z is -CH2OH, -(CH2)2OH, -(CH2)3OH, -(CH2)4OH, -CH2OMe, -(CH2)2OMe, -(CH2)3OMe, -(CH2)4OMe, -CH2SH, -(CH2)2SH, -(CH2)3SH, -(CH2)4SH, -CH2SMe, -(CH2)2SMe, -(CH2)3SMe, -(CH2)4SMe, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -(CH2)4NH2.

[00201] In some embodiments, -L1-Z is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-OR6, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-SR6, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SR6, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SSR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-OR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-SR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SR6. In some embodiments, -L1-Z is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SSR6.

[00202] In some embodiments, -L1-Z is -CH2NHC(=O)CH2OH, -CH2NHC(=O)(CH2)2OH, -CH2NHC(=O)(CH2)3OH, -CH2NHC(=O)(CH2)4OH, -CH2NHC(=O)(CH2)5OH, -CH2NHC(=O)CH2OMe, -CH2NHC(=O)(CH2)2OMe, -CH2NHC(=O)(CH2)3OMe, -CH2NHC(=O)(CH2)4OMe, -CH2NHC(=O)(CH2)5OMe, -CH2NHC(=O)CH2SH, -CH2NHC(=O)(CH2)2SH, -CH2NHC(=O)(CH2)3SH, -CH2NHC(=O)(CH2)4SH, -CH2NHC(=O)(CH2)5SH, -CH2NHC(=O)CH2SMe, -CH2NHC(=O)(CH2)2SMe, -CH2NHC(=O)(CH2)3SMe, -CH2NHC(=O)(CH2)4SMe, -CH2NHC(=O)(CH2)5SMe, -CH2SCH2OH, -CH2S(CH2)2OH, -CH2S(CH2)3OH, -CH2S(CH2)4OH, -CH2S(CH2)5OH, -CH2SCH2OMe, -CH2S(CH2)2OMe, -CH2S(CH2)3OMe, -CH2S(CH2)4OMe, -CH2S(CH2)5OMe,-CH2SCH2SH, -CH2S(CH2)2SH, -CH2S(CH2)3SH, -CH2S(CH2)4SH, -CH2S(CH2)5SH, -CH2SCH2SMe, -CH2S(CH2)2SMe, -CH2S(CH2)3SMe, -CH2S(CH2)4SMe, or -CH2S(CH2)5SMe.

[00203] In some embodiments, each R5 is independently -H, methyl, or benzyl. In some embodiments, each R5 is independently -H. In some embodiments, each R5 is methyl. In some embodiments, each R5 is benzyl.

[00204] In some embodiments, each R6 is independently -H, methyl, or benzyl. In some embodiments, each R6 is independently -H. In some embodiments, each R6 is methyl. In some embodiments, each R6 is benzyl.

[00205] In some embodiments, -L1-Z is -X1’-(C1-C4 alkylene)-X2. In some embodiments, -L1-Z is -OCH2OH, -O(CH2)2OH, -O(CH2)3OH, -O(CH2)4OH, -SCH2OH, -S(CH2)2OH, -S(CH2)3OH, -S(CH2)4OH, -S(O)CH2OH, -S(O)(CH2)2OH, -S(O)(CH2)3OH, -S(O)(CH2)4OH, -S(O)2CH2OH, -S(O)2(CH2)2OH, -S(O)2(CH2)3OH, -S(O)2(CH2)4OH, -OCH2SMe, -O(CH2)2SMe, - O(CH2)3SMe, -O(CH2)4SMe, -SCH2SMe, - S(CH2)2SMe, -S(CH2)3SMe, -S(CH2)4SMe, -S(O)CH2SMe, -S(O)(CH2)2SMe, -S(O)(CH2)3SMe, -S(O)(CH2)4SMe, -S(O)2CH2SMe, -S(O)2(CH2)2SMe, -S(O)2(CH2)3SMe, or -S(O)2(CH2)4SMe.

[00206] In some embodiments, -L1-Z is -(C1-C6 alkylene)-X1-L2-X2. In some embodiments, -

[00207] In another aspect, the invention provides a compound of Formula II, or apharmaceutically acceptable salt thereof:E—A—Z’—L1—D (Formula II)wherein:D is represented by the following structural formula:R1 is -H, -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring; with the proviso that both R1 and R2 cannot be -H;R3 is H or C1-C6 alkyl;R4 is C1-C6 alkyl;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, X1’-(C1-C6 alkylene)-* or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z’;X1 is -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NR5-, -NR5C(=O)-, or -C(=O)NR5-;X1’ is -O-, -S-, -S(O)-, or -S(O)2-;L2 is phenylene;each R5 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;Z’ is -O-CH2-NR8-*, -S-CH2-NR8-*, -NR8-*; where * is the site covalently attached to A;each R8 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;L1 and L2 are each independently optionally substituted with 1-4 substituents selected from halogen, -CN, -OR7, -SR7, -N(R7)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl; andeach R7 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;A is a peptide comprising 2 to 10 amino acids; wherein A is optionally substituted with one or more polyol; andE is -C(=O)-L3-X3;L3 is -(C1-C10 alkylene)- or -Y1-(C1-C10 alkylene)-X4-Y2-(C1-C10 alkylene)-*; where * is the site covalently attached to X3;Y1 is absent, -(CRaRbO)n-, or -(CRaRbCRa’Rb’O)m-;X4 is -NR9C(=O)- or -C(=O)NR9-;Y2 is absent, -(CRcRdO)o-, or -(CRcRdCRc’Rd’O)p-;n, m, o, and p are each independently 1-10;each Ra, Rb, Ra’, Rb’, Rc, Rd, Rc’, and Rd’ are independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;wherein L3 is optionally substituted with 0-4 substituents selected from halogen, -CN, -OR11, -SR11, -N(R11)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, heteroaryl, and polyol;each R11 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;each W’ is independently -H, -N(Rgg)2, C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -(CH2CH2O)q-Rff;q is 1 to 24;each Raa, Rbb, Rcc, Ree, and Rff are independently -H or optionally substituted C1-C6 alkyl;each RYY and RXX are independently -H or C1-C6 alkyl;Rgg are each independently -H or C1-C6 alkyl; andR9 and R10 are each independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.

