DOT1L Degrader and Its Use

Abstract

Provided herein are bifunctional compounds having a portion (e.g., lenalidomide, thalidomide) that is a binder of an E3 ubiquitin ligase (e.g., cereblon) and another portion that is a binder of a target protein, DOT1L, and induces degradation of DOT1L. Also provided are pharmaceutical compositions containing the bifunctional compounds, as well as methods for treating and / or preventing diseases (e.g., proliferative diseases such as cancer). Also provided are methods for inducing degradation of DOT1L by administering a bifunctional compound or composition described herein, wherein one component of the bifunctional compound is a binder of an E3 ubiquitin ligase (e.g., lenalidomide, thalidomide) and another component of the compound is a binder of a target protein, DOT1L, in a subject. [Formula 1]

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 690,791, filed June 27, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] Government subsidies This disclosure was made with government support under grant R01 CA176745 awarded by the National Institutes of Health (NIH). The U.S. Government has certain rights in this invention. [Background technology]

[0003] Background of the Invention E3 ubiquitin ligases, in combination with E2 ubiquitin-conjugating enzymes, are proteins that facilitate the attachment of ubiquitin to lysines on target proteins via an isopeptide bond (e.g., an amide bond that is not present in the protein backbone). Ubiquitination of target proteins leads to their degradation by the proteasome.

[0004] There is still a need to identify compounds that can effectively promote the degradation of target proteins (such as DOT1L) that are known to be associated with certain pathological conditions, such as proliferative diseases and cancer.DOT1L is known to be associated with certain pathological conditions, such as proliferative diseases and cancer.In particular, compounds that can utilize the cellular mechanisms involved in protein homeostasis (such as ubiquitination and proteasome degradation) to target the degradation of certain proteins may be useful as therapeutic agents.There is a need for compounds that can both target the target protein DOT1L and bind to E3 ubiquitin ligase, thereby inducing the degradation of the target protein DOT1L by proteasome. Summary of the Invention

[0005] Summary of the Invention The present disclosure stems from the recognition that a selected target protein (e.g., DOT1L) is associated with a particular disease (e.g., a proliferative disease, cancer). Based on this recognition, targeting a selected protein and using an E3 ubiquitin ligase binding moiety (e.g., lenalidomide, thalidomide) results in ubiquitination of the selected target protein DOT1L, thereby leading to its degradation by the proteasome. DOT1L has been found to be associated with certain pathological conditions, such as proliferative diseases and cancers (e.g., cancers associated with specific mutations (e.g., mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia, acute myeloid leukemia with a mutation in the nucleophosmin (NPM1) gene, acute myeloid leukemia with a mutation in the DNMT3A gene); or cancers resistant to proteasome inhibitors). Therefore, the present disclosure provides new compounds, compositions, and methods for treating various diseases (e.g., cancer) based on this finding. The present specification describes compounds of formula (I'). The compounds described herein include a component that is an E3 ubiquitin ligase binding moiety based on an immunomodulatory imide drug (e.g., lenalidomide, thalidomide), and a component that can bind to the target protein DOT1L and thus promote the degradation of DOT1L. The compounds can be useful for treating and / or preventing diseases or conditions associated with DOT1L, such as treating and / or preventing diseases (e.g., proliferative diseases (e.g., cancer)) in subjects in need thereof. Pharmaceutical compositions and kits containing the compounds described herein are also provided.

[0006] In one aspect, the present disclosure provides a compound of formula (I'): [ka] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof, wherein R 8 , R 9, R 10’ , R 11 , R 12 , R 13 , R 14 , W, Z, L and D1 are as defined herein. In certain embodiments, the compound of formula (I') is a compound of formula (I).

[0007] In one aspect, the present disclosure provides Formula (I): [ka] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof, wherein R 8 , R 9 , R 10 , R 11 , R 12 , L and D1 are as defined herein.

[0008] In formula (I'), D1 is an E3 ubiquitin ligase binding moiety. In certain embodiments, D1 is derived from an immunomodulatory imide drug. In certain embodiments, D1 is derived from lenalidomide. In certain embodiments, D1 is derived from thalidomide. In certain embodiments, D1 is an E3 ubiquitin ligase binding moiety, and D1 is of formula (IA) or (IB).

