WO2016148674A1 - Conjugates for treating diseases - Google Patents

Conjugates for treating diseases Download PDF

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Publication number
WO2016148674A1
WO2016148674A1 PCT/US2015/020397 US2015020397W WO2016148674A1 WO 2016148674 A1 WO2016148674 A1 WO 2016148674A1 US 2015020397 W US2015020397 W US 2015020397W WO 2016148674 A1 WO2016148674 A1 WO 2016148674A1
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WIPO (PCT)
Prior art keywords
alkyl
alkenyl
alkynyl
cycloalkyl
aryl
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PCT/US2015/020397
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English (en)
French (fr)
Inventor
Iontcho Radoslavov Vlahov
Christopher Paul Leamon
Longwu Qi
Yingcai Wang
Kevin Yu Wang
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Endocyte Inc
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Endocyte Inc
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Application filed by Endocyte Inc filed Critical Endocyte Inc
Priority to CN201580079950.0A priority Critical patent/CN107847609A/zh
Priority to JP2017548170A priority patent/JP6676650B2/ja
Priority to PCT/US2015/020397 priority patent/WO2016148674A1/en
Priority to CA2979527A priority patent/CA2979527A1/en
Priority to EP15885705.2A priority patent/EP3268046A4/en
Priority to US15/557,703 priority patent/US10624972B2/en
Publication of WO2016148674A1 publication Critical patent/WO2016148674A1/en
Anticipated expiration legal-status Critical
Priority to US16/825,566 priority patent/US20200289659A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to pyrrolobenzodiazepine (PBD) prodrugs and conjugates thereof.
  • PBD pyrrolobenzodiazepine
  • the present disclosure also relates to pharmaceutical compositions of the conjugates described herein, methods of making and methods of using the same.
  • the mammalian immune system provides a means for the recognition and elimination of pathogenic cells, such as tumor cells, and other invading foreign pathogens. While the immune system normally provides a strong line of defense, there are many instances where pathogenic cells, such as cancer cells, and other infectious agents evade a host immune response and proliferate or persist with concomitant host pathogenicity.
  • Chemotherapeutic agents and radiation therapies have been developed to eliminate, for example, replicating neoplasms.
  • many of the currently available chemotherapeutic agents and radiation therapy regimens have adverse side effects because they lack sufficient selectivity to preferentially destroy pathogenic cells, and therefore, may also harm normal host cells, such as cells of the hematopoietic system, and other non-pathogenic cells.
  • the adverse side effects of these anticancer drugs highlight the need for the development of new therapies selective for pathogenic cell populations and with reduced host toxicity.
  • Another approach for targeting populations of pathogenic cells, such as cancer cells or foreign pathogens, in a host is to enhance the host immune response against the pathogenic cells to avoid the need for administration of compounds that may also exhibit independent host toxicity.
  • One reported strategy for immunotherapy is to bind antibodies, for example, genetically engineered multimeric antibodies, to the surface of tumor cells to display the constant region of the antibodies on the cell surface and thereby induce tumor cell killing by various immune-system mediated processes (De Vita, V.T., Biologic Therapy of Cancer, 2d ed. Philadelphia, Lippincott, 1995; Soulillou, J.P., U.S. Patent 5,672,486).
  • these approaches have been complicated by the difficulties in defining tumor-specific antigens.
  • Folate plays important roles in nucleotide biosynthesis and cell division, intracellular activities which occur in both malignant and certain normal cells.
  • the folate receptor has a high affinity for folate, which, upon binding the folate receptor, impacts the cell cycle in dividing cells.
  • folate receptors have been implicated in a variety of cancers (e.g., ovarian, endometrial, lung and breast) which have been shown to demonstrate high folate receptor expression.
  • folate receptor expression in normal tissues is limited (e.g., kidney, liver, intestines and placenta). This differential expression of the folate receptor in neoplastic and normal tissues makes the folate receptor an ideal target for small molecule drug
  • folate conjugates represents one avenue for the discovery of new treatments that take advantage of differential expression of the folate receptor.
  • the present disclosure provides conjugates comprising a binding ligand, a linker and a drug, having the formula B-(AA) z1 -L 2 -(L 3 ) z2 -(AA) z3 -(L 1 ) z4 -(L 4 ) z5 -D 1 -L 5 -D 2 , B-(AA) z10 -L 2 -D 2 , B-(AA) z11 -L 2 -D 1 -L 5 -D 1 -L 2 -(AA) z12 -B or
  • each of B, AA, L 1 , L 2 , L 3 , L 4 , L 5 , D 1 , D 2 , z1, z2, z3, z4, z5, z6, z7, z8, z9, z10, z11 and z12 are defined as described herein; or a pharmaceutically acceptable salt thereof.
  • compositions comprising a therapeutically effective amount of the conjugates described herein, or a pharmaceutically acceptable salt thereof, and at least on excipient.
  • the disclosure provides a method of treating abnormal cell growth in a mammal, including a human, the method comprising administering to the mammal any of the conjugates or compositions described herein.
  • a conjugate comprising a binding ligand, a linker and a drug, having the formula B- (AA) z1 -L 2 -(L 3 ) z2 -(AA) z3 -(L 1 ) z4 -(L 4 ) z5 -D 1 -L 5 -D 2 ,
  • each z1, z10, z11 and z12 is each independently 2, 3, 4 or 5;
  • z2 is 0, 1 or 2;
  • z3 is 0, 1, 2, 3 or 4;
  • z4 is 0, 1 or 2;
  • z5 is 0, 1 or 2
  • z6 is 0, 1 or 2;
  • z7 is 0, 1 or 2;
  • z8 is 0, 1, 2, 3 or 4;
  • z9 is 0, 1 or 2;
  • R 1 and R 2 in each instance are independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -OR 7 , -SR 7 and -NR 7 R 7’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2- C 6 alkynyl is independently optionally substituted by halogen,–OR 8 , -SR 8 , -NR 8 R 8’ , -C(O)R 8 , -C(O)OR 8 or -C(O)NR 8 R 8’ ;
  • R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -CN, -NO 2 , -NCO, -OR 9 , -SR 9 ,–NR 9 R 9’ , -C(O)R 9 , -C(O)OR 9 and -C(O)NR 9 R 9’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2- C 6 alkynyl is independently optionally substituted by halogen,–OR 10 , -SR 10 , -NR 10 R 10’ , -C(O)R 10 , -C(O)OR 10 or -C(O)NR 10 R 10’ ;
  • each R 7 , R 7’ , R 8 , R 8’ , R 9 , R 9’ , R 10 and R 10’ is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2- C 6 alkynyl;
  • X 5 is NR 12 or CR 12 R 12’ ;
  • R 11 , R 11’ , R 11’’ , R 12 , R 12’ , R 13 , R 13’ , R 14 and R 14’ are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, -C(O)R 15 , -C(O)OR 15 and -C(O)NR 15 R 15’ ;
  • R 15 and R 15’ are each independently H or C 1 -C 6 alkyl
  • n 1, 2, 3 or 4;
  • AA is an amino acid
  • L 1 is a linker of the formula II
  • R 16 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -C(O)R 19 , -C(O)OR 19 and -C(O)NR 19 R 19’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2- C 6 alkynyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2- C 6 alkynyl, -OR 20 , -OC(O)R 20 , -OC(O)NR 20 R 20’ , -OS(O)R 20 , -OS(O) 2 R 20 , -SR 20 , -S(O)R 20 , -S(O) 2 R 20 , -S(O)NR 20 R 20’ , -S(O) 2
  • each R 17 and R 17’ is independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 22 , -OC(O)R 22 ,
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -OR 24 , -OC(O)R 24 ,
  • R 17 and R 17’ may combine to form a C 4 -C 6 cycloalkyl or a 4- to 6- membered heterocycle, wherein each hydrogen atom in C 4 -C 6 cycloalkyl or 4- to 6- membered heterocycle is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10
  • R 18 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 26 , -OC(O)R 26 , -OC(O)NR 26 R 26’ , -OS(O)R 26 , -OS(O) 2 R 26 , -SR 26 , -S(O)R 26 , -S(O) 2 R 26 , -S(O)NR 26 R 26’ , -S(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(CH 2 ) p OR 28 , -(CH 2 ) p (OCH 2 ) q OR 28 , -(CH 2 ) p (OCH 2 CH 2 ) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O) 2 R 29 , -(CH 2 ) p OS(
  • each R 19 , R 19’ , R 20 , R 20’ , R 21 , R 21’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10
  • R 27 and R 27’ are each independently selected from the group consisting of H, C 1 -C 9 alkyl, C 2 -C 9 alkenyl, C 2- C 9 alkynyl, C 3- C 6 cycloalkyl, -(CH 2 ) p (sugar), -(CH 2 ) p (OCH 2 CH 2 ) q - (sugar) and -(CH 2 ) p (OCH 2 CH 2 CH 2 ) q (sugar);
  • R 28 is a H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl or sugar;
  • n 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q 1, 2, 3, 4 or 5;
  • L 2 is a releasable linker
  • L 3 is selected from the group consisting of C 1 -C 6 alkyl,–(CR 39 R 39’ ) r C(O)-,
  • each R 39 and R 39’ is independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 40 , -OC(O)R 40 ,
  • R 40 , R 40’ , R 41 and R 41’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • r in each instance is 1, 2, 3, 4, or 5;
  • L 4 is selected from the group consisting of–C(O)(CR 44 R 44’ ) t -,
  • R 42 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 45 , -OC(O)R 45 , -OC(O)NR 45 R 45’ , -OS(O)R 45 ,
  • each R 43 , R 43’ , R 44 and R 44 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 47 , -OC(O)R 47 , -OC(O)NR 47 R 47’ , -OS(O)R 47 , -OS(O) 2 R 47
  • R 45 , R 45’ , R 46 , R 46’ , R 47 , R 47’ , R 48 and R 48’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl;
  • t is in each instance 1, 2, 3, 4, or 5;
  • each R 49 and R 49’ is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 50 , -OC(O)R 50 ,
  • R 50 , R 50’ , R 51 and R 51’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl; u is in each instance 0, 1, 2, 3, 4 or 5;
  • D 1 is a PBD prodrug
  • D 2 is a DNA binding agent
  • R 1a , R 2a , R 3a and R 4a are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 11a , -C(O)OR 11a ,
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 11a , -OC(O)R 11a , -OC(O)NR 11a R 11a’ , -OS(O)R 11a , -OS(O) 2 R 11a ,
  • R 5a , R 6a and R 7a are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 13a , -C(O)OR 13a and -C(O)NR 13a R 13a’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 al
  • heterocycloalkyl or 5- to 7-membered heteroaryl wherein each hydrogen atom in 3- to 7- membered heterocycloalkyl or 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 16a , -OC(O)R 16a ,
  • R 8a and R 9a are each independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 18a , -OC(O)R 18a , -OC(O)NR 18a R 18a’ , -OS(O)R 18a , -OS(O) 2 R 18a , -SR 18a , -S(O)R 18a , -S(O) 2 R 18a , -S(O)NR 18a R 18a’ , -S(O) 2 NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O) 2 NR 18a R 18a’ , -NR 18a R 18a’ , -NR 18a C(O)R 19a , -NR 18a C(O)OR 19a , -NR 18a C(O
  • R 10a is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 22a , -OC(O)R 22a , -OC(O)NR 22a R 22a’ , -OS(O)R 22a , -OS(O) 2 R 22a , -SR 22a ,
  • each R 11a , R 11a’ , R 12a , R 12a’ , R 13a , R 13a’ , R 14a , R 14a’ , R 15a , R 15a’ , R 16a , R 16a’ , R 17a , R 17a’ , R 18a , R 18a’ , R 19a , R 19a’ , R 20a , R 20a’ , R 21a , R 21a’ , R 22a , R 22a’ , R 23a , R 23a’ , R 24a , R 24a’ , R 25a and R 25a’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7- membered heteroaryl;
  • R 1a , R 4a and R 5a are a bond, or when R 5a and R 6a taken together with the atoms to which they are attached optionally combine to form a 3- to 7- membered heterocycloalkyl or 5- to 7-membered heteroaryl, one hydrogen atom in 5- to 7- membered heteroaryl is a bond and one of R 1a or R 4a is a bond; or a pharmaceutically acceptable salt thereof.