[00208] In some embodiments, R1 is -H or -F. In some embodiments, R1 is -F. In some embodiments, R2 is–H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, -S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl. In some embodiments, R2 is -F. In some embodiments, R2 is -OMe, -SMe, -S(O)Me, or methyl. In some embodiments, R2 is methyl. In some embodiments, R1 is -F and R2 is -F. In some embodiments, R1 is methyl and R2 is -F. In some embodiments, R1 is -F and R2 is -methyl.

[00209] In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-O-CH2-NR8-*, -(C1-C4 alkylene)-S-CH2-NR8-*, or -(C1-C4 alkylene)-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-O-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C4 alkylene)-NR8-*.

[00210] In some embodiments, -L1-Z’-* is -CH2O-CH2NH-*, -(CH2)2O-CH2NH-*, -(CH2)3O-CH2NH-*, -(CH2)4O-CH2NH-*, -CH2S-CH2NH-*, -(CH2)2S-CH2NH-*, -(CH2)3S-CH2NH-*, -(CH2)4S-CH2NH-*, -CH2NH-*, -(CH2)2NH-*, -(CH2)3NH-*, or -(CH2)4NH-*.

[00211] In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*. In some embodiments, -L1-Z’-* is -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*.

[00212] In some embodiments, -L1-Z’-* is -CH2NHC(=O)CH2O-CH2-NH-*, -CH2NHC(=O)(CH2)2O-CH2-NH-*, -CH2NHC(=O)(CH2)3O-CH2-NH-*, -CH2NHC(=O)(CH2)4O-CH2-NH-*, -CH2NHC(=O)(CH2)5O-CH2-NH-*, -CH2NHC(=O)CH2S-CH2-NH-*, -CH2NHC(=O)(CH2)2S-CH2-NH-*, -CH2NHC(=O)(CH2)3S-CH2-NH-*, -CH2NHC(=O)(CH2)4S-CH2-NH-*, -CH2NHC(=O)(CH2)5S-CH2-NH-*, -CH2SCH2O-CH2-NH-*, -CH2S(CH2)2O-CH2-NH-*, -CH2S(CH2)3O-CH2-NH-*, -CH2S(CH2)4O-CH2-NH-*, -CH2S(CH2)5O-CH2-NH-*, -CH2SCH2S-CH2-NH-*, -CH2S(CH2)2S-CH2-NH-*, -CH2S(CH2)3S-CH2-NH-*, -CH2S(CH2)4S-CH2-NH-*, or -CH2S(CH2)5S-CH2-NH-*.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I, or a pharmaceutically acceptable salt, thereof:Z—L1—D (Formula I)wherein:D is represented by the following structural formula:R1 is -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring;R3 is H or C1-C6 alkyl;R4 is C1-C6 alkyl;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z;X1 is -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NR5-, -NR5C(=O)-, or -C(=O)NR5-;X1’ is -O-, -S-, -S(O)-, or -S(O)2-;L2 is phenylene;each R5 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;Z is -H or -X2;X2 is -OR6, -SR6, -S(O)R6, -S(O)2R6, -SSR6, or -N(R6)2;each R6 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;L1 and L2 are each independently optionally substituted with 1-4 substituents selected from halogen, -CN, -OR7, -SR7, -N(R7)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, or heteroaryl; andeach R7 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;with the proviso that if R1 is F, then L1 is -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1- (C1-C6 alkylene)-, -X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z; and Z is -X2; andwith the proviso that if R1 is F and R2 is–OMe, then–L1-Z cannot be–NH2.

2. A compound of Formula I, or a pharmaceutically acceptable salt, thereof:with the proviso that if R1 is F and R2 is–OMe, then–L1-Z cannot be–NH2; and with the proviso that if R1 is F and R2 is–Me, then–L1-Z cannot be–CH2OH.

3. The compound of claim 1 or claim 2, wherein R1 is -H or -F.

4. The compound of any one of claims 1-3, wherein R1 is -F.

5. The compound of any one of claims 1-4, R2 is -H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, - S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl.

6. The compound of any one of claims 1-5, wherein R2 is -F.

7. The compound of any one of claims 1-5, wherein R2 is -OMe, -SMe, -S(O)Me, or methyl.

8. The compound of any one of claims 1-5, wherein R2 is methyl.

9. The compound of claim 1 or claim 2, wherein R1 is -F and R2 is -F.

10. The compound of claim 1 or claim 2, wherein R1 is methyl and R2 is -F.

11. The compound of claim 1 or claim 2, wherein R1 is -F and R2 is -methyl.

12. The compound of any one of claims 1-11, wherein -L1-Z is -H.

13. The compound of any one of claims 1-11, wherein -L1-Z is -(C1-C6 alkylene)-H, or -(C1- C6 alkylene)-X2.

14. The compound of claim 13, wherein -L1-Z is methyl, ethyl, propyl, or butyl.

15. The compound of any one of claims 1-11, wherein -L1-Z is -(C1-C4 alkylene)-OR6, -(C1- C4 alkylene)-SR6, or -(C1-C4 alkylene)-N(R6)2.

16. The compound of claim 15, wherein -L1-Z is -CH2OH, -(CH2)2OH, -(CH2)3OH, - (CH2)4OH, -CH2OMe, -(CH2)2OMe, -(CH2)3OMe, -(CH2)4OMe, -CH2SH, -(CH2)2SH, - (CH2)3SH, -(CH2)4SH, -CH2SMe, -(CH2)2SMe, -(CH2)3SMe, -(CH2)4SMe, -CH2NH2, - (CH2)2NH2, -(CH2)3NH2, -(CH2)4NH2.

17. The compound of claims any one of 1-11, wherein -L1-Z is -(C1-C5 alkylene)-NR5C(=O)- (C1-C5 alkylene)-OR6, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-SR6, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SR6, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SSR6.