[0009] In certain embodiments, D1 is represented by formula (IA): [ka] wherein R 1A , R 3A , R 4A , R 5A , R 3’ , X A , a1, m and n are as defined herein.

[0010] In certain embodiments, D1 is represented by formula (IB): [ka] wherein R 1A , R 3A , R 4A , R 3’ , X 1 , X 2 , a1, m and n are as defined herein.

[0011] Exemplary compounds of formula (I') include, but are not limited to: [ka] [ka] [ka] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof.

[0012] Exemplary compounds of formula (I') include, but are not limited to: [ka] [ka] [ka] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof.

[0013] Exemplary compounds of formula (I') described herein include, but are not limited to: [ka] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof.

[0014] Exemplary compounds of formula (I') described herein include, but are not limited to, the compounds of Examples 1-5, as well as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, exemplary compounds of formula (I') described herein include, but are not limited to, the compounds of Examples 1 and 5.

[0015] In another aspect, this document describes pharmaceutical compositions comprising the compounds described herein and optionally pharmaceutically acceptable excipients.In some specific embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount or a prophylactically effective amount of the compounds described herein.The pharmaceutical compositions can be useful for inducing the degradation of DOT1L in a subject or biological sample, tissue or cell, treating a disease (for example, a proliferative disease) in a subject in need thereof, or preventing a disease in a subject in need thereof.In some specific embodiments, the compound administered or used induces the degradation of DOT1L in a subject, biological sample, tissue or cell, treating a disease (for example, a proliferative disease) in a subject in need thereof, or preventing a disease in a subject in need thereof.

[0016] In yet another aspect, the present specification describes a kit comprising a container with the compound or pharmaceutical composition described herein.The kit described herein can comprise a single dose of the compound or pharmaceutical composition or a multiple dose of the compound or pharmaceutical composition.The kit described herein can be useful for inducing the degradation of DOT1L.In some embodiments, the kit described herein further comprises instructions for using the compound or pharmaceutical composition contained in the kit.

[0017] In certain embodiments, the compound administered or used induces the degradation of DOT1L. Another aspect of the present disclosure relates to a method for treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In another aspect, the present disclosure provides a method for preventing a disease in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a compound or pharmaceutical composition described herein.

[0018] In another aspect, the disclosure provides compounds and pharmaceutical compositions described herein for use in the methods of the disclosure (e.g., methods of inducing degradation of DOT1L, methods of treating and / or preventing diseases (e.g., proliferative diseases)).

[0019] definition The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS Periodic Table of the Elements, inside cover of Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the list of exemplary substituents described herein.

[0020] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, such as racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, such as chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0021] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 ” is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5, C 3~4 , C 4~6 , C 4~5 and C 5~6 is intended to encompass the following:

[0022] The term "aliphatic" encompasses both saturated and unsaturated straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, optionally substituted with one or more functional groups. As will be recognized by those skilled in the art, "aliphatic" is intended herein to encompass, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" encompasses linear, branched, and cyclic alkyl groups. A similar rule applies to other generic terms, such as "alkenyl," "alkynyl," and the like. Furthermore, the terms "alkyl," "alkenyl," "alkynyl," and the like encompass both substituted and unsubstituted groups. In certain embodiments, "lower alkyl" is used to refer to alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 6 carbon atoms.

[0023] In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-6 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-4 carbon atoms. Thus, illustrative aliphatic groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH-cyclohexyl moieties, and the like, which may further bear one or more substituents. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

[0024] The term "alkyl" refers to a group of straight or branched saturated hydrocarbon groups having 1 to 10 carbon atoms ("C 1~10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1~6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, the alkyl group in each instance is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl"). In some particular embodiments, the alkyl group is an unsubstituted C 1~10 Alkyl (e.g., unsubstituted C 1~6 Alkyl, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1~10 Alkyl (e.g., substituted C 1~6alkyl, for example -CF3, Bn).

[0025] "Alkenyl" refers to a group of atoms of a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2~20 In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, the alkenyl group in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 In an alkenyl group, a C=C double bond with no specified stereochemical configuration (e.g., -CH=CHCH3 or [ka] ) may be an (E)-double bond or a (Z)-double bond.