  • R 1b , R 2b , R 3b and R 4b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 13b , -C(O)OR 13b , and -C(O)NR 13b R 13b’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7- membered heteroaryl, -OR 13b , -OC(O)R 13b ,
  • R 5b , R 6b and R 7b are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 15b , -C(O)OR 15b , and -C(O)NR 15b R 15b’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-
  • heterocycloalkyl or 5- to 7-membered heteroaryl wherein each hydrogen atom in 3- to 7- membered heterocycloalkyl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 17b , -OC(O)R 17b ,
  • R 8b and R 9b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 19b , -OC(O)R 19b ,
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 21b , -OC(O)R
  • R 10b , R 11b and R 12b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 23b , -OC(O)R 23b ,
  • each R 13b , R 13b’ , R 14b , R 14b’ , R 15b , R 15b’ , R 16b , R 16b’ , R 17b , R 17b’ , R 18b , R 18b’ , R 19b , R 19b’ , R 20b , R 20b’ , R 21b , R 21b’ , R 22b , R 22b’ , R 23b , R 23b’ , R 24b , R 24b’ , R 25b , R 25b’ , R 26b and R 26b’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl(C 6 -C 10 aryl) and 5- to
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OH, -SH, -NH 2 , -SO 3 H, -C(O)OH and -C(O)NH 2 ;
  • R 1b , R 2b , R 3b , R 4b , R 5b , R 6b and R 7b is a bond
  • R 1c , R 2c and R 5c are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 6c , -C(O)OR 6c and -C(O)NR 6c R 6c’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6
  • R 3c and R 4c are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 9c , -OC(O)R 9c , -OC(O)NR 9c R 9c’ , -
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 11c , -OC(O)R 11c ,
  • R 1d is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 2d , -SR 2d and -NR 2d R 2d’ ,
  • R 2d and R 2d’ are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is optionally substituted by–OR 3d , -SR 3d , and–NR 3d R 3d’ ;
  • R 3d and R 3d’ are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl and 5- to 7-membered heteroaryl;
  • R 1e is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7- membere
  • each R 2e , R 2e’ , R 3e and R 3e’ is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl is optionally substituted by –OR 4e , -SR 4e or–NR 4e R 4e’ ;
  • R 4e and R 4e’ are independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl;
  • v 1, 2 or 3;
  • each AA is independently selected from the group consisting of L-lysine, L-asparagine, L-threonine, L-serine, L-isoleucine, L- methionine, L-proline, L-histidine, L-glutamine, L-arginine, L-glycine, L-aspartic acid, L- glutamic acid, L-alanine, L-valine, L-phenylalanine, L-leucine, L-tyrosine, L-cysteine, L- tryptophan, L-phosphoserine, L-sulfo-cysteine, L-arginosuccinic acid, L-hydroxyproline, L- phosphoethanolamine, L-sarcosine, L-taurine, L-carnosine, L-citrulline, L-anserine, L-1,3- methyl-histidine, L-alpha-amino-a
  • each R 17 and R 17’ is independently selected from the group consisting of H, C 1 -C 6 alkyl and -OR 22 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by -OR 24 ; or R 17 and R 17’ may combine to form a C 4 -C 6 cycloalkyl or a 4- to 6- membered heterocycle, wherein each hydrogen atom in C 4 -C 6 cycloalkyl or 4- to 6- membered heterocycle is independently optionally substituted by halogen, C 1 -C 6 alkyl or -OR 24 ; or a pharmaceutically acceptable salt thereof.
  • R 18 is selected from the group consisting of H, C 1 -C 6 alkyl, 5- to 7-membered heteroaryl, -OR 26 , -NR 26 C(O)R 27 ,
  • each hydrogen atom in C 1 -C 6 alkyl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, -OR 29 , -(CH 2 ) p OS(O) 2 OR 29 , -OS(O) 2 OR 29 , or -C(O)NR 29 R 29’ ;
  • each R 26 , R 26’ , R 26’’ , R 29 and R 29’ is independently H or C 1 -C 7 alkyl, wherein each hydrogen atom in C 1 -C 7 alkyl, is independently optionally substituted by halogen, -OH, -SH, -NH 2 or -CO 2 H;
  • R 27 and R 27’ are each independently selected from the group consisting of H, C 1 -C 9 alkyl, C 2 -C 9 alkenyl, C 2- C 9 alkynyl, C 3- C 6 cycloalkyl, -(CH 2 ) p (sugar), -(CH 2 ) p (OCH 2 CH 2 ) q - (sugar) and -(CH 2 ) p (OCH 2 CH 2 CH 2 ) q (sugar);
  • n 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q 1, 2, 3, 4 or 5;
  • R 16 is H, and * is a covalent bond; or a pharmaceutically acceptable salt thereof.
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • X 6 is C 1 -C 6 alkyl or C 6 -C 10 aryl(C 1 -C 6 alkyl), wherein each hydrogen atom in C 1 -C 6 alkyl and C 6 -C 10 aryl(C 1 -C 6 alkyl) is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 34
  • each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7-membered heteroaryl;
  • R 36 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 ,
  • R 37 , R 37’ , R 38 and R 38’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl
  • R 31 is H; and X 6 is C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • R 31 is H; and X 6 is C 6 -C 10 aryl(C 1 -C 6 alkyl); or a pharmaceutically acceptable salt thereof. 18. The conjugate of any one of clauses 1 to 15, wherein L 2 is of the formula
  • R 36 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 ,
  • R 37 , R 37’ , R 38 and R 38’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl
  • R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 2c , R 3c , R 4c , R 5c are H; or a pharmaceutically acceptable salt thereof.
  • R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a and R 10a are H; or a pharmaceutically acceptable salt thereof.
  • L 5 is C 1 -C 10 alkyl or–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof.
  • 35 The conjugate of any of clauses 1-28, wherein–D 1 -L 5 -D 2 is of the formula
  • R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a and R 1e are H; or a pharmaceutically acceptable salt thereof.
  • R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 1d are H; or a pharmaceutically acceptable salt thereof.
  • R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a and R 10a are H; or a pharmaceutically acceptable salt thereof.
  • R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a and R 10a are H; or a pharmaceutically acceptable salt thereof.
  • R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 11b and R 12b are H; or a pharmaceutically acceptable salt thereof.
  • each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5; or a
  • a pharmaceutical composition comprising a therapeutically effective amount of a conjugate according to any one of clauses 1-45, or a pharmaceutically acceptable salt thereof, and at least on excipient.
  • the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS)
  • FIG.1 shows that EC1629 dosed at 2 ⁇ mol/kg TIW for two weeks decreases KB tumors in test animals compared to untreated control ( ⁇ ). The dotted line indicates the last dosing day.
  • FIG.2 shows that EC1744 ( ⁇ ) dosed at 2 ⁇ mol/kg TIW for two weeks decreases KB tumors in test animals compared to untreated control ( ⁇ ).
  • FIG.2 also shows and that EC1788 ( ⁇ ) dosed at 0.2 ⁇ mol/kg TIW for two weeks decreases KB tumors in test animals compared to untreated control ( ⁇ ), and that EC1788 gave a complete response.
  • the dotted line indicates the last dosing day.
  • FIG.3 shows that EC1884 (d) dosed at 2 ⁇ mol/kg TIW for two weeks decreases KB tumors in test animals compared to untreated control ( a ).
  • FIG. 3 also shows and that EC1879 (c) dosed at 2 ⁇ mol/kg TIW for 1 week decreases KB tumors in test animals compared to untreated control ( a ), and that EC1879 gave a partial response.
  • FIG. 3 also shows and that EC1788 (b) dosed at 0.4 ⁇ mol/kg BIW for 2 weeks decreases KB tumors in test animals compared to untreated control (a), and that EC1788 gave a complete response, and cure.
  • the dotted line indicates the last dosing day.
  • FIG.4 shows that EC1879 ( ⁇ ) dosed at 2 ⁇ mol/kg TIW for two weeks decreases KB tumors in test animals compared to untreated control ( ⁇ ),and that EC1879 gave a complete response in 5/5 test animals, and cure in 5/5 test animals.
  • the dotted line indicates the last dosing day.
  • FIG.5 shows that EC1744 dosed at 2 ⁇ mol/kg TIW for two weeks decreases MDA- MB-231 tumors in test animals compared to untreated control ( ⁇ ), and that EC1744 gave a complete response in 5/5 test animals, and cure in 4/5 test animals.
  • the dotted line indicates the last dosing day.
  • alkyl includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C 1 -C 12 , C 1 -C 10 , C 1 -C 9 , C 1 -C 8 , C 1 -C 7 , C 1 -C 6 , and C 1 -C 4 , Illustratively, such particularly limited length alkyl groups, including C 1 -C 8 , C 1 -C 7 , C 1 -C 6 , and C 1 -C 4 , and the like may be referred to as“lower alkyl.” Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
  • Alkyl may be substituted or unsubstituted.
  • “alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl.
  • a“carboxyalkyl” group By way of example, the combination of an“alkyl” group, as described herein, with a“carboxy” group may be referred to as a“carboxyalkyl” group.
  • Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.
  • alkenyl groups including C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 may be referred to as lower alkenyl.
  • Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3- butenyl, and the like.