18. The compound of claim 17, wherein -L1-Z is -CH2NHC(=O)CH2OH, - CH2NHC(=O)(CH2)2OH, -CH2NHC(=O)(CH2)3OH, -CH2NHC(=O)(CH2)4OH, - CH2NHC(=O)(CH2)5OH, -CH2NHC(=O)CH2OMe, -CH2NHC(=O)(CH2)2OMe, - CH2NHC(=O)(CH2)3OMe, -CH2NHC(=O)(CH2)4OMe, -CH2NHC(=O)(CH2)5OMe, - CH2NHC(=O)CH2SH, -CH2NHC(=O)(CH2)2SH, -CH2NHC(=O)(CH2)3SH, - CH2NHC(=O)(CH2)4SH, -CH2NHC(=O)(CH2)5SH, -CH2NHC(=O)CH2SMe, - CH2NHC(=O)(CH2)2SMe, -CH2NHC(=O)(CH2)3SMe, -CH2NHC(=O)(CH2)4SMe, - CH2NHC(=O)(CH2)5SMe, -CH2SCH2OH, -CH2S(CH2)2OH, -CH2S(CH2)3OH, - CH2S(CH2)4OH, -CH2S(CH2)5OH, -CH2SCH2OMe, -CH2S(CH2)2OMe, - CH2S(CH2)3OMe, -CH2S(CH2)4OMe, -CH2S(CH2)5OMe,-CH2SCH2SH, -CH2S(CH2)2SH, -CH2S(CH2)3SH, -CH2S(CH2)4SH, -CH2S(CH2)5SH, -CH2SCH2SMe, -CH2S(CH2)2SMe, -CH2S(CH2)3SMe, -CH2S(CH2)4SMe, or -CH2S(CH2)5SMe.

19. The compound of claim 17 or claim 18, wherein each R5 is independently -H, methyl, or benzyl.

20. The compound of any one of claims 15-18, wherein each R6 is independently -H, methyl, or benzyl.

21. The compound of any one of claims 1-11, wherein -L1-Z is -X1’-(C1-C4 alkylene)-X2.

22. The compound of claim 21, wherein -L1-Z is -OCH2OH, -O(CH2)2OH, -O(CH2)3OH, - O(CH2)4OH, -SCH2OH, -S(CH2)2OH, -S(CH2)3OH, -S(CH2)4OH, -S(O)CH2OH, -S(O)(CH2)2OH, -S(O)(CH2)3OH, -S(O)(CH2)4OH, -S(O)2CH2OH, -S(O)2(CH2)2OH, - S(O)2(CH2)3OH, -S(O)2(CH2)4OH, -OCH2SMe, - O(CH2)2SMe, - O(CH2)3SMe, - O(CH2)4SMe, -SCH2SMe, - S(CH2)2SMe, -S(CH2)3SMe, -S(CH2)4SMe, -S(O)CH2SMe, - S(O)(CH2)2SMe, -S(O)(CH2)3SMe, -S(O)(CH2)4SMe, -S(O)2CH2SMe, -S(O)2(CH2)2SMe, -S(O)2(CH2)3SMe, or -S(O)2(CH2)4SMe.

23. The compound of any one of claims 1-11, wherein -L1-Z is -(C1-C6 alkylene)-X1-L2-X2.

24. The compound of claim 23, wherein -L1-Z is25. The compound of claim 1, wherein the compound is any one of the compounds selected from the following:

26. The compound of claim 1, wherein the compound is any one of the compounds selected from Table 1B.

27. A compound of Formula II, or a pharmaceutically acceptable salt thereof:E—A—Z’—L1—D (Formula II)R1 is -H, -F, -CH3, or -CF3;R2 is -H, -F, -OR3, -SR3, -S(O)R4, -S(O)2R4, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R1 and R2 taken together with the carbon atoms to which they are attached form a methylenedioxy or a difluoromethylenedioxy ring; with the proviso that both R1 and R2 cannot be -H;L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, X1’-(C1-C6 alkylene)-* or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z’;Z’ is -O-CH2-NR8-*, -S-CH2-NR8-*, -NR8-*; where * is the site covalently attached to A;each R8 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;A is a peptide comprising 2 to 10 amino acids; wherein A is optionally substituted with one or more polyol; andE is -C(=O)-L3-X3;L3 is -(C1-C10 alkylene)- or -Y1-(C1-C10 alkylene)-X4-Y2-(C1-C10 alkylene)-*; where * is the site covalently attached to X3;Y1 is absent, -(CRaRbO)n-, or -(CRaRbCRa’Rb’O)m-;X4 is -NR9C(=O)- or -C(=O)NR9-;Y2 is absent, -(CRcRdO)o-, or -(CRcRdCRc’Rd’O)p-;n, m, o, and p are each independently 1-10;each Ra, Rb, Ra’, Rb’, Rc, Rd, Rc’, and Rd’ are independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;wherein L3 is optionally substituted with 0-4 substituents selected from halogen, -CN, -OR11, -SR11, -N(R11)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C10 heterocycloalkyl, aryl, heteroaryl, and polyol;each R11 is independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl;each W’ is independently -H, -N(Rgg)2, C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -(CH2CH2O)q-Rff;q is 1 to 24;each Raa, Rbb, Rcc, Ree, and Rff are independently -H or optionally substituted C1-C6 alkyl;each RYY and RXX are independently -H or C1-C6 alkyl;Rgg are each independently -H or C1-C6 alkyl; andR9 and R10 are each independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.

28. The compound of claim 27, wherein R1 is -H or -F.

29. The compound of claim 27 or claim 28, wherein R1 is -F.

30. The compound of any one of claims 27-29, R2 is–H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, -S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl.

31. The compound of any one of claims 27-30, wherein R2 is -F.

32. The compound of any one of claims 27-30, wherein R2 is -OMe, -SMe, -S(O)Me, or33. The compound of any one of claims 27-30, wherein R2 is methyl.