[0026] "Alkynyl" refers to a group of straight or branched chain hydrocarbon groups having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2~20 In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., as in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, the alkynyl group at each occurrence is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0027] "Carbocyclyl" or "carbocyclic" refers to a group of atoms of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6 Examples include carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. As illustrated in the examples above, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclic ring; in such cases, the number of carbons is continued as the number of carbons in the carbocyclic ring system. Unless otherwise specified, the carbocyclyl group in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0028] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the aforementioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, the cycloalkyl group at each occurrence is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0029] "Heterocyclyl" or "heterocyclic" refers to a 3- to 10-membered non-aromatic ring system containing a carbon atom and one to four heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spirocyclic ring systems, e.g., bicyclic ring systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyls of bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclic ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being either on the carbocyclyl or on the heterocyclic ring, or a heterocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclic ring; in such cases, the number of ring members is continued by the number of ring members of the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0030] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having an annular carbon atom and 1-4 annular heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having an annular carbon atom and 1-4 annular heteroatoms, each of which is independently selected from nitrogen, oxygen, and sulfur (a "5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having an annular carbon atom and 1-4 annular heteroatoms, each of which is independently selected from nitrogen, oxygen, and sulfur (a "5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 annular heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0031] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Examples of 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Examples of 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0032] "Aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms, and zero heteroatoms in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also encompasses ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the bonding atom or point of attachment is on the aryl ring; in such cases, the number of carbon atoms is continued to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, the aryl group in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0033] "Aralkyl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, an aralkyl is an optionally substituted benzyl. In certain embodiments, an aralkyl is benzyl. In certain embodiments, an aralkyl is an optionally substituted phenethyl. In certain embodiments, an aralkyl is phenethyl.

[0034] "Heteroaryl" refers to a group of 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared within the cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, as long as valency allows. Heteroaryl of bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" encompasses ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members is followed by the number of ring members of the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or the heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can have the point of attachment on either ring, i.e., on the ring bearing the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl).

[0035] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, the heteroaryl group at each occurrence is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0036] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0037] "Heteroaralkyl" is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0038] "Unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. A "partially unsaturated" ring system is further intended to encompass rings with multiple sites of unsaturation, but is not intended to contain aromatic groups (e.g., aryl or heteroaryl groups). Similarly, "saturated" refers to a group that does not contain double or triple bonds, i.e., all bonds contained therein are single bonds.

[0039] The divalent bridging alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are further referred to with the suffix -ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

[0040] Unless explicitly stated otherwise, atoms, moieties, or groups described herein may be unsubstituted or substituted where valences allow. The term "optionally substituted" indicates substituted or unsubstituted.

[0041] Groups are optionally substituted unless expressly stated otherwise. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on a group (e.g., a carbon atom or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc., or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to encompass substitution with any acceptable substituent of an organic compound, any substituent described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations that result in stable compounds. For purposes of the present disclosure, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