  • alkynyl includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e. C ⁇ C). It will be understood that in certain embodiments alkynyl may each be advantageously of limited length, including C 2 -C 12 , C 2 -C 9 , C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 .
  • alkynyl groups including C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 may be referred to as lower alkynyl.
  • Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative alkenyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3- butynyl, and the like.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. It will be understood that in certain embodiments, aryl may be advantageously of limited size such as C 6 -C 10 aryl. Illustrative aryl groups include, but are not limited to, phenyl, naphthalenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • cycloalkyl refers to a 3 to 15 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system.
  • cycloalkyl may be advantageously of limited size such as C 3 -C 13 , C 3 -C 6 , C 3 -C 6 and C 4 -C 6 .
  • Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like.
  • heterocycloalkyl refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms.
  • heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H- pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, and the like.
  • heteroaryl refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl,
  • “hydroxy” or““hydroxyl” refers to an -OH group.
  • alkoxy refers to both an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • aryloxy refers to an -O-aryl or an -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and the like.
  • mercapto refers to an -SH group.
  • alkylthio refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • arylthio refers to an -S-aryl or an -S-heteroaryl group. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.
  • halo or“halogen” refers to fluorine, chlorine, bromine or iodine.
  • trihalomethyl refers to a methyl group having three halo substituents, such as a trifluoromethyl group.
  • cyano refers to a -CN group.
  • “sulfinyl” refers to a -S(O)R" group, where R" is any R group as described in the various embodiments provided herein, or R" may be a hydroxyl group.
  • “sulfonyl” refers to a -S(O) 2 R" group, where R" is any R group as described in the various embodiments provided herein, or R" may be a hydroxyl group.
  • “S-sulfonamido” refers to a -S(O) 2 NR"R" group, where R" is any R group as described in the various embodiments provided herein.
  • N-sulfonamido refers to a -NR"S(O) 2 R" group, where R" is any R group as described in the various embodiments provided herein.
  • “O-carbamyl” refers to a -OC(O)NR"R" group, where R" is any R group as described in the various embodiments provided herein.
  • N-carbamyl refers to an R"OC(O)NR"- group, where R" is any R group as described in the various embodiments provided herein.
  • “O-thiocarbamyl” refers to a -OC(S)NR"R" group, where R" is any R group as described in the various embodiments provided herein.
  • N-thiocarbamyl refers to a R"OC(S)NR"- group, where R" is any R group as described in the various embodiments provided herein.
  • amino refers to an -NR"R" group, where R" is any R group as described in the various embodiments provided herein.
  • C-amido refers to a -C(O)NR"R" group, where R" is any R group as described in the various embodiments provided herein.
  • N-amido refers to a R"C(O)NR"- group, where R" is any R group as described in the various embodiments provided herein.
  • nitro refers to a–NO 2 group.
  • “optional” or“optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “heterocycle group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.
  • “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances.
  • the use of“independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different.
  • the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
  • salts which counter ions which may be used in pharmaceuticals.
  • Such salts include:
  • acid addition salts which can be obtained by reaction of the free base of the parent conjugate with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or
  • amino acid means any molecule that includes an alpha- carbon atom covalently bonded to an amino group and an acid group.
  • the acid group may include a carboxyl group.
  • Amino acid may include molecules having one of the formulas: wherein R’ is a side group and ⁇ includes at least 3 carbon atoms.
  • Amino acid includes stereoisomers such as the D-amino acid and L-amino acid forms.
  • Illustrative amino acid groups include, but are not limited to, the twenty endogenous human amino acids and their derivatives, such as lysine (Lys), asparagine (Asn), threonine (Thr), serine (Ser), isoleucine (Ile), methionine (Met), proline (Pro), histidine (His), glutamine (Gln), arginine (Arg), glycine (Gly), aspartic acid (Asp), glutamic acid (Glu), alanine (Ala), valine (Val), phenylalanine (Phe), leucine (Leu), tyrosine (Tyr), cysteine (Cys), tryptophan (Trp), phosphoserine (PSER), sulfo- cysteine, arginosuccinic acid (ASA), hydroxyproline, phosphoethanolamine (PEA), sarcosine (SARC), taurine (TAU), carnosine (CARN), citrulline
  • D-lysine D-Lys
  • D-asparagine D-Asn
  • D-Thr D-threonine
  • D-Ser D-isoleucine
  • D-Met D-proline
  • D-Pro D-histidine
  • D-glutamine D-Gln
  • D-arginine D-Arg
  • D-glycine D-Gly
  • D-aspartic acid D-Asp
  • D-Glu D-alanine
  • D-Ala D-valine
  • D-Val D-phenylalanine
  • D-Tyr D-cysteine
  • D-Cys D-Cys
  • amino acids can be covalently attached to other portions of the conjugates described herein through their alpha-amino and carboxy functional groups (i.e. in a peptide bond configuration), or through their side chain functional groups (such as the side chain carboxy group in glutamic acid) and either their alpha-amino or carboxy functional groups. It will be understood that amino acids, when used in connection with the conjugates described herein, may exist as zwitterions in a conjugate in which they are incorporated.
  • “sugar” refers to carbohydrates, such as monosaccharides,
  • sugars include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, galactose, ribulose, fructose, sorbose, tagatose, and the like. It will be undertsood that as used in connection with the present disclosure, sugar includes cyclic isomers of amino sugars, deoxy sugars, acidic sugars, and combinations thereof.
  • Non-limiting examples of such sugars include, galactosamine, glucosamine, deoxyribose, fucose, rhamnose, glucuronic acid, ascorbic acid, and the like.
  • sugars for use in connection with the present disclosure include
  • prodrug refers to a compound that can be administered to a subject in a pharmacologically inactive form which then can be converted to a pharmacologically active form through a normal metabolic process, such as hydrolysis of an oxazolidine. It will be understood that the metabolic processes through which a prodrug can be converted to an active drug include, but are not limited to, one or more spontaneous chemical reaction(s), enzyme- catalyzed chemical reaction(s), and/or other metabolic chemical reaction(s), or a combination thereof. It will be appreciated that understood that a variety of metabolic processes are known in the art, and the metabolic processes through which the prodrugs described herein are converted to active drugs are non-limiting.
  • a prodrug can be a precursor chemical compound of a drug that has a therapeutic effect on a subject.
  • the term“therapeutically effective amount” refers to an amount of a drug or pharmaceutical agent that elicits the biological or medicinal response in a subject (i.e. a tissue system, animal or human) that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes, but is not limited to, alleviation of the symptoms of the disease or disorder being treated.
  • the therapeutically effective amount is that amount of an active which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutically effective amount is that amount of an inactive prodrug which when converted through normal metabolic processes to produce an amount of active drug capable of eliciting the biological or medicinal response in a subject that is being sought.
  • the dose is advantageously selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the conjugates described herein.
  • the co-therapies described herein may allow for the administration of lower doses of conjugates that show such toxicity, or other undesirable side effect, where those lower doses are below thresholds of toxicity or lower in the therapeutic window than would otherwise be administered in the absence of a cotherapy.
  • administering includes all means of introducing the conjugates and compositions described herein to the host animal, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like.
  • the conjugates and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and/or vehicles.
  • composition refers to a mixture of one or more of the conjugates described herein, or pharmaceutically acceptable salts, solvates, hydrates thereof, with other chemical components, such as pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a conjugate to a subject.
  • Pharmaceutical compositions suitable for the delivery of conjugates described and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in
  • A“pharmaceutically acceptable excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a conjugate such as a diluent or a carrier.
  • the formulae include and represent not only all pharmaceutically acceptable salts of the conjugates, but also include any and all hydrates and/or solvates of the conjugate formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination conjugates with water and/or various solvents, in the various physical forms of the conjugates. Accordingly, the above formulae are to be understood to include and represent those various hydrates and/or solvates. It is also to be understood that the non-hydrates and/or non-solvates of the conjugate formulae are described by such formula, as well as the hydrates and/or solvates of the conjugate formulae.
  • the conjugates described herein can be expressed by the generalized descriptors B, L and Drug, where B is a cell surface receptor binding ligand (a.k.a. a“binding ligand”), L is a linker that may include a releasable portion (i.e. a releasable linker) and L may be described by one or more of the groups AA, L 1 , L 2 , L 3 , L 4 or L 5 as defined herein, and Drug represents one or more drugs (e.g. D 1 and D 2 ) covalently attached to the conjugate.
  • B is a cell surface receptor binding ligand (a.k.a. a“binding ligand”)
  • L is a linker that may include a releasable portion (i.e. a releasable linker) and L may be described by one or more of the groups AA, L 1 , L 2 , L 3 , L 4 or L 5 as defined herein
  • B, AA, L 1 , L 2 , L 3 , L 4 , L 5 , D 1 and D 2 are defined by the various embodiments described herein, and z1 is 2, 3, 4 or 5; z2 is 0, 1 or 2; z3 is 0, 1, 2, 3 or 4; z4 is 0, 1 or 2; z5 is 0, 1 or 2; y1 is 0, 1 or 2; y2 is 0, 1 or 2; y3 is 0, 1, 2, 3 or 4; and y4 is 0, 1 or 2.
  • cell surface receptor binding ligand generally refers to compounds that bind to and/or target receptors that are found on cell surfaces, and in particular those that are found on, over-expressed by, and/or preferentially expressed on the surface of pathogenic cells.
  • Illustrative ligands include, but are not limited to, vitamins and vitamin receptor binding compounds.
  • Illustrative vitamin moieties include carnitine, inositol, lipoic acid, pyridoxal, ascorbic acid, niacin, pantothenic acid, folic acid, riboflavin, thiamine, biotin, vitamin B 12 , and the lipid soluble vitamins A, D, E and K. These vitamins, and their receptor-binding analogs and derivatives, constitute the targeting entity covalently attachment to the linker.
  • Illustrative biotin analogs that bind to biotin receptors include, but are not limited to, biocytin, biotin sulfoxide, oxybiotin, and the like).
  • the B is folate or derivative thereof. In some embodiments, the B is of the formula I
  • R 1 and R 2 in each instance are independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -OR 7 , -SR 7 and -NR 7 R 7’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2- C 6 alkynyl is independently optionally substituted by halogen,–OR 8 , -SR 8 , -NR 8 R 8’ , -C(O)R 8 , -C(O)OR 8 or -C(O)NR 8 R 8’ ;
  • R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -CN, -NO 2 , -NCO, -OR 9 , -SR 9 ,–NR 9 R 9’ , - C(O)R 9 , -C(O)OR 9 and -C(O)NR 9 R 9’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2- C 6 alkynyl is independently optionally substituted by halogen,–OR 10 , - SR 10 , -NR 10 R 10’ , -C(O)R 10 , -C(O)OR 10 or -C(O)NR 10 R 10’ ;
  • each R 7 , R 7’ , R 8 , R 8’ , R 9 , R 9’ , R 10 and R 10’ is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2- C 6 alkynyl;
  • X 5 is NR 12 or CR 12 R 12’ ;
  • R 11 , R 11’ , R 11’’ , R 12 , R 12’ , R 13 , R 13’ , R 14 and R 14’ are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, -C(O)R 15 , -C(O)OR 15 and -C(O)NR 15 R 15’ ;
  • R 15 and R 15’ are each independently H or C 1 -C 6 alkyl
  • n 1, 2, 3 or 4;
  • B is described according to the formula I, that both the D- and L- forms are contemplated.