34. The compound of claim 27, wherein R1 is -F and R2 is -F.

35. The compound of claim 27, wherein R1 is methyl and R2 is -F.

36. The compound of claim 27, wherein R1 is -F and R2 is -methyl.

37. The compound of any one of claims 27-36, wherein -L1-Z’-* is -(C1-C4 alkylene)-O-CH2- NR8-*, -(C1-C4 alkylene)-S-CH2-NR8-*, or -(C1-C4 alkylene)-NR8-*, where * is the site covalently attached to A.

38. The compound of claim 37, wherein -L1-Z’-* is -CH2O-CH2NH-*, -(CH2)2O-CH2NH-*, - (CH2)3O-CH2NH-*, -(CH2)4O-CH2NH-*, -CH2S-CH2NH-*, -(CH2)2S-CH2NH-*, - (CH2)3S-CH2NH-*, -(CH2)4S-CH2NH-*, -CH2NH-*, -(CH2)2NH-*, -(CH2)3NH-*, or - (CH2)4NH-.

39. The compound of any one of claims 27-36, wherein -L1-Z’-* is -(C1-C5 alkylene)- NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*, where * is the site covalently attached to A.

40. The compound of claim 39, wherein -L1-Z’-* is -CH2NHC(=O)CH2O-CH2-NH-*, - CH2NHC(=O)(CH2)2O-CH2-NH-*, -CH2NHC(=O)(CH2)3O-CH2-NH-*, - CH2NHC(=O)(CH2)4O-CH2-NH-*, -CH2NHC(=O)(CH2)5O-CH2-NH-*, -CH2NHC(=O)CH2S-CH2-NH-*, -CH2NHC(=O)(CH2)2S-CH2-NH-*, - CH2NHC(=O)(CH2)3S-CH2-NH-*, -CH2NHC(=O)(CH2)4S-CH2-NH-*, - CH2NHC(=O)(CH2)5S-CH2-NH-*, -CH2SCH2O-CH2-NH-*, -CH2S(CH2)2O-CH2-NH-*, - CH2S(CH2)3O-CH2-NH-*, -CH2S(CH2)4O-CH2-NH-*, -CH2S(CH2)5O-CH2-NH-*, - CH2SCH2S-CH2-NH-*, -CH2S(CH2)2S-CH2-NH-*, -CH2S(CH2)3S-CH2-NH-*, - CH2S(CH2)4S-CH2-NH-*, or -CH2S(CH2)5S-CH2-NH-*, where * is the site covalently attached to A.

41. The compound of claim 39 or claim 40, wherein each R5 is independently -H, methyl, or benzyl.

42. The compound of any one of claims 37-41, wherein each R8 is independently -H, methyl, or benzyl.

43. The compound of any one of claims 27-36, wherein -L1-Z’-* is -X1’-(C1-C4 alkylene)-O- CH2-NR8-*, -X1’-(C1-C4 alkylene)-S-CH2-NR8-*, or -X1’-(C1-C4 alkylene)-NR8-*, where * is the site covalently attached to A.

44. The compound of claim 43, wherein -L1-Z’-* is -OCH2O-CH2-NH-*, - O(CH2)2O-CH2- NH-*, - O(CH2)3O-CH2-NH-*, -O(CH2)4O-CH2-NH-*, -SCH2O-CH2-NH-*, - S(CH2)2O- CH2-NH-*, -S(CH2)3O-CH2-NH-*, -S(CH2)4O-CH2-NH-*, -S(O)CH2O-CH2-NH-*, - S(O)(CH2)2O-CH2-NH-*, -S(O)(CH2)3O-CH2-NH-*, -S(O)(CH2)4O-CH2-NH-*, - S(O)2CH2O-CH2-NH-*, -S(O)2(CH2)2O-CH2-NH-*, -S(O)2(CH2)3O-CH2-NH-*, - S(O)2(CH2)4O-CH2-NH-*, -OCH2S-CH2-NH-*, -O(CH2)2S-CH2-NH-*, -O(CH2)3S-CH2- NH-*, -O(CH2)4S-CH2-NH-*, -SCH2S-CH2-NH-*, - S(CH2)2S-CH2-NH-*, -S(CH2)3S- CH2-NH-*, -S(CH2)4S-CH2-NH-*, -S(O)CH2S-CH2-NH-*, -S(O)(CH2)2S-CH2-NH-*, - S(O)(CH2)3S-CH2-NH-*, -S(O)(CH2)4S-CH2-NH-*, -S(O)2CH2S-CH2-NH-*, - S(O)2(CH2)2S-CH2-NH-*, -S(O)2(CH2)3S-CH2-NH-*, -S(O)2(CH2)4S-CH2-NH-*, -OCH2- NH-*, -O(CH2)2-NH-*, - O(CH2)3-NH-*, -O(CH2)4S-NH-*, -SCH2-NH-*, - S(CH2)2-NH- *, -S(CH2)3-NH-*, -S(CH2)4-NH-*, -S(O)CH2-NH-*, -S(O)(CH2)2-NH-*, -S(O)(CH2)3- NH-*, -S(O)(CH2)4-NH-*, -S(O)2CH2-NH-*, -S(O)2(CH2)2-NH-*, -S(O)2(CH2)3-NH-*, or -S(O)2(CH2)4-NH-*.

45. The compound of any one of claims 27-36, wherein -L1-Z’-* is -(C1-C6 alkylene)-X1-L2- Z’-*, where * is the site co46. The compound of claim 45, wherein -L1-Z’-* is47. The compound of any one of claims 27-46, wherein A is a peptide comprising 2 to 8amino acids.

48. The compound of any one of claims 27-47, wherein A is a peptide comprising 2 to 449. The compound of any one of claims 27-48, wherein at least one amino acid in saidpeptide is a L amino acid.