[0042] Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(Raa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc )、C 1~10 アルキル、C 1~10 ペルハロアルキル、C 2~10 アルケニル、C2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 and aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X groups; - is a counterion; Alternatively, two geminal hydrogens on a carbon atom may be bonded to a group ═O, ═S, ═NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc has been replaced by; Each R aa The entity of C is independent. 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Each R bb The entities are independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bb groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X groups; - is the counterion; Each R cc The entities are independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Each R dd The entities are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff)2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may be joined to form =O or =S; X - is the counterion; Each R ee The entity of C is independent. 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; Each R ff The entities are independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; Each R gg The entities are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be joined to form =O or =S; X - is a counterion. In some embodiments, the optional substituents are halogen, —NO, —N, —SOH, —SOH, acyl (e.g., —C(═O)C 1~10 alkyl), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 Aryl, 5-14 membered heteroaryl, branched C 1~10 Alkyl, -OH, -O(C 1~10 alkyl), -O(C 2~10alkenyl), -O(C 2~10 alkynyl), acids (e.g., -COOH), esters (e.g., -COO(C 1~10 alkyl), amines (e.g., -NH, -NH(C 1~10 alkyl), -N(C 1~10 alkyl)2), substituted amines, amides (e.g., -C(=O)N(C 1~10 In some embodiments, the carbon atom is selected from the group consisting of halogen, -NO2, -N3, -SO2H, -SO3H, acyl (e.g., -C(=O)C 1~10 alkyl), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 Aryl, 5-14 membered heteroaryl, branched C 1~10 Alkyl, -OH, -O(C 1~10 alkyl), -O(C 2~10 alkenyl), -O(C 2~10 alkynyl), acids (e.g., -COOH), esters (e.g., -COO(C 1~10 alkyl), amines (e.g., -NH, -NH(C 1~10 alkyl), -N(C 1~10 alkyl)2), substituted amines, amides (e.g., -C(=O)N(C 1~10 In some embodiments, the carbon atom is optionally substituted with a halogen, an acyl (e.g., —C(═O)C 1~10 alkyl), C 1~10 Alkyl, branched C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 Aryl, 5-14 membered heteroaryl, -OH, -O(C 1~10 alkyl), -CN, -NO2, -N3, -SO2H or amines (e.g., -NH2, -NH(C 1~10 In some embodiments, the optional substituents are halogen, acyl (e.g., —C(═O)C 1~10 alkyl), C 1~10 Alkyl, branched C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 Aryl, 5-14 membered heteroaryl, -OH, -O(C 1~10 alkyl), -CN, -NO2, -N3, -SO2H or amines (e.g., -NH2, -NH(C 1~10 alkyl).

[0043] A "counterion" or "anion of a counterion" is a negatively charged group that associates with a positively charged group to maintain electroneutrality. The anion of a counterion can be monovalent (i.e., containing one formal negative charge). The anion of a counterion can also be multivalent (i.e., containing more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 -, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.) and carboranes.

[0044] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0045] "Acyl" is -C(=O)R aa , -CHO, -CO2R aa , -C(=O)N(Rbb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2, -C(=O)SR aa or -C(=S)SR aa where R aa and R bb is as defined herein.

[0046] Nitrogen atoms may be substituted or unsubstituted where valence allows, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as defined above.

[0047] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0048] For example, an amide group (e.g., —C(═O)R aaNitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide. In certain embodiments, the nitrogen protecting group is formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, or o-(benzoyloxymethyl)benzamide; or

[0049] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as, but not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluorenylmethylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trichloroethylcarbamate (Troc), 2-trichloroethylcarbamate (Troc), 2-trichloroethylcarbamate (Tm ... Methylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bume oc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio Carbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethicone Oxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutylcarbamate methyl 1-(4-pyridyl)ethyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0050] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide, sulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilyl. Azacyclopentane adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamines, N-allylamines, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline) n)-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylamine N-methylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinoamide (Dpp), dimethylthiophosphinoamide (Mpt), diphenylthiophosphinoamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0051] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc)2 and -P(=O)(N(R bb )2)2, where X - , R aa , R bb and R ccis as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, the oxygen protecting group is methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, ... Thiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl , 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-Dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl) ) methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl-t-hexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl or diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS).

[0052] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl, and the like. methyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl] [Chemical]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloro ethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl )methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylsilyl isopropylsilyl (DEIPS), dimethyl-t-hexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxy Acetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Ethyl trichlorocarbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0053] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb)2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where R aa , R bb and R cc is as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0054] As used herein, "leaving group" (LG) is an art-recognized term that refers to a molecular fragment that departs with an electron pair in a heterolytic bond cleavage, where the molecular fragment is an anion or a neutral molecule. As used herein, a leaving group can be an atom or group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry, 6th Edition (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb)2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2 and -OP(=O)(NR bb )2, where R aa , R bb and R cc are as defined herein).