  • B is of the formula Ia or Ib
  • R 1 and R 2 are H. In some embodiments described herein, m is 1. In some embodiments described herein, R 3 is H. In some embodiments described herein, R 4 is H. In some embodiments described herein, R 5 is H. In some embodiments described herein,
  • B is of the formula Id
  • the linker for connected B and Drug in the conjugates described herein can be represented by the groups AA, L 1 , L 2 , L 3 , L 4 or L 5 .
  • AA is an amino acid as defined herein. In certain embodiments, AA is a naturally occurring amino acid. In certain embodiments, AA is in the L-form. In certain embodiments, AA is in the D-form. It will be appreciated that in certain embodiments, the conjugates described herein will comprise more than one amino acid as portions of the linker, and the amino acids can be the same or different, and can be selected from a group of amino acids. It will be appreciated that in certain embodiments, the conjugates described herein will comprise more than one amino acid as portions of the linker, and the amino acids can be the same or different, and can be selected from a group of amino acids in D- or L-form. In some
  • each AA is independently selected from the group consisting of L-lysine, L- asparagine, L-threonine, L-serine, L-isoleucine, L-methionine, L-proline, L-histidine, L- glutamine, L-arginine, L-glycine, L-aspartic acid, L-glutamic acid, L-alanine, L-valine, L- phenylalanine, L-leucine, L-tyrosine, L-cysteine, L-tryptophan, L-phosphoserine, L-sulfo- cysteine, L-arginosuccinic acid, L-hydroxyproline, L-phosphoethanolamine, L-sarcosine, L- taurine, L-carnosine, L-citrulline, L-anserine, L-1,3-methyl-histidine, L-alpha-amino-adipic acid, D-lysine, D-asparagine, L
  • each AA is independently selected from the group consisting of L-asparagine, L-arginine, L-glycine, L-aspartic acid, L-glutamic acid, L-glutamine, L-cysteine, L-alanine, L-valine, L-leucine, L-isoleucine, L-citrulline, D-asparagine, D-arginine, D-glycine, D-aspartic acid, D-glutamic acid, D-glutamine, D-cysteine, D-alanine, D-valine, D-leucine, D- isoleucine and D-citrulline.
  • each AA is independently selected from the group consisting of Asp, Arg, Val, Ala, Cys and CIT. In some embodiments, each AA is independently selected from the group consisting of Asp, Arg, Val, Ala, D-Cys and CIT. In some embodiments, each AA is independently selected from the group consisting of Asp, Arg, Val, Ala and CIT. In some embodiments, z1 is 4 and the sequence of AA therein is -Asp-Arg- Asp-Asp-. In some embodiments, z3 is 2 and the sequence of AA therein is Val-Ala. In some embodiments, z3 is 2 and the sequence of AA therein is Val-CIT.
  • z1 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-, and z3 is 2 and the sequence of AA therein is Val-Ala. In some embodiments, z1 is 4 and the sequence of AA therein is -Asp-Arg- Asp-Asp-, and z3 is 2 and the sequence of AA therein is Val-CIT.
  • z8 is 3. In some embodiments, z8 is 2. In some embodiments, z8 is 2, and the sequence of AA therein is Val-Ala. In some embodiments, z10 is 5. In some embodiments, z10 is 4. In some embodiments, z10 is 3. In some embodiments, z10 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-. In some embodiments, z11 is 5. In some embodiments, z11 is 4. In some embodiments, z11 is 3. In some embodiments, z11 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-. In some embodiments, z12 is 5.
  • z12 is 4. In some embodiments, z12 is 3. In some embodiments, z12 is 4 and the sequence of AA therein is -Asp-Asp-Arg-Asp-. In some embodiments, z11 is 4 and z12 is 4. In some embodiments, z11 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-, and z12 is 4 and the sequence of AA therein is -Asp-Asp-Arg-Asp-. In some embodiments, z8 is 2, and the sequence of AA is–Glu-Glu-, wherein the amino acids are covalently attached at their alpha- amino functionality and their side chain carboxylate.
  • L 1 can be present or absent in the conjugates described herein. When L 1 is present, L 1 can be any group covalently attaching portions of the linker to the binding ligand, portions of the linker to one another, or to D 1 , or to D 2 . It will be understood that the structure of L 1 is not particularly limited in any way.
  • L 1 can comprise numerous functionalities well known in the art to covalently attach portions of the linker to the binding ligand, portions of the linker to one another, or to D 1 , or to D 2 , including but not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonate groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, and the like.
  • L 1 is a linker of the formula II
  • R 16 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -C(O)R 19 , -C(O)OR 19 and -C(O)NR 19 R 19’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2- C 6 alkynyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2- C 6 alkynyl, -OR 20 , -OC(O)R 20 , -OC(O)NR 20 R 20’ , -OS(O)R 20 , -OS(O) 2 R 20 , -SR 20 , -S(O)R 20 , -S(O) 2 R 20 , -S(O)NR 20 R 20’ , -S(O) 2
  • each R 17 and R 17’ is independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 22 , -OC(O)R 22 ,
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -OR 24 , -OC(O)R 24 ,
  • R 17 and R 17’ may combine to form a C 4 -C 6 cycloalkyl or a 4- to 6- membered heterocycle, wherein each hydrogen atom in C 4 -C 6 cycloalkyl or 4- to 6- membered heterocycle is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10
  • R 18 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 26 , -OC(O)R 26 , -OC(O)NR 26 R 26’ , -OS(O)R 26 , -OS(O) 2 R 26 , -SR 26 , -S(O)R 26 , -S(O) 2 R 26 , -S(O)NR 26 R 26’ , -S(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(CH 2 ) p OR 28 , -(CH 2 ) p (OCH 2 ) q OR 28 , -(CH 2 ) p (OCH 2 CH 2 ) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O) 2 R 29 , -(CH 2 ) p OS(
  • each R 19 , R 19’ , R 20 , R 20’ , R 21 , R 21’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10
  • R 27 and R 27’ are each independently selected from the group consisting of H, C 1 -C 9 alkyl, C 2 -C 9 alkenyl, C 2- C 9 alkynyl, C 3- C 6 cycloalkyl, -(CH 2 ) p (sugar), -(CH 2 ) p (OCH 2 CH 2 ) q - (sugar) and -(CH 2 ) p (OCH 2 CH 2 CH 2 ) q (sugar);
  • R 28 is a H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl or sugar;
  • n 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q is 1, 2, 3, 4 or 5;
  • L 1 is described according to the formula II, that both the R- and S- configurations are contemplated.
  • L 1 is of the formula IIa or IIb
  • each L 1 is selected from the group consisting of
  • R 16 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, -C(O)R 19 , -C(O)OR 19 and -C(O)NR 19 R 19’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2- C 6 alkynyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2- C 6 alkynyl, -OR 20 , -OC(O)R 20 , -OC(O)NR 20 R 20’ , -OS(O)R 20 , - OS(O) 2 R 20 , -SR 20 , -S(O)R 20 , -S(O) 2 R 20 , -S(O)NR 20 R 20’ , -S(O) 2
  • R 18 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 26 , -OC(O)R 26 , -OC(O)NR 26 R 26’ , -OS(O)R 26 , -OS(O) 2 R 26 , -SR 26 , -S(O)R 26 , -S(O) 2 R 26 , -S(O)NR 26 R 26’ , -S(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(CH 2 ) p OR 28 , -(CH 2 ) p (OCH 2 ) q OR 28 , -(CH 2 ) p (OCH 2 CH 2 ) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O) 2 R 29 , -(CH 2 ) p OS(
  • each each R 19 , R 19’ , R 20 , R 20’ , R 21 , R 21’ , R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl, wherein each hydrogen atom in C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, -OH, -SH, -
  • R 27 and R 27’ are each independently selected from the group consisting of H, C 1 -C 9 alkyl, C 2 -C 9 alkenyl, C 2- C 9 alkynyl, C 3- C 6 cycloalkyl, -(CH 2 ) p (sugar), -(CH 2 ) p (OCH 2 CH 2 ) q - (sugar) and -(CH 2 ) p (OCH 2 CH 2 CH 2 ) q (sugar);
  • R 28 is H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl or sugar; n is 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q is 1, 2, 3, 4 or 5;
  • each L 1 is selected from the group consisting of
  • R 16 is defined as described herein, and * is a covalent bond.
  • R 16 is H.