50. The compound of any one of claims 27-49, wherein each amino acid in said peptide is a L amino acid.

51. The compound of any one of claims 27-48, wherein at least one amino acid in saidpeptide is a D amino acid.

52. The compound of any one of claims 27-46, wherein A is -(AA1)-(AA2)a1-*, where * is the site covalently attached to E; AA1 and AA2 are each independently an amino acid residue; and a1 is an integer from 1-9.

53. The compound of claim 52, wherein -AA1-(AA2)a1-* is -Gly-Gly-Gly-*, -Ala-Val-*, -Val-Ala-*, -Val-Cit-*, -Val-Lys-*, -Lys-Val-*, -Phe-Lys-*,-Lys-Phe-*, -Lys-Lys-*, -Ala-Lys-*, -Lys-Ala-*, -Phe-Cit-*,-Cit-Phe-*, -Leu-Cit-*,- Cit-Leu-* - Ile -Cit-* , -Phe-Ala-*,-Ala-Phe-*, -Phe-N9-tosyl-Arg-*, -N9-tosyl-Arg-Phe-*, -Phe-N9-nitro-Arg-*, -N9-nitro-Arg-Phe *, -Phe-Phe-Lys-*, -Lys-Phe-Phe-*, -Gly-Phe-Lys-*, Lys-Phe-Gly-*, -Leu-Ala-Leu-*, -Ile-Ala-Leu-*, -Leu-Ala-Ile-*, -Val-Ala-Val-*, -Ala-Leu-Ala-Leu-*,-Leu-Ala-Leu-Ala-*, -b-Ala-Leu-Ala-Leu-*, -Gly-Phe-Leu-Gly-*,-Gly-Leu-Phe-Gly-*, -Val-Arg-*, -Arg-Val-*, -Arg-Arg-*, -Ala-Ala-*, -Ala-Met-*, -Met-Ala-*, -Thr-Thr-*, -Thr-Met-*, -Met-Thr-*, -Leu-Ala-*, -Ala-Leu-*, -Cit-Val-*, -Gln-Val-*, -Val-Gln-*, -Ser-Val-*, -Val-Ser-*, -Ser-Ala-*, - Ser-Gly-*, -Ala-Ser-*, -Gly-Ser-*, -Leu-Gln-*, -Gln-Leu-*, -Phe-Arg-*, -Arg-Phe-*, -Tyr-Arg-*, -Arg-Tyr-*, -Phe-Gln-*, -Gln-Phe-*, -Val-Thr-*, -Thr-Val-*, -Met-Tyr-*, and -Tyr-Met-*.

54. The compound of claim 52, wherein -AA1-(AA2)a1-* is -Val-D-Lys-*, -Val-D-Arg-*, -L- Val-Cit-*, -L-Val-Lys-*, -L-Val-Arg-*, -L-Val-D-Cit-*, -L-Phe-Phe-Lys-*, -L-Val-D- Lys-*, -L-Val-D-Arg-*, -L-Arg-D-Arg-*, -L-Ala-Ala-*, -L-Ala-D-Ala-*, -Ala-D-Ala-*, - Val-D-Cit-*, -L-Ala-L-Ala-*, -L-Ala-L-Val-*, -L-Gln-L-Val-*, -L-Gln-L-Leu-*, or -L- Ser-L-Val-*.

55. The compound of claim 52, wherein -AA1-(AA2)a1-* is:-Ala-Ala-Ala-*,-Ala-Ala-Ala-Ala-*,-Gly-Ala-Gly-Gly-*,-Gly-Gly-Ala-Gly-*,-Gly-Val-Gly-Gly-*,-Gly-Gly-Val-Gly-*,-Gly-Phe-Gly-Gly-*, or-Gly-Gly-Phe-Gly-*.

56. The compound of claim 52, wherein -AA1-(AA2)a1-* is:-L-Ala-D-Val-*,-L-Val-L-Ala-*,-L-Val-D-Ala-*-L-Gln-D-Leu-*,-L-Leu-L-Gln-*,-L-Leu-D-Gln-*,-L-Ala-L-Ala-L-Ala-*,-L-Ala-D-Ala-L-Ala-*,-L-Ala-L-Ala-D-Ala-*,-L-Ala-L-Ala-L-Ala-L-Ala-*,-L-Ala-D-Ala-L-Ala-L-Ala-*,-L-Ala-L-Ala-D-Ala-L-Ala-*,-L-Ala-L-Ala-L-Ala-D-Ala-*,-Gly-L-Ala-Gly-Gly-*,-Gly-Gly-L-Ala-Gly-*,-Gly-D-Ala-Gly-Gly-*,-Gly-Gly-D-Ala-Gly-*,-Gly-L-Val-Gly-Gly-*,-Gly-Gly-L-Val-Gly-*,-Gly-D-Val-Gly-Gly-*,-Gly-Gly-D-Val-Gly-*,-Gly-L-Phe-Gly-Gly-*, or-Gly-Gly-L-Phe-Gly-*.

57. The compound of claim 52, wherein -AA1-(AA2)a1-* is:-L-Ala-D-Ala-LAla-*,-L-Ala-L-Ala-L-Ala-*, or-L-Ala-L-Ala-L-Ala-L-Ala-*.

58. The compound of any one of claims 27-57, wherein A is substituted with one or more polyol.

59. The compound of any one of claims 27-58, wherein E is substituted with one or more polyol.

60. The compound of any one of claims 27-59, wherein polyol is -(C1-C6 alkylene)-X5-Y3; wherein:X5 is -NR12C(=O)- or -C(=O)NR12-;Y3 is -C1-C10 alkyl, where Y3 is substituted with 0-10 OH groups; andR12 is -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.

61. The compound of claim 60, wherein polyol wherein R12 is H or methyl.

62. The compound of any one of claims 27-61, wherein E is -C(=O)-(C1-C10 alkylene)-X3.

63. The compound of claim 62, wherein E is64. The compound of any one of claims 27-61, wherein E is -C(=O)-Y1-(C1-C10 alkylene)- X4-(C1-C10 alkylene)-X3;Y1 is -(CRaRbO)n-, or -(CRaRbCRa’Rb’O)m-;X4 is -NR9C(=O)-; and65. The compound of any one of claims 27-61, wherein E is -C(=O)-Y1-(CH2)2-X4-(CH2)2- X3;Y1 is -(CH2O)n- or -(CH2CH2O)m-;X4 is -NHC(=O)-;n is 2; m is 2 to 6; .