[0055] "Hydrocarbon chain" refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. The hydrocarbon chain includes (1) one or more adjacent carbon atom chains between two atomic groups of the hydrocarbon chain; (2) optionally, one or more hydrogen atoms on the carbon atom chain(s); and (3) optionally, one or more substituents ("non-chain substituents" that are not hydrogen) on the carbon atom chain(s). The carbon atom chain consists of carbon atoms ("chain atoms") that are bonded consecutively and does not include hydrogen atoms or heteroatoms. However, the hydrocarbon chain of a non-chain substituent can include any atom, such as hydrogen atoms, carbon atoms, and heteroatoms. For example, the hydrocarbon chain -C A H(C B H2C C H3)- is one chain atom C A , C A One hydrogen atom and a non-chain substituent -(C B H2C C H3), where x is a positive integer. xThe term "hydrocarbon chain" refers to a hydrocarbon chain containing x atoms in the chain (or atoms) between two atomic groups of the hydrocarbon chain. If there is more than one possible value for x, the smallest possible value of x is used to define the hydrocarbon chain. For example, -CH(C2H5)- is a C1 hydrocarbon chain; [ka] is a C3 hydrocarbon chain. When a range of values ​​is used, the meaning of the range is as defined herein. For example, C 3~10 The hydrocarbon chain refers to a hydrocarbon chain in which the number of atoms in the shortest carbon atom chain adjacent between two atomic groups in the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. The hydrocarbon chain can be saturated (e.g., -(CH2)4-). The hydrocarbon chain can also be unsaturated and can contain one or more C=C bonds and / or C≡C bonds anywhere in the hydrocarbon chain. For example, -CH=CH-(CH2)2-, -CH2-C≡C-CH2-, and -C≡C-CH=CH- are all examples of unsubstituted unsaturated hydrocarbon chains. In certain embodiments, the hydrocarbon chain is unsubstituted (e.g., -C≡C- or -(CH2)4-). In certain embodiments, the hydrocarbon chain is substituted (e.g., -CH(C2H5)- and -CF2-). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl ring, for example: [ka] are all examples of hydrocarbon chains. In contrast, in some particular embodiments, [ka] is not included in the scope of hydrocarbon chains described herein. x When an intrachain atom of a hydrocarbon chain is replaced with a heteroatom, the resulting group is C x-1C, which is not a hydrocarbon chain but has atoms in the chain replaced with heteroatoms x These are called hydrocarbon chains. For example, [ka] is a C3 hydrocarbon chain in which one atom in the chain has been replaced by an oxygen atom.

[0056] The term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are reported in detail by Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4 Alkyl)4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0057] As used herein, use of the phrase "at least one instance" refers to 1, 2, 3, 4 or more instances, but also encompasses ranges such as 1-4, 1-3, 1-2, 2-4, 2-3 or 3-4 instances, inclusive.

[0058] A "non-hydrogen group" refers to any group defined for a particular variable that is not hydrogen.

[0059] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0060] Other definitions The following definitions are of more general terms used throughout this application.

[0061] The term "solvate" refers to a compound or its salt form that is associated with a solvent, usually through solvolysis. This physical association may include hydrogen bonding. Common solvents that can form solvates include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form, and solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both liquid-phase solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0062] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a constant ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form more than one type of hydrate, including monohydrates (x is 1), lower hydrates (x is a number greater than 0 but less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0063] The terms "tautomer" or "tautomeric" refer to two or more interconvertible compounds resulting from at least one formal shift of a hydrogen atom and at least one valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, such as temperature, solvent, and pH. Tautomerization (i.e., the reaction resulting in a tautomeric pair) can be catalyzed by acids or bases. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0064] It will also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0065] Stereoisomers that are not mirror images of one another are termed "diastereomers," and those that are not superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, as indicated by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0066] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0067] The term "prodrug" refers to a compound having a cleavable group that becomes a pharmaceutically active compound described herein upon solvolysis or under physiological conditions in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid-derivative forms, but the acid-labile forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant to the compounds described herein are specific prodrugs. In some cases, it may be desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C8 alkyl esters of the compounds described herein may be used. 12 Substituted aryl and C7-C 12Arylalkyl esters may be preferred. In certain embodiments, the prodrugs comprise (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C8 alkyl esters of the compounds described herein are also suitable. 12 Substituted aryl or C7-C 12 Arylalkyl esters. In certain embodiments, prodrugs include glycyl ester derivatives of the compounds described herein.

[0068] As used herein, the term "inhibit" or "inhibition" refers to a reduction in the level of a protein by promoting proteolysis in the context of enzymes, for example, in the context of an enzyme. Thus, a reduction in the level of a protein reduces the activity level of the protein. As used herein, the term "inhibit" or "inhibition" refers to a reduction in the level of proteasomal activity, for example, a reduction in the level of proteasomal degradation, for example, in the context of proteasomes. In some embodiments, this term refers to a reduction in the level of proteasomal activity to a level that is statistically significantly lower than the initial level, which may be, for example, the baseline level of proteasomal activity. In some embodiments, the term refers to a decrease in the level of proteasome activity to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may be, for example, a baseline level of proteasome activity.