  • each R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, -OH, -SH, -NH 2 or -CO 2 H;
  • R 27 and R 27’ are each independently selected from the group consisting of H, C 1 -C 9 alkyl, C 2 -C 9 alkenyl, C 2- C 9 alkynyl, C 3- C 6 cycloalkyl, -(CH 2 ) p (sugar), -(CH 2 ) p (OCH 2 CH 2 ) q - (sugar) and -(CH 2 ) p (OCH 2 CH 2 CH 2 ) q (sugar);
  • R 28 is a H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl or sugar; n is 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q is 1, 2, 3, 4 or 5;
  • each hydrogen atom 5- to 7-membered heteroaryl is independently optionally substituted by -(CH 2 ) p OR 28 , -OR 29 , -(CH 2 ) p OS(O) 2 OR 29 and
  • each R 26 , R 26’ , R 26’’ and R 29 is independently H or C 1 -C 7 alkyl, wherein each hydrogen atom in C 1 -C 7 alkyl is independently optionally substituted by halogen, -OH, -SH, -NH 2 or -CO 2 H;
  • R 27 and R 27’ are each independently selected from the group consisting of H,
  • R 28 is H or sugar
  • n 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q is 1, 2, 3, 4 or 5;
  • each L 1 is selected from the group consisting of
  • R 18 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 26 , -OC(O)R 26 , -OC(O)NR 26 R 26’ , -OS(O)R 26 , -OS(O) 2 R 26 , -SR 26 , -S(O)R 26 , -S(O) 2 R 26 , -S(O)NR 26 R 26’ , -S(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O) 2 NR 26 R 26’ , -
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(CH 2 ) p OR 28 , -(CH 2 ) p (OCH 2 ) q OR 28 , -(CH 2 ) p (OCH 2 CH 2 ) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O) 2 R 29 , -(CH 2 ) p OS(
  • each R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, -OH, -SH, -NH 2 or -CO 2 H;
  • R 27 and R 27’ are each independently selected from the group consisting of H, C 1 -C 9 alkyl, C 2 -C 9 alkenyl, C 2- C 9 alkynyl, C 3- C 6 cycloalkyl, -(CH 2 ) p (sugar), -(CH 2 ) p (OCH 2 CH 2 ) q - (sugar) and -(CH 2 ) p (OCH 2 CH 2 CH 2 ) q (sugar);
  • R 28 is a H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl or sugar;
  • n 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q is 1, 2, 3, 4 or 5;
  • each hydrogen atom 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(CH 2 ) p OR 28 ,
  • each R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, -OH, -SH, -NH 2 or -CO 2 H;
  • R 27 and R 27’ are each independently selected from the group consisting of H, C 1 -C 9 alkyl, C 2 -C 9 alkenyl, C 2- C 9 alkynyl, C 3- C 6 cycloalkyl, -(CH 2 ) p (sugar), -(CH 2 ) p (OCH 2 CH 2 ) q - (sugar) and -(CH 2 ) p (OCH 2 CH 2 CH 2 ) q (sugar);
  • R 28 is a H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl or sugar;
  • n 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q is 1, 2, 3, 4 or 5;
  • each hydrogen atom 5- to 7-membered heteroaryl is independently optionally substituted by -(CH 2 ) p OR 28 , -OR 29 , -(CH 2 ) p OS(O) 2 OR 29 and
  • each R 26 , R 26’ , R 26’’ and R 29 is independently H or C 1 -C 7 alkyl, wherein each hydrogen atom in C 1 -C 7 alkyl is independently optionally substituted by halogen, -OH, -SH, -NH 2 or -CO 2 H;
  • R 27 and R 27’ are each independently selected from the group consisting of H,
  • R 28 is H or sugar
  • n 1, 2, 3, 4 or 5;
  • p 1, 2, 3, 4 or 5;
  • q is 1, 2, 3, 4 or 5;
  • L 1 is present. In some embodiments of the conjugates described herein, L 1 is absent. In some embodiments, z4 is 0. In some embodiments, z4 is 1. In some embodiments, z4 is 2.
  • L 2 is a releasable linker.
  • the term“releasable linker” refers to a linker that includes at least one bond that can be broken under physiological conditions, such as a pH- labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labile, or enzyme-labile bond. It is appreciated that such physiological conditions resulting in bond breaking do not necessarily include a biological or metabolic process, and instead may include a standard chemical reaction, such as a hydrolysis reaction, for example, at physiological pH, or as a result of compartmentalization into a cellular organelle such as an endosome having a lower pH than cytosolic pH.
  • a cleavable bond can connect two adjacent atoms within the releasable linker and/or connect other linkers or B, D 1 and/or D 2 , as described herein, at either or both ends of the releasable linker.
  • a cleavable bond connects two adjacent atoms within the releasable linker, following breakage of the bond, the releasable linker is broken into two or more fragments.
  • the releasable linker becomes separated from the other moiety following breaking of the bond.
  • the lability of the cleavable bond can be adjusted by, for example, substituents at or near the cleavable bond, such as including alpha-branching adjacent to a cleavable disulfide bond, increasing the hydrophobicity of substituents on silicon in a moiety having silicon- oxygen bond that may be hydrolyzed, homologating alkoxy groups that form part of a ketal or acetal that may be hydrolyzed, and the like.
  • Illustrative releasable linkers described herein include linkers that include hemiacetals and sulfur variations thereof, acetals and sulfur variations thereof, hemiaminals, aminals, and the like, and can be formed from methylene fragments substituted with at least one heteroatom, 1-alkoxyalkylene, 1-alkoxycycloalkylene, 1-alkoxyalkylenecarbonyl, 1- alkoxycycloalkylenecarbonyl, and the like.
  • Illustrative releasable linkers described herein include linkers that include carbonylarylcarbonyl, carbonyl(carboxyaryl)carbonyl,
  • linkers that include alkylene(dialkylsilyl),
  • Illustrative releasable linkers described herein include oxycarbonyloxy, oxycarbonyloxyalkyl, sulfonyloxy, oxysulfonylalkyl, and the like.
  • Illustrative releasable linkers described herein include linkers that include iminoalkylidenyl,
  • Illustrative releasable linkers described herein include linkers that include alkylenethio, alkylenearylthio, and carbonylalkylthio, and the like.
  • L 2 is selected from the group consisting of ,
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • X 6 is C 1 -C 6 alkyl or C 6 -C 10 aryl(C 1 -C 6 alkyl), wherein each hydrogen atom in C 1 -C 6 alkyl and C 6 -C 10 aryl(C 1 -C 6 alkyl) is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -OR 34 , -OC(O)R 34 , -OC(O)NR 34 R 34’ , -OS(O)R 34 , -OS(O) 2 R 34 , -SR 34 , -S(O)R 34 , -S(O) 2 R 34 , -S(O)NR 34 R 34’ , -S(O
  • each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7-membered heteroaryl;
  • R 36 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 ,
  • R 37 , R 37’ , R 38 and R 38’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl
  • R 31 is H.
  • R 36 is H.
  • X 6 is C 1 -C 6 alkyl.
  • X 6 is C 1 -C 6 alkyl.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • X 6 is C 1 -C 6 alkyl or C 6 -C 10 aryl(C 1 -C 6 alkyl), wherein each hydrogen atom in C 1 -C 6 alkyl and C 6 -C 10 aryl(C 1 -C 6 alkyl) is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -OR 34 , -OC(O)R 34 , -OC(O)NR 34 R 34’ , -OS(O)R 34 , -OS(O) 2 R 34 , -SR 34 , -S(O)R 34 , -S(O) 2 R 34 , -S(O)NR 34 R 34’ , -S(O
  • each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7-membered heteroaryl; and
  • R 31 is H, and X 6 is C 1 -C 6 alkyl. In some embodiments, R 31 is H, and X 6 is C 6 -C 10 aryl(C 1 -C 6 alkyl).
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • X 6 is C 1 -C 6 alkyl or C 6 -C 10 aryl(C 1 -C 6 alkyl), wherein each hydrogen atom in C 1 -C 6 alkyl and C 6 -C 10 aryl(C 1 -C 6 alkyl) is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 4
  • each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7-membered heteroaryl; and * is a covalent bond.
  • R 31 is H, and X 6 is C 1 -C 6 alkyl. In some embodiments, R 31 is H, and X 6 is C 6 -C 10 aryl(C 1 -C 6 alkyl).
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • X 6 is C 1 -C 6 alkyl or C 6 -C 10 aryl(C 1 -C 6 alkyl), wherein each hydrogen atom in C 1 -C 6 alkyl and C 6 -C 10 aryl(C 1 -C 6 alkyl) is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -OR 34 , -OC(O)R 34 , -OC(O)NR 34 R 34’ , -OS(O)R 34 , -OS(O) 2 R 34 , -SR 34 , -S(O)R 34 , -S(O) 2 R 34 , -S(O)NR 34 R 34’ , -S(O
  • each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7-membered heteroaryl; and
  • R 31 is H, and X 6 is C 1 -C 6 alkyl. In some embodiments, R 31 is H, and X 6 is C 6 -C 10 aryl(C 1 -C 6 alkyl).
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 31 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 ,
  • each R 32 , R 32’ , R 33 and R 33’ are independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • R 31 is H.
  • L 2 is
  • R 36 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 ,
  • R 37 , R 37’ , R 38 and R 38’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl
  • R 36 is H.
  • L 2 is
  • R 36 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 ,
  • R 37 , R 37’ , R 38 and R 38’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl
  • R 36 is H.
  • L 2 is
  • R 36 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 ,
  • R 37 , R 37’ , R 38 and R 38’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl
  • R 36 is H.
  • L 3 can be present or absent in the conjugates described herein. When L 3 is present, L 3 can be any group covalently attaching portions of the linker to one another, or to D 1 , or to D 2 . It will be understood that the structure of L 3 is not particularly limited in any way. It will be further understood that L 3 can comprise numerous functionalities well known in the art to covalently attach portions of the linker to one another, or to D 1 , or to D 2 , including but not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonate groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, and the like.
  • L 3 is selected from the group consisting of C 1 -C 6 alkyl, –(CR 39 R 39’ ) r C(O)-,–(CR 39 R 39’ ) r OC(O)-,–NR 39 R 39’ C(O)(CR 39 R 39’ ) r -,–(CH 2 ) r NR 39 -, –(OCR 39 R 39’ CR 39 R 39’ ) r C(O)-, and–(OCR 39 R 39’ CR 39 R 39’ CR 39 R 39’ )- r C(O)-,
  • each R 39 and R 39’ is independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 40 , -OC(O)R 40 ,
  • R 40 , R 40’ , R 41 and R 41’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, and 5- to 7-membered heteroaryl
  • r in each instance is 1, 2, 3, 4, or 5.
  • L 3 is present. In some embodiments of the conjugates described herein, L 3 is absent.
  • z2 is 0. In some embodiments, z2 is 1. In some embodiments, z2 is 2. In some embodiments, z6 is 0. In some embodiments, z6 is 1. In some embodiments, z6 is 2. In some embodiments, r is 5. In some embodiments, r is 4. In some embodiments, r is 3. In some embodiments, r is 5, each R 39 is H, and each R 39’ is H. In some embodiments, r is 4, each R 39 is H, and each R 39’ is H. In some embodiments, r is 3, each R 39 is H, and each R 39’ is H. In some embodiments, r is 3, each R 39 is H, and each R 39’ is H.
  • L 3 is–(CR 39 R 39’ ) r C(O)-. In some embodiments, L 3 is
  • each R 39 is H
  • each R 39’ is H
  • L 3 is –(CR 39 R 39’ ) r C(O)-, r is 4
  • each R 39 is H
  • each R 39’ is H
  • L 3 is –(CR 39 R 39’ ) r C(O)-, r is 3, each R 39 is H, and each R 39’ is H.
  • L 3 is–(CR 39 R 39’ ) r OC(O)-, r is 5, each R 39 is H, and each R 39’ is H. In some embodiments, L 3 is–(CR 39 R 39’ ) r OC(O)-, r is 4, each R 39 is H, and each R 39’ is H. In some embodiments, L 3 is–(CR 39 R 39’ ) r OC(O)-, r is 3, each R 39 is H, and each R 39’ is H.
  • L 3 is–NR 39 R 39’ C(O)(CR 39 R 39’ ) r -, r is 5, each R 39 is H, and each R 39’ is H.