66. The compound of claim 27, wherein the compound is any one of the compounds selected from Table 2.

67. A compound of Formula III, or a pharmaceutically acceptable salt thereof:CBA—E’—A—Z’—L1—D (Formula III)L1 is absent, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-X1-(C1-C6 alkylene)-, X1’-(C1-C6 alkylene)-*, or -(C1-C6 alkylene)-X1-L2-*; where * is the site covalently attached to Z’;E’ is -C(=O)-L3-X6-*; where * is the site covalently linked to CBA;L3 is -(C1-C10 alkylene)- or -Y1-(C1-C10 alkylene)-X4-Y2-(C1-C10 alkylene)-*; where * is the site covalently attached to X6;Y1 is absent, -(CRaRbO)n- or -(CRaRbCRa’Rb’O)m-;-C(=O)-CRbbRcc-*, or -NRee-C(=O)-CRbbRcc-*; where * is the site covalently attached to CBA;each Raa, Rbb, Rcc, and Ree are independently -H or optionally substituted C1-C6 alkyl; each RYY and RXX are independently -H or C1-C6 alkyl;R9 is independently -H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl; andCBA is a cell binding agent.

68. The compound of claim 67, wherein R1 is -H or -F.

69. The compound of claim 67 or claim 68, wherein R1 is -F.

70. The compound of any one of claims 67-69, R2 is–H, -F, -OCF3, -CF3, -OMe, -OEt, -SMe, -S(O)Me, -S(O)2Me, -SEt, -S(O)Et, -S(O2)Et, methyl, or ethyl.

71. The compound of any one of claims 67-70, wherein R2 is -F.

72. The compound of any one of claims 67-70, wherein R2 is -OMe, -SMe, -S(O)Me, or73. The compound of any one of claims 67-70, wherein R2 is methyl.

74. The compound of claim 67, wherein R1 is -F and R2 is -F.

75. The compound of claim 67, wherein R1 is methyl and R2 is -F.

76. The compound of claim 67, wherein R1 is -F and R2 is -methyl.

77. The compound of any one of claims 67-76, wherein -L1-Z’-* is -(C1-C4 alkylene)-O-CH2- NR8-*, -(C1-C4 alkylene)-S-CH2-NR8-*, or -(C1-C4 alkylene)-NR8-*, where * is the site covalently attached to A.

78. The compound of claim 77, wherein -L1-Z’-* is -CH2O-CH2NH-*, -(CH2)2O-CH2NH-*, - (CH2)3O-CH2NH-*, -(CH2)4O-CH2NH-*, -CH2S-CH2NH-*, -(CH2)2S-CH2NH-*, - (CH2)3S-CH2NH-*, -(CH2)4S-CH2NH-*, -CH2NH-*, -(CH2)2NH-*, -(CH2)3NH-*, or - (CH2)4NH-.

79. The compound of any one of claims 67-76, wherein -L1-Z’-* is -(C1-C5 alkylene)- NR5C(=O)-(C1-C5 alkylene)-O-CH2-NR8-*, -(C1-C5 alkylene)-NR5C(=O)-(C1-C5 alkylene)-S-CH2-NR8-*, -(C1-C5 alkylene)-S-(C1-C5 alkylene)-S-CH2-NR8-*, or -(C1-C5 alkylene)-S-(C1-C5 alkylene)-SS-CH2-NR8-*, where * is the site covalently attached to A.

80. The compound of claim 79, wherein -L1-Z’-* is -CH2NHC(=O)CH2O-CH2-NH-*, - CH2NHC(=O)(CH2)2O-CH2-NH-*, -CH2NHC(=O)(CH2)3O-CH2-NH-*, - CH2NHC(=O)(CH2)4O-CH2-NH-*, -CH2NHC(=O)(CH2)5O-CH2-NH-*, - CH2NHC(=O)CH2S-CH2-NH-*, -CH2NHC(=O)(CH2)2S-CH2-NH-*, - CH2NHC(=O)(CH2)3S-CH2-NH-*, -CH2NHC(=O)(CH2)4S-CH2-NH-*, - CH2NHC(=O)(CH2)5S-CH2-NH-*, -CH2SCH2O-CH2-NH-*, -CH2S(CH2)2O-CH2-NH-*, - CH2S(CH2)3O-CH2-NH-*, -CH2S(CH2)4O-CH2-NH-*, -CH2S(CH2)5O-CH2-NH-*, - CH2SCH2S-CH2-NH-*, -CH2S(CH2)2S-CH2-NH-*, -CH2S(CH2)3S-CH2-NH-*, - CH2S(CH2)4S-CH2-NH-*, or -CH2S(CH2)5S-CH2-NH-*.

81. The compound of claim 79 or claim 80, wherein each R5 is independently -H, methyl, or benzyl.

82. The compound of any one of claims 77-81, wherein each R8 is independently -H, methyl, or benzyl.

83. The compound of any one of claims 67-76, wherein -L1-Z’-* is -X1’-(C1-C4 alkylene)-O- CH2-NR8-*, -X1’-(C1-C4 alkylene)-S-CH2-NR8-*, or -X1’-(C1-C4 alkylene)-NR8-*, where * is the site covalently attached to A.