[0069] When a compound, pharmaceutical composition, method, use, or kit is said to "selectively," "specifically," or "competitively" bind to or inhibit a target (e.g., an enzyme, an E3 ligase), the compound, pharmaceutical composition, method, use, or kit inhibits the target enzyme to a greater extent (e.g., 2-fold or more, 5-fold or more, 10-fold or more, 30-fold or more, 100-fold or more, 1,000-fold or more, or 10,000-fold or more; and / or: 2-fold or less, 5-fold or less, 10-fold or less, 30-fold or less, 100-fold or less, 1,000-fold or less, or 10,000-fold or less) than the binding or inhibition of a different target (e.g., an enzyme, DOT1L).

[0070] The terms "composition" and "formulation" are used interchangeably.

[0071] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially important mammal (e.g., a cattle, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially important bird, such as a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any stage of development. The non-human animal may be a transgenic or genetically engineered animal. A "patient" refers to a human subject in need of treatment for a disease. The subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a land plant without vascular tissue. In certain embodiments, the plant is a land plant with vascular tissue. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicotyledonous plant. In certain embodiments, the plant is a monocotyledonous plant. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, such as maize, corn, wheat, rice, oats, barley, rye, or millet. In some embodiments, the plant is a legume, such as a bean plant, for example, a soybean plant. In some embodiments, the plant is a tree or shrub.

[0072] The term "biological sample" refers to any sample, such as a tissue sample (e.g., tissue sections and tissue needle biopsy samples); a cell sample (e.g., a cytological smear (e.g., a Pap or blood smear) or a sample of cells obtained by microdissection); a sample of a whole organism (e.g., a yeast or bacterial sample); or a cell fraction, fragment, or organelle (e.g., obtained by lysing cells and separating their components by centrifugation, etc.). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swab (e.g., buccal swab), or any material containing biomolecules derived from a biological sample.

[0073] The term "tissue" refers to any biological tissue (e.g., a group of cells, a body part, or an organ) or part thereof, such as a blood vessel and / or a lymphatic vessel, of a subject to which the compounds, particles, and / or compositions of the present invention are delivered. The tissue may be an abnormal or unhealthy tissue that may require treatment. The tissue may also be a normal or healthy tissue that is at higher than normal risk of becoming abnormal or unhealthy and may require prevention. In certain embodiments, the tissue is the central nervous system. In certain embodiments, the tissue is the brain.

[0074] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing into a subject a compound described herein or a composition thereof.

[0075] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or preventing the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have appeared or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject before symptoms appear (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0076] The terms "condition," "disease," and "disorder" are used interchangeably.

[0077] The "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment amount. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the total amount of a compound described herein in multiple doses.

[0078] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapeutic agents, provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to bind to (and / or induce degradation of) a target (e.g., a protein (e.g., DOT1L)).

[0079] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a disease state or one or more signs or symptoms associated with the disease state, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease state. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient to bind to a target (e.g., a protein (e.g., DOT1L). In certain embodiments, a prophylactically effective amount is an amount sufficient to treat a disease (e.g., a proliferative disease (e.g., cancer)). In certain embodiments, a prophylactically effective amount is an amount sufficient to bind to a target (e.g., a protein (e.g., DOT1L) and / or induce degradation of the target (e.g., a protein (e.g., DOT1L)), and treat a disease (e.g., a proliferative disease (e.g., cancer)).

[0080] "Proliferative disease" refers to a disease caused by abnormal proliferation of cells or widespread cell growth (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with: 1) pathological proliferation of normal, dormant cells; 2) pathological migration of cells from their usual location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes, such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, as in proliferative retinopathies and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0081] The term "angiogenesis" refers to the physiological process by which new blood vessels are formed from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesodermally derived precursor cells. The first blood vessels in the developing embryo are formed by vasculogenesis, and angiogenesis is subsequently responsible for most vascular growth during normal and abnormal development. Angiogenesis is a vital process during growth and development, as well as during wound healing and granulation tissue formation. However, angiogenesis is also a critical first step in the transition of tumors from a benign to a malignant state, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis can be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). "Pathological angiogenesis" refers to aberrant (e.g., excessive or insufficient) angiogenesis that results in and / or is associated with disease.