  • L 3 is–NR 39 R 39’ C(O)(CR 39 R 39’ ) r -, r is 4, each R 39 is H, and each R 39’ is H.
  • L 3 is–NR 39 R 39’ C(O)(CR 39 R 39’ ) r -, r is 3, each R 39 is H, and each R 39’ is H.
  • L 3 is–(CH 2 ) r NR 39 -, r is 5 and R 39 is H.
  • L 3 is–(CH 2 ) r NR 39 -, r is 4 and R 39 is H. In some embodiments, L 3 is–(CH 2 ) r NR 39 -, r is 3 and R 39 is H. In some embodiments, L 3 is–(CH 2 ) r NR 39 -, r is 2 and R 39 is H.
  • L 3 is–(OCR 39 R 39’ CR 39 R 39’ ) r C(O)-, r is 5, each R 39 is H, and each R 39’ is H. In some embodiments, L 3 is–(OCR 39 R 39’ CR 39 R 39’ ) r C(O)-, r is 4, each R 39 is H, and each R 39’ is H. In some embodiments, L 3 is–(OCR 39 R 39’ CR 39 R 39’ ) r C(O)-, r is 3, each R 39 is H, and each R 39’ is H.
  • L 4 can be present or absent in the conjugates described herein. When L 4 is present, L 4 can be any group covalently attaching portions of the linker to one another, or to D 1 , or to D 2 . It will be understood that the structure of L 4 is not particularly limited in any way. It will be further understood that L 4 can comprise numerous functionalities well known in the art to covalently attach portions of the linker to one another, or to D 1 , or to D 2 , including but not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonate groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, and the like. In some embodiments, L 4 is selected from the group consisting of
  • R 42 is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 45 , -OC(O)R 45 , -OC(O)NR 45 R 45’ , -OS(O)R 45 ,
  • each R 43 , R 43’ , R 44 and R 44 is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 47 , -OC(O)R 47 , -OC(O)NR 47 R 47’ , -OS(O)R 47 , -OS(O) 2 R 47
  • R 45 , R 45’ , R 46 , R 46’ , R 47 , R 47’ , R 48 and R 48’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl;
  • t is in each instance 1, 2, 3, 4, or 5;
  • L 4 is present. In some embodiments of the conjugates described herein, L 4 is absent. In some embodiments, z5 is 0. In some embodiments, z5 is 1. In some embodiments, z5 is 2. In some embodiments, z7 is 0. In some embodiments, z7 is 1. In some embodiments, z7 is 2. In some embodiments, z9 is 0. In some embodiments, z9 is 1. In some embodiments, z9 is 2. In some embodiments, z7 is 0 and z9 is 0. In some embodiments, z7 is 0 and z9 is 1. In some embodiments, z7 is 1 and z9 is 1. In some embodiments, z7 is 1 and z9 is 0.
  • L 4 is -NR 42 C 6 -C 10 aryl(C 1 -C 6 alkyl)OC(O)-, wherein R 42 is H.
  • z5 is 1, and L 4 is -NR 42 C 6 -C 10 aryl(C 1 -C 6 alkyl)OC(O)-, wherein R 42 is H.
  • z7 is 1, and L 4 is -NR 42 C 6 -C 10 aryl(C 1 -C 6 alkyl)OC(O)-, wherein R 42 is H.
  • L 4 is -NR 42 C 6 -C 10 aryl(C 1 -C 6 alkyl)OC(O)-, wherein R 42 is H.
  • L 4 is -NR 42 CR 43 R 43’ CR 43 R 43’ (OCR 44 R 44’ CR 44 R 44’ ) t C(O)- wherein each R 42 , R 43 , R 43’ , R 44 and R 44’ is H, and t is 4.
  • L 4 is
  • -L 3 -L 4 - is–(CH 2 ) r NR 39 C(O)(CR 44 R 44’ ) t -, wherein r is 2, t is 2, R 39 is H, each R 44 is H, and each R 44’ is H.
  • -L 3 -L 4 -(AA) 2 is
  • L 5 can be present or absent in the conjugates described herein. When L 5 is present, L 5 can be any group covalently attaching D 1 to D 2 . It will be understood that the structure of L 5 is not particularly limited in any way. It will be further understood that L 5 can comprise numerous functionalities well known in the art to covalently attach D 1 to D 2 , including but not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonate groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, and the like.
  • each R 49 and R 49’ is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl and C 3- C 6 cycloalkyl is independently optionally substituted by halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 50 , -OC(O)R 50 ,
  • R 50 , R 50’ , R 51 and R 51’ are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl
  • u is in each instance 0, 1, 2, 3, 4 or 5;
  • L 5 is present. In some embodiments of the conjugates described herein, L 5 is absent. In some embodiments, L 5 is C 1 - C 6 alkyl. In some embodiments, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 3. In some embodiments, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 4. In some embodiments, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 5.
  • the linker is of the formula -(AA) z1 -L 2 -(L 3 ) z2 -(AA) z3 -(L 1 ) z4 - (L 4 ) z5 -, wherein AA, L 1 , L 2 , L 3 , L 4 , z1, z2, z3, z4 and z5 are defined as described herein.
  • the linker is of the formula -L 1 -AA-L 1 -AA-L 1 -L 2 -(L 3 ) z6 -(L 4 ) z7 -(AA) z8 - (L 4 ) z9 -, wherein AA, L 1 , L 2 , L 3 , L 4 , z6, z7, z8 and z9 are defined as described herein.
  • the linker is of the formula -(AA) z10 -L 2 -, wherein AA, L 2 and z10 are defined as described herein.
  • the linker is of the formula -(AA) z11 -L 2 -, wherein AA, L 2 , and z11 are defined as described herein. In some embodiments, the linker is of the formula - L 2 -(AA) z12 -, wherein AA, L 2 , and z12 are defined as described herein. In some embodiments, the linker is of the formula -(AA) 4 -L 2 -, wherein AA and L 2 are defined as described herein.
  • the linker is of the formula -(AA) 4 -L 2 -, wherein the sequence of -(AA) 4 - is -Asp-Arg-Asp-Asp-, and L 2 is defined as described herein.
  • the linker is of the formula -(AA) 4 -L 2 -L 3 -AA-L 1 -L 4 -, wherein the sequence of -(AA) 4 - is -Asp-Arg-Asp- Asp-, and AA, L 1 , L 2 , L 3 and L 4 are defined as described herein.
  • the linker is of the formula -(AA) 4 -L 2 -L 3 -(AA) 2 -, wherein AA, L 1 , L 2 and L 3 are defined as described herein. In some embodiments, the linker is of the formula -(AA) 4 -L 2 -L 3 -(AA) 2 -, wherein the sequence of -(AA) 4 - is -Asp-Arg-Asp-Asp-, the sequence of -(AA) 2 - is Val-Ala, and L 1 , L 2 and L 3 are defined as described herein.
  • the linker is of the formula -(AA) 4 -L 2 -L 3 -(AA) 2 -, wherein the sequence of -(AA) 4 - is -Asp-Arg-Asp-Asp-, the sequence of -(AA) 2 - is Val-CIT, and L 1 , L 2 and L 3 are defined as described herein.
  • the linker is of the formula -L 1 -AA-L 1 -AA-L 1 -L 2 -, wherein AA, L 1 and L 2 are defined as described herein.
  • the linker is of the formula -L1-AA-L1-AA- L1-L2-L3-(AA) 2 -L4-, wherein AA, L 1 , L 2 , L 3 and L 4 are defined as described herein. In some embodiments, the linker is of the formula -L 1 -AA-L 1 -AA-L 1 -L 2 -L 3 -L 4 -(AA) 2 -L 4 -, wherein AA, L 1 , L 2 , L 3 and L 4 are defined as described herein.
  • the linker is of the formula -L 1 -AA-L 1 -AA-L 1 -L 2 -L 3 -L 4 -, AA, L 1 , L 2 , L 3 and L 4 are defined as described herein.
  • the linker is of the formula -L 1 -AA-L 1 -AA-L 1 -L 2 -L 3 -(AA) 2 -, wherein AA, L 1 , L 2 and L 3 are defined as described herein.
  • the linker is of the formula
  • the linker is of the formula
  • the linker is of the formula
  • the linker is of the formula
  • the linker is of the formula
  • the linker is of the formula
  • the linker is of the formula
  • the linker is of the formula
  • the linker is of the formula
  • Drug describes one or two drugs selected D 1 and/or D 2 , covalently attached to one or more linker portions of the conjugate. In some embodiments, both D 1 and D 2 are present. In some embodiments, D comprises the structure -D 1 -L 5 -D 2 . In some embodiments, Drug comprises the structure -D 1 -L 5 -D 1 -.
  • drugs D 1 and D 2 described herein comprise pyrrolobenzodiazepine (PBD) prodrugs. It will be understood that such PBD prodrugs undergo conversion to a therapeutically active PBD compound through processes in the body after delivery of a conjugate as decribed herein.
  • PBD prodrugs undergo conversion to a therapeutically active PBD compound through processes in the body after delivery of a conjugate as decribed herein.
  • at least one of the drugs incorporated into conjugates decribed herein is a PBD prodrug as described herein.
  • D 1 can be described as a PBD prodrug of the formula III
  • R 1a , R 2a , R 3a and R 4a are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 11a , -C(O)OR 11a ,
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 11a , -OC(O)R 11a , -OC(O)NR 11a R 11a’ , -OS(O)R 11a , -OS(O) 2 R 11a ,
  • R 5a , R 6a and R 7a are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 13a , -C(O)OR 13a and -C(O)NR 13a R 13a’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 al
  • R 8a and R 9a are each independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 18a , -OC(O)R 18a , -OC(O)NR 18a R 18a’ , -OS(O)R 18a , -OS(O) 2 R 18a , -SR 18a , -S(O)R 18a , -S(O) 2 R 18a , -S(O)NR 18a R 18a’ , -S(O) 2 NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O) 2 NR 18a R 18a’ , -NR 18a R 18a’ , -NR 18a C(O)R 19a , -NR 18a C(O)OR 19a , -NR 18a C(O
  • R 10a is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 22a , -OC(O)R 22a , -OC(O)NR 22a R 22a’ , -OS(O)R 22a , -OS(O) 2 R 22a , -SR 22a ,
  • each R 11a , R 11a’ , R 12a , R 12a’ , R 13a , R 13a’ , R 14a , R 14a’ , R 15a , R 15a’ , R 16a , R 16a’ , R 17a , R 17a’ , R 18a , R 18a’ , R 19a , R 19a’ , R 20a , R 20a’ , R 21a , R 21a’ , R 22a , R 22a’ , R 23a , R 23a’ , R 24a , R 24a’ , R 25a and R 25a’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7- membered heteroaryl;
  • R 1a , R 4a and R 5a are a bond, or when R 5a and R 6a taken together with the atoms to which they are attached optionally combine to form a 3- to 7- membered heterocycloalkyl or 5- to 7-membered heteroaryl, one hydrogen atom in 5- to 7- membered heteroaryl is a bond and one of R 1a or R 4a is a bond.