84. The compound of claim 83, wherein -L1-Z’-* is -OCH2O-CH2-NH-*, - O(CH2)2O-CH2- NH-*, - O(CH2)3O-CH2-NH-*, -O(CH2)4O-CH2-NH-*, -SCH2O-CH2-NH-*, -S(CH2)2O- CH2-NH-*, -S(CH2)3O-CH2-NH-*, -S(CH2)4O-CH2-NH-*, -S(O)CH2O-CH2-NH-*, - S(O)(CH2)2O-CH2-NH-*, -S(O)(CH2)3O-CH2-NH-*, -S(O)(CH2)4O-CH2-NH-*, - S(O)2CH2O-CH2-NH-*, -S(O)2(CH2)2O-CH2-NH-*, -S(O)2(CH2)3O-CH2-NH-*, - S(O)2(CH2)4O-CH2-NH-*, -OCH2S-CH2-NH-*, -O(CH2)2S-CH2-NH-*, -O(CH2)3S-CH2- NH-*, -O(CH2)4S-CH2-NH-*, -SCH2S-CH2-NH-*, - S(CH2)2S-CH2-NH-*, -S(CH2)3S- CH2-NH-*, -S(CH2)4S-CH2-NH-*, -S(O)CH2S-CH2-NH-*, -S(O)(CH2)2S-CH2-NH-*, - S(O)(CH2)3S-CH2-NH-*, -S(O)(CH2)4S-CH2-NH-*, -S(O)2CH2S-CH2-NH-*, - S(O)2(CH2)2S-CH2-NH-*, -S(O)2(CH2)3S-CH2-NH-*, -S(O)2(CH2)4S-CH2-NH-*, -OCH2- NH-*, -O(CH2)2-NH-*, -O(CH2)3-NH-*, -O(CH2)4S-NH-*, -SCH2-NH-*, -S(CH2)2-NH- *, -S(CH2)3-NH-*, -S(CH2)4-NH-*, -S(O)CH2-NH-*, -S(O)(CH2)2-NH-*, -S(O)(CH2)3- NH-*, -S(O)(CH2)4-NH-*, -S(O)2CH2-NH-*, -S(O)2(CH2)2-NH-*, -S(O)2(CH2)3-NH-*, or -S(O)2(CH2)4-NH-*.

85. The compound of any one of claims 67-76, wherein -L1-Z’-* is -(C1-C6 alkylene)-X1-L2- Z’-*, where * is the site covalently attached to A.

86. The compound of claim 85, wherein -L1-Z’-* is87. The compound of any one of claims 67-86, wherein A is a peptide comprising 2 to 888. The compound of any one of claims 67-87, wherein A is a peptide comprising 2 to 4 amino acids.

89. The compound of any one of claims 67-88, wherein at least one amino acid in said90. The compound of any one of claims 67-89, wherein each amino acid in said peptide is a L amino acid.

91. The compound of any one of claims 67-88, wherein at least one amino acid in said92. The compound of any one of claims 67-86, wherein A is -(AA1)-(AA2)a1-*, where * is the point of attachment to E’, AA1 and AA2 are each independently an amino acid residue; and a1 is an integer from 1-9.

93. The compound of claim 92, -AA1-(AA2)a1-* is -Gly-Gly-Gly-*, -Ala-Val-*, -Val-Ala-*, -Val-Cit-*, -Val-Lys-*, -Lys-Val-*, -Phe-Lys-*,-Lys-Phe-*, -Lys-Lys-*, -Ala-Lys-*, -Lys-Ala-*, -Phe-Cit-*,-Cit-Phe-*, -Leu-Cit-*,- Cit-Leu-* - Ile -Cit-* , -Phe-Ala-*,-Ala-Phe-*, -Phe-N9-tosyl-Arg-*, -N9-tosyl-Arg-Phe-*, -Phe-N9-nitro-Arg-*, -N9-nitro-Arg-Phe *, -Phe-Phe-Lys-*, -Lys-Phe-Phe-*, -Gly-Phe-Lys-*, Lys-Phe-Gly-*, -Leu-Ala-Leu-*, -Ile-Ala-Leu-*, -Leu-Ala-Ile-*, -Val-Ala-Val-*, -Ala-Leu-Ala-Leu-*,-Leu-Ala-Leu-Ala-*, -b-Ala-Leu-Ala-Leu-*, -Gly-Phe-Leu-Gly-*,-Gly-Leu-Phe-Gly-*, -Val-Arg-*, -Arg-Val-*, -Arg-Arg-*, -Ala-Ala-*, -Ala-Met-*, -Met-Ala-*, -Thr-Thr-*, -Thr-Met-*, -Met-Thr-*, -Leu-Ala-*, -Ala-Leu-*, -Cit-Val-*, -Gln-Val-*, -Val-Gln-*, -Ser-Val-*, -Val-Ser-*, -Ser-Ala-*, -Ser-Gly-*, -Ala-Ser-*, -Gly-Ser-*, -Leu-Gln-*, -Gln-Leu-*, -Phe-Arg-*, -Arg-Phe-*, -Tyr-Arg-*, -Arg-Tyr-*, -Phe-Gln-*, -Gln-Phe-*, -Val-Thr-*, -Thr-Val-*, -Met-Tyr-*, and -Tyr-Met-*.

94. The compound of claim 92, wherein -AA1-(AA2)a1-* is -Val-D-Lys-*, -Val-D-Arg-*, -L- Val-Cit-*, -L-Val-Lys-*, -L-Val-Arg-*, -L-Val-D-Cit-*, -L-Phe-Phe-Lys-*, -L-Val-D- Lys-*, -L-Val-D-Arg-*, -L-Arg-D-Arg-*, -L-Ala-Ala-*, -L-Ala-D-Ala-*, -Ala-D-Ala-*, - Val-D-Cit-*, -L-Ala-L-Ala-*, -L-Ala-L-Val-*, -L-Gln-L-Val-*, -L-Gln-L-Leu-*, or -L- Ser-L-Val-*.

95. The compound of claim 92, wherein -AA1-(AA2)a1-* is:

96. The compound of claim 92, wherein -AA1-(AA2)a1-* is:

97. The compound of claim 92, wherein -AA1-(AA2)a1-* is:

98. The compound of any one of claims 67-97, wherein A is substituted with one or more polyol.

99. The compound of any one of claims 67-98, wherein E’ is substituted with one or more polyol.

100. The compound of any one of claims 67-99, wherein polyol is -(C1-C6 alkylene)-X5- Y3;101. The compound of claim 100, wherein polyol 102. The compound of claims 63 93 wherein E’ is C(=O) (C1 C10 alkylene)-X6-*.