  • R 1a is a bond, and R 5a is a bond. In some embodiments, R 1a is a bond, and R 4a is a bond. In some embodiments, R 1a is a bond, and R 2a is C 1 -C 6 alkyl. In some embodiments, R 1a is a bond, R 3a is H, and R 4a is H. In some embodiments, R 1a is a bond, and R 2a is C 1 -C 6 alkyl. In some embodiments, R 1a is a bond, R 2a is C 1 -C 6 alkyl, R 3a is H, and R 4a is H. In some embodiments, R 1a is a bond, R 5a is a bond, and R 6a and R 7a taken together with the atoms to which they are attached optionally combine to form a 3- to 7-membered
  • R 1a is a bond
  • R 5a and R 6a taken together with the atoms to which they are attached optionally combine to form a 3- to 7-membered
  • heterocycloalkyl or 5- to 7-membered heteroaryl wherein one hydrogen atom in 5- to 7- membered heteroaryl is a bond.
  • R 5a , R 6a and R 7a are each independently selected from the group consisting of H, C 1 -C 6 alkyl, -C(O)R 13a , -C(O)OR 13a , wherein each hydrogen atom in C 1 -C 6 alkyl is optionally substituted by -OC(O)R 14a ; wherein R 6a and R 7a taken together with the atoms to which they are attached optionally combine to form a 3- to 7-membered
  • R 5a and R 6a taken together with the atoms to which they are attached optionally combine to form a 3- to 7-membered heterocycloalkyl or 5- to 7-membered heteroaryl, provided that at least two of R 1a , R 4a and R 5a are a bond, or when R 5a and R 6a taken together with the atoms to which they are attached optionally combine to form a 3- to 7- membered heterocycloalkyl or 5- to 7-membered heteroaryl, one hydrogen atom in 5- to 7- membered heteroaryl is a bond and one of R 1a or R 4a is a bond; and each R 13a and R 14a is independently H or C 1 -C 7 alkyl.
  • D 1 is a PBD prodrug of the formula IIIa
  • R 2a , R 3a and R 4a are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 11a , -C(O)OR 11a , and -C(O)NR 11a R 11a’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-
  • R 8a and R 9a are each independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 18a , -OC(O)R 18a , -OC(O)NR 18a R 18a’ , -OS(O)R 18a , -OS(O) 2 R 18a , -SR 18a , -S(O)R 18a , -S(O) 2 R 18a , -S(O)NR 18a R 18a’ , -S(O) 2 NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O) 2 NR 18a R 18a’ , -NR 18a R 18a’ , -NR 18a C(O)R 19a , -NR 18a C(O)OR 19a , -NR 18a C(O
  • each R 11a , R 11a’ , R 12a , R 12a’ , R 18a , R 18a’ , R 19a , R 19a’ , R 20a , R 20a’ , R 21a and R 21a’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7- membered heteroaryl; and
  • R 2a , R 3a and R 4a are each independently H or C 1 -C 6 alkyl; R 8a and R 9a are each H, and * is a bond.
  • D 1 is a PBD prodrug of the formula IIIb
  • R 2a and R 3a are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 11a , -C(O)OR 11a , and -C(O)NR 11a R 11a’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkyn
  • R 5a is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 13a , -C(O)OR 13a and -C(O)NR 13a R 13a’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl and 5- to 7-membered heteroaryl is optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycl
  • R 8a and R 9a are each independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 18a , -OC(O)R 18a , -OC(O)NR 18a R 18a’ , -OS(O)R 18a , -OS(O) 2 R 18a , -SR 18a , -S(O)R 18a , -S(O) 2 R 18a , -S(O)NR 18a R 18a’ , -S(O) 2 NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O)NR 18a R 18a’ , -OS(O) 2 NR 18a R 18a’ , -NR 18a R 18a’ , -NR 18a C(O)R 19a , -NR 18a C(O)OR 19a , -NR 18a C(O
  • each R 11a , R 11a’ , R 12a , R 12a’ , R 13a , R 13a’ , R 14a , R 14a’ , R 15a , R 15a’ , R 18a , R 18a’ , R 19a , R 19a’ , R 20a , R 20a’ , R 21a and R 21a’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7-
  • R 2a and R 3a are each independently H or C 1 -C 6 alkyl;
  • R 5a is selected from the group consisting of H, C 1 -C 6 alkyl, -C(O)R 13a , and -C(O)OR 13a , wherein each hydrogen atom in C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 14a , -OC(O)R 14a ,
  • R 13a and R 14a are each independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to
  • D 1 is a PBD prodrug of the formula IIIc
  • R 2a , R 3a and R 4a are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 11a , -C(O)OR 11a , and -C(O)NR 11a R 11a’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-
  • R 7a is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 13a , -C(O)OR 13a and -C(O)NR 13a R 13a’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl and 5- to 7-membered heteroaryl is optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycl
  • each R 11a , R 11a’ , R 12a , R 12a’ , R 13a , R 13a’ , R 14a , R 14a’ , R 15a , R 15a’ , R 18a , R 18a’ , R 19a , R 19a’ , R 20a , R 20a’ , R 21a and R 21a’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 7-membered heteroaryl; and * is a bond.
  • R 2a , R 3a and R 4a are each independently H or C 1 -C 6 alkyl;
  • R 7a is H or C 1 -C 6 alkyl;
  • R 8a and R 9a are each H, and * is a bond.
  • D 2 can be any other drug useful for eliciting a desired biological effect. It will be understood that the identity of D 2 is not particularly limited, and a variety of drugs known in the art can be used in connection with the conjugates described herein as D 2 .
  • D 2 can be a DNA binding agent.
  • D 2 can be a DNA alkylating agent. It will be understood that DNA binding agents and DNA alkylating agents are well known in the art and the identity of such DNA binding agents and DNA alkylating agents is not limited.
  • D 2 can be a DNA minor groove binding drug.
  • D 2 is selected from the group consisting of
  • R 1b , R 2b , R 3b and R 4b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 13b , -C(O)OR 13b , and -C(O)NR 13b R 13b’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7- membered heteroaryl, -OR 13b , -OC(O)R 13b , -OC(
  • R 5b , R 6b and R 7b are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 15b , -C(O)OR 15b , and -C(O)NR 15b R 15b’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-
  • heterocycloalkyl or 5- to 7-membered heteroaryl wherein each hydrogen atom in 3- to 7- membered heterocycloalkyl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 17b , -OC(O)R 17b ,
  • R 8b and R 9b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 19b , -OC(O)R 19b ,
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 21b , -OC(O)R
  • R 10b , R 11b and R 12b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 23b , -OC(O)R 23b ,
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 25b , -OC(O)R
  • each R 13b , R 13b’ , R 14b , R 14b’ , R 15b , R 15b’ , R 16b , R 16b’ , R 17b , R 17b’ , R 18b , R 18b’ , R 19b , R 19b’ , R 20b , R 20b’ , R 21b , R 21b’ , R 22b , R 22b’ , R 23b , R 23b’ , R 24b , R 24b’ , R 25b , R 25b’ , R 26b and R 26b’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl(C 6 -C 10 aryl) and 5- to
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OH, -SH, -NH 2 , -SO 3 H, -C(O)OH and -C(O)NH 2 ;
  • R 1b , R 2b , R 3b , R 4b , R 5b , R 6b and R 7b is a bond
  • R 1c , R 2c and R 5c are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 6c , -C(O)OR 6c and -C(O)NR 6c R 6c’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl and 5- to
  • R 3c and R 4c are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 9c , -OC(O)R 9c , -OC(O)NR 9c R 9c’ , -OS(O)R 9c , -OS(O) 2 R 9c , -SR 9c , -S(O)R 9c , -S(O) 2 R 9c , -S(O)NR 9c R 9c’ , -S(O) 2 NR 9c R 9c’ , -S(O) 2 NR 9c R 9c’ , -S(O)
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 11c , -OC(O)R 11c ,
  • R 1d is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 2d , -SR 2d and -NR 2d R 2d’ , R 2d and R 2d’ are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C
  • R 3d and R 3d’ are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl and 5- to 7-membered heteroaryl;
  • R 1e is selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7- membere
  • each R 2e , R 2e’ , R 3e and R 3e’ is independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl and 5- to 7-membered heteroaryl is optionally substituted by –OR 4e , -SR 4e or–NR 4e R 4e’ ;
  • R 4e and R 4e’ are independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl;
  • v 1, 2 or 3;
  • Drug can be described by the general formula–D 1 -L 5 -D 2 .
  • Drug can be described by the formula , wherein, L 5 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 11b and R 12b are defined as described herein.
  • R 49 R 49’ CR 49 R 49’ CR 49 R 49’ ) u -,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)- or– CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H, and L 5 is C 1 -C 10 alkyl.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H
  • L 5 is–(OCR 49 R 49’ CR 49 R 49’ ) u -, wherein each R 49 and R 49’ is H, and u is 4.
  • R 4a is a bond
  • R 2a , R 3a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H
  • R 4a is a bond
  • R 2a , R 3a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H
  • L 5 is C 1 -C 10 alkyl.
  • R 5a is a bond
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H
  • R 5a is a bond
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H
  • L 5 is C 1 -C 10 alkyl.
  • Drug can be described by the general formula–D 1 -L 5 -D 2 . In some embodiments, Drug can be described by the formula
  • L 5 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 2c , R 3c , R 4c , R 5c and J are as defined herein.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2c , R 3c , R 4c and R 5c are H
  • L 5 is C 1 -C 10 alkyl
  • R(CR 49 CR 49’ ) u -,–(CR 49 R 49’ ) u C(O)-,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u -, –CH 2 CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ CR 49 R 49’ ) u -,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)- or –CH 2 CH 2 (OCR 49 R 49’ CR 49’ CR 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5.
  • J is–C(O)-, R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2c , R 3c , R 4c and R 5c are H, and L 5 is C 1 -C 10 alkyl.
  • J is–(CR 13c R 13c’ )-, R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2c , R 3c , R 4c , R 5c , R 13c and R 13c’ are H, and L 5 is C 1 -C 10 alkyl.
  • Drug can be described by the general formula–D 1 -L 5 -D 2 . In some embodiments, Drug can be described by the formula
  • L 5 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a and R 10a are as defined herein.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H
  • R 49 R 49’ CR 49 R 49’ CR 49 R 49’ ) u -,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)- or –CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H
  • L 5 is C 1 -C 10 alkyl.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 3.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 4.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 5.
  • Drug can be described by the general formula–D 1 -L 5 -D 2 . In some embodiments, Drug can be described by the formula
  • L 5 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a and R 1e are as defined herein.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is C 1 -C 10 alkyl,
  • R 49 R 49’ CR 49 R 49’ CR 49 R 49’ ) u -,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)- or –CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, and L 5 is C 1 -C 10 alkyl.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)- ,wherein each R 49 and R 49’ is H, and u is 3.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-,wherein each R 49 and R 49’ is H, and u is 4.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-,wherein each R 49 and R 49’ is H, and u is 5.
  • Drug can be described by the general formula–D 1 -L 5 -D 2 . In some embodiments, Drug can be described by the formula
  • L 5 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 1d and v are as defined herein.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is C 1 -C 10 alkyl,
  • R 49 R 49’ CR 49 R 49’ CR 49 R 49’ ) u -,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)- or –CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, and L 5 is C 1 -C 10 alkyl.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 4.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 5.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is C 1 -C 10 alkyl, and v is 2. In some embodiments, R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is C 1 -C 10 alkyl, and v is 3.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, u is 4, and v is 2.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, u is 4, and v is 3.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, u is 5, and v is 2.
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a and R 1e are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, u is 5, and v is 3.
  • Drug can be described by the general formula–D 1 -L 5 -D 2 . In some embodiments, Drug can be described by the formula
  • L 5 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a and R 10a are as defined herein.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H
  • R 49 R 49’ CR 49 R 49’ CR 49 R 49’ ) u -,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)- or –CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H
  • L 5 is C 1 -C 10 alkyl.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 4.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 5.
  • Drug can be described by the general formula–D 1 -L 5 -D 2 . In some embodiments, Drug can be described by the formula
  • L 5 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a and R 10a are as defined herein.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H
  • R 49 R 49’ CR 49 R 49’ CR 49 R 49’ ) u -,–CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)- or –CH 2 CH 2 (OCR 49 R 49’ CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 1, 2, 3, 4 or 5.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H
  • L 5 is C 1 -C 10 alkyl.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 4.
  • R 2a , R 3a , R 4a , R 8a , R 9a and R 10a are H, L 5 is–(CR 49 R 49’ ) u C(O)-, wherein each R 49 and R 49’ is H, and u is 5.
  • Drug can be described by the general formula–D 1 -L 5 -D 2 . In some embodiments, Drug can be described by the formula
  • L 5 , R 2a , R 3a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 11b and R 12b are defined as described herein.
  • R 2a , R 3a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H
  • R 2a , R 3a , R 4a , R 8a , R 9a , R 10a , R 2b , R 3b , R 4b , R 8b and R 9b are H, and L 5 is C 1 -C 10 alkyl.
  • D 1 can be absent.
  • D 2 is of the formula
  • R 1b , R 2b , R 3b and R 4b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 13b , -C(O)OR 13b , and -C(O)NR 13b R 13b’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7- membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alken
  • R 5b , R 6b and R 7b are each independently selected from the group consisting of H, D, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -C(O)R 15b , -C(O)OR 15b , and -C(O)NR 15b R 15b’ , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-
  • heterocycloalkyl or 5- to 7-membered heteroaryl wherein each hydrogen atom in 3- to 7- membered heterocycloalkyl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 17b , -OC(O)R 17b ,
  • R 8b and R 9b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OR 19b , -OC(O)R 19b ,
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 21b , -OC(O)R
  • R 10b , R 11b and R 12b are each independently selected from the group consisting of H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 23b , -OC(O)R 23b ,
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C 3- C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -OR 25b , -OC(O)R
  • each R 13b , R 13b’ , R 14b , R 14b’ , R 15b , R 15b’ , R 16b , R 16b’ , R 17b , R 17b’ , R 18b , R 18b’ , R 19b , R 19b’ , R 20b , R 20b’ , R 21b , R 21b’ , R 22b , R 22b’ , R 23b , R 23b’ , R 24b , R 24b’ , R 25b , R 25b’ , R 26b and R 26b’ is independently selected from the group consisting of H, D, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2- C 7 alkynyl, C 3- C 13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl(C 6 -C 10 aryl) and 5- to
  • heterocycloalkyl C 6 -C 10 aryl, 5- to 7-membered heteroaryl, -CN, -NO 2 , -NCO, -OH, -SH, -NH 2 , -SO 3 H, -C(O)OH and -C(O)NH 2 ; and * is a bond.
  • the conjugates described herein can be used for both human clinical medicine and veterinary applications.
  • the host animal harboring the population of pathogenic cells and treated with the conjugates described herein can be human or, in the case of veterinary applications, can be a laboratory, agricultural, domestic, or wild animal.
  • the conjugates described herein can be applied to host animals including, but not limited to, humans, laboratory animals such rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.
  • pathogenic cells or“population of pathogenic cells” generally refers to cancer cells, infectious agents such as bacteria and viruses, bacteria- or virus-infected cells, inflammatory cells, activated macrophages capable of causing a disease state, and any other type of pathogenic cells that uniquely express, preferentially express, or overexpress cell surface receptors or cell surface anitgens that may be bound by or targeted by the conjugates described herein.
  • Pathogenic cells can also include any cells causing a disease state for which treatment with the conjugates described herein results in reduction of the symptoms of the disease.
  • the pathogenic cells can be host cells that are pathogenic under some circumstances such as cells of the immune system that are responsible for graft versus host disease, but not pathogenic under other circumstances.
  • the population of pathogenic cells can be a cancer cell population that is tumorigenic, including benign tumors and malignant tumors, or it can be non-tumorigenic.
  • the cancer cell population can arise spontaneously or by such processes as mutations present in the germline of the host animal or somatic mutations, or it can be chemically-, virally-, or radiation- induced.
  • the conjugates described herein can be utilized to treat such cancers as carcinomas, sarcomas, lymphomas, Hodgekin’s disease, melanomas, mesotheliomas, Burkitt’s lymphoma, nasopharyngeal carcinomas, leukemias, and myelomas.
  • the cancer cell population can include, but is not limited to, oral, thyroid, endocrine, skin, gastric, esophageal, laryngeal, pancreatic, colon, bladder, bone, ovarian, cervical, uterine, breast, testicular, prostate, rectal, kidney, liver, and lung cancers.
  • the disclosure includes all pharmaceutically acceptable isotopically-labelled conjugates, and their Drug(s) incorporated therein, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the conjugates, and their Drug(s) incorporated therein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopes of hydrogen such as 2 H and 3 H
  • carbon such as 11 C, 13 C and 14 C
  • chlorine such as 36 Cl
  • fluorine such as 18 F
  • iodine such as 123 I and 125 I
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 O, 17 O and 18 O
  • phosphorus such as 32 P
  • sulfur such as 35 S.
  • Radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled conjugates, and their Drug(s) incorporated therein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • conjugates and compositions described herein may be administered orally.
  • Oral administration may involve swallowing, so that the conjugate or composition enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the conjugate or composition enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the conjugates and compositions described herein may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
  • the conjugate may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants examples include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to 25 about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol.1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a conjugate as described herein, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent.
  • Some components of the formulation may perform more than one function.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the disaclosure are described in US Patent No.6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • conjugates described herein can also be administered directly into the blood stream, into muscle, or into an internal organ.
  • suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including micro-needle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of conjugates described herein used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • conjugates described herein can be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(lactic-coglycolic)acid
  • the conjugates described herein can also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J. Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the conjugates described herein can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane.
  • a suitable propellant such as 1,1,1,2-tetrafluoroe
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the conjugates(s) of the present disclosure comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the conjugate Prior to use in a dry powder or suspension formulation, the conjugate is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the conjugate described herein, a suitable powder base such as lactose or starch and a performance modifier such as Iso-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a typical formulation may comprise a conjugate of the present disclosure, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • conjugates described here can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • kits suitable for co-administration of the compositions may conveniently be combined in the form of a kit suitable for co-administration of the compositions.
  • the kit of the present disclosure comprises two or more separate pharmaceutical compositions, at least one of which contains a conjugate as described herein, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the present disclosure is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the conjuagtes described herein were prepared according to the processes described herein and/or conventional processes.
  • the stereocenters of the conjugates described herein may be substantially pure (S), the substantially pure (R), or any mixture of (S) and (R) at any asymmetric carbon atom, and each may be used in the processes described herein.
  • the processes described in these illustrative examples may be adapted to prepare other conjuagtes described herein by carrying out variations of the processes described herein with routine selection of alternative starting materials and reagents. It is also to be understood that radicals of these examples are included in the PBD prodrugs, poly-PBD prodrugs, mixed PBDs, conjugates, and conjuagtes described herein.
  • MOM ether EC2173 was synthesized in 58% yield following the procedure described in Boger, D. L.; Hughes, T. V.; Hedrick, H. P. J. Org. Chem. 2001, 66, 2207-2216.
  • EC2176 was separated into (R)- EC2176 and (S)- EC217 using Normal phase HPLC on Chiral Stationary Phase was used for chiral separation of racemic EC 2176. Conditions as follows: Column Name: (S,S)-Whelk-O1, Column Size: 250 mm x 4.6 mm, Mobile Phase: Hexane/IPA (70/30).
  • Boc amine, (S)-EC2176 (49 mg, 0.13 mmol) was dissolved in a 30% TFA in CH 2 Cl 2 solution (5ml) at 0 o C and let stir for 3 hr. LCMS was used to monitor the reaction until complete deprotection. The reaction mixture was quenched with saturated NaHCO 3 and extracted three times with ethyl acetate. The organic extracts were combined, dried over Na 2 SO 4 , filtered and the solvent was removed under vacuum to yield the crude amine. The amine and EC2180 (40 mg, 0.13 mmol) were dissolved in DMF (1ml) under Agron atmosphere.
  • Ester EC2256 (19 mg, 0.033mmol) was dissolved in a 3:1:1 mixture of THF:H 2 O:MeOH (1ml) and LiOH (0.33 ml, 0.33mmol) was added. The reaction was monitored until full conversion was complete. The organic solvents were removed under vacuum and the crude product was purified by low pressure chromatography using C18 stationary phase and eluted with H 2 O and ACN. Fractions of the desired product were combined, CAN was removed, the aqueous layer was extracted with ethyl acetate, dried over Na 2 SO 4 and concentrated to yield acid EC2257 (17.5 mg, 94%).

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CA2979527A CA2979527A1 (en) 2015-03-13 2015-03-13 Conjugates of pyrrolobenzodiazepine (pbd) prodrugs for treating disease
EP15885705.2A EP3268046A4 (en) 2015-03-13 2015-03-13 Conjugates for treating diseases
US15/557,703 US10624972B2 (en) 2015-03-13 2015-03-13 Conjugates for treating diseases
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