103. The compound of claim 102, wherein E’ is, -C(=O)CH2CH2-C(=O)-CRbbRcc-*, or -C(=O)CH2CH2-NRee-C(=O)- CRbbRcc-*; where * is the site covalently attached to CBA.

104. The compound of claims any one of claims 63-93, wherein E’ is -C(=O)-Y1-(C1-C10 alkylene)-X4-(C1-C10 alkylene)-X6-*;, -C(=O)-CRbbRcc-*, or -NRee-C(=O)-CRbbRcc-*; where 105. The compound of any one of claims 63-93, wherein E’ is -C(=O)-Y1-(CH2)2-X4- (CH2)2-X6-*;Y1 is -(CH2O)n-, or -(CH2CH2O)m-;, , -C(=O)-CRbbRcc-*, or -NRee-C(=O)-CRbbRcc-*; where * is the site covalently attached to the CBA.

106. The compound of any one of claims 63-105, wherein the CBA comprises a -SH groupthat covalently links with E’ to provideC(=O)-CRbbRcc-S-CBA, or -NRee-C(=O)-CRbbRcc-S-CBA.

107. The compound of any one of claims 67-106, wherein CBA is an antibody and—E’— A—Z’—L1— D is a drug-linker structure, the average number of drug-linker structures conjugated per antibody is in the range of from 2 to 10.

108. The compound of claim 107, wherein the average number of drug-linker structures conjugated per antibody is in the range of from 2 to 10.

109. The compound of claim 107, wherein the average number of drug-linker structures conjugated per antibody is in the range of from 6 to 8.

110. The compound of claim 107, wherein the average number of drug-linker structures conjugated per antibody is 8.

111. The compound of any one of claims 67-110, wherein the CBA is an antibody, a single chain antibody, an antibody fragment that specifically binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that specifically binds to a target cell, a chimeric antibody, a chimeric antibody fragment that specifically binds to the target cell, a domain antibody, a domain antibody fragment that specifically binds to the target cell, a probody, a nanobody, a hexabody, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule.

112. The compound of any one of claims 67-111, wherein the CBA binds to target cells selected from tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes; cells expressing any one or more of 5T4, ADAM-9, ALK, AMHRII, ASCT2, Axl, B7-H3, BCMA, C4.4a, CA6, CA9, CanAg, CD123, CD138, CD142, CD166, CD184, CD19, CD20, CD205, CD22, CD248, CD25, CD3, CD30, CD33, CD352, CD37, CD38, CD40L, CD44v6, CD45, CD46, CD48, CD51, CD56, CD7, CD70, CD71, CD74, CD79b, CDH6, CEACAM5, CEACAM6, cKIT, CLDN18.2, CLDN6, CLL-1, c-MET, Cripto, CSP-1, CXCR5, DLK-1, DLL3, DPEP3, Dysadherin, EFNA4 , EGFR, EGFRviii, ENPP3, EpCAM, EphA2, EphA3, ETBR, FGFR2, FGFR3, FLT3, FOLR-alpha, FSH, GCC, GD2, GD3, Globo H, GPC-1, GPC3, gpNMB, HER-2, HER-3, HLA-DR, HSP90, IGF-1R, IL-13R, IL1RAP, IL7R, Interleukin-4 Receptor (IL4R), KAAG-1, LAMP-1, Lewis CG, LHRH, LIV-1,LRP-1, LRRC15, Ly6E, MAGE, Mesothelin (MSLN), MET, MHC class I chain-related protein A and B (MICA and MICB), MT1-MMP, MTX3, MTX5, MUC1, MUC16, NaPi2b, Nectin-4, NOTCH3, OAcGD2, OX001L, p-Cadherin, PD-L1,Phosphatidylserine (PS), Polymorphic epithelial mucin (PEM), Prolactin Receptor (PRLR), PSMA, PTK7, RNF43, ROR1, ROR2, SAIL, SLAMF7, SLC44A4, SLITRK6, SSTR2, STEAP-1, STING, STn, TIM-1, TM4SF1, TNF- alpha, TRA, TROP-2, Tumor- associated glycoprotein 72 (TAG-72), tumor-specific epitope of mucin-1 (TA-MUC1), CD5, TIM-3, UPK2, or UPK1b antigen.

113. The compound of any one of claims 67-110, wherein the cell-binding agent is an anti- folate receptor antibody or an antibody fragment thereof, an anti-EGFR antibody or an antibody fragment thereof, an anti-CD33 antibody or an antibody fragment thereof, an anti-CD19 antibody or an antibody fragment thereof, an anti-Muc1 antibody or an antibody fragment thereof, an anti-CD37 antibody or an antibody fragment thereof, or an anti-EpCAM antibody or an antibody fragment thereof.

114. A pharmaceutical composition comprising a compound according to any one ofclaims 1-113, or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

115. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 114.

116. The method of claim 115, wherein the cancer is a lymphoma or a leukemia.

117. The method of claim 116, wherein the cancer is acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), acute B lymphoblastic leukemia or B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), acute promyelocytic leukemia (APL), B-cell chroniclymphoproliferative disease (B-CLPD), atypical chronic lymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), blastic plasmacytoid dendritic cell neoplasm(BPDCN), non-Hodgkin lymphomas (NHL), mantel cell leukemia (MCL), smalllymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, and Burkitt's lymphoma.

118. The method of claim 115, wherein the cancer is endometrial cancer, lung cancer, colorectal cancer, bladder cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, prostate cancer, esophageal cancer, breast cancer, head and neck cancer, uterine cancer, ovarian cancer, liver cancer, cervical cancer, thyroid cancer, testicular cancer, myeloid cancer, melanoma, and lymphoid cancer.

119. The method of claim 115, wherein the lung cancer is non-small cell lung cancer or small-cell lung cancer.