[0082] The terms "neoplasm" and "tumor" are used interchangeably herein to refer to an abnormal tissue mass in which growth exceeds and is uncoordinated over that of normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (e.g., morphology and functionality), growth rate, local invasion, and metastasis. "Benign neoplasms" are generally well-differentiated, characteristically grow slower than malignant neoplasms, and remain localized at the site of appearance. Benign neoplasms also lack the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, soft fibromas, senile hemangiomas, seborrheic keratoses, lentigines, and sebaceous gland hyperplasia. In some cases, certain "benign" tumors can later give rise to malignant neoplasms, which may result from additional genetic alterations in a subpopulation of neoplastic cells in the tumor; such tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characteristically have rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasize" refer to the spread or migration of cancerous cells from a primary or initial tumor to another organ or tissue, typically identifiable by the presence of a "secondary tumor" or "secondary cell population" of the histological type of the primary or initial tumor, and that the "secondary tumor" or "secondary cell population" is not of the histological type of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is referred to as metastatic prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0083] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl, ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, hematopoietic malignancies. Further exemplary cancers include, but are not limited to, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma). ;bladder cancer;cancer of the breast (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast);cancer of the brain (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma);cancer of the bronchus;carcinoid tumor;cervical cancer (e.g., cervical adenocarcinoma);choriocarcinoma;chordoma;craniopharyngioma;colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma);cancer of connective tissue;epithelial carcinoma;ependymoma;endosarcoma tumors (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat Cancers (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); heavy chain diseases (e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immune cell amyloidosis; liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma;Myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancers (e.g., andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors); penile Cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., , malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovium; testicular cancer (e.g., seminoma, embryonal carcinoma of the testis); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0084] "Hematologic disorders" encompass diseases affecting hematopoietic cells or tissues. Hematologic disorders include disorders associated with abnormalities in hematologic cell content and / or function. Examples of hematologic disorders include diseases resulting from bone marrow irradiation or chemotherapy treatment for cancer, pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus, or other viruses, myelophthisic anemia caused by bone marrow defects, renal failure due to anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute nonlymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMLL), acute myelomonocytic leukemia (AML), acute myelomonocytic leukemia (AMLL), acute myelomonocytic leukemia (AC ... The blood disorders include, but are not limited to, erythrocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilms' tumor, Ewing's sarcoma, retinoblastoma, hemophilia, disorders associated with high risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as microangiopathic hemolytic anemia, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infection with parasites such as Plasmodium, chemical injury such as lead poisoning, and hypersplenism. In certain embodiments, the blood disorder is a hematopoietic malignancy. The term "hematopoietic malignancy" refers to a tumor affecting the blood, bone marrow, and / or lymph nodes.Exemplary hematopoietic malignancies include, but are not limited to, leukemias, such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL), and non-Hodgkin's lymphoma (HL). lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, central nervous system (CNS) lymphomas (e.g., primary CNS lymphoma and secondary CNS lymphoma); and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma, (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and aplastic large cell lymphoma); lymphomas of immune-privileged sites (e.g., lymphoma of the brain, lymphoma of the eye, lymphoma of the placenta, fetal lymphoma, testicular lymphoma); mixed leukemia / lymphoma of one or more of the above; myelodysplasia; and multiple myeloma (MM).

[0085] The term "small molecule" refers to a molecule having a relatively low molecular weight, whether naturally occurring or artificially created (e.g., by chemical synthesis). Typically, small molecules are organic compounds (i.e., contain carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocyclic rings, and the like). In certain embodiments, small molecules have a molecular weight of about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol but not more than about 500 g / mol) are also contemplated. In certain embodiments, the small molecule is a therapeutically active agent, e.g., a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as set forth in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule may also be referred to as an "organometallic small molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include but are not limited to radionuclides and imaging agents.In some particular embodiments, small molecules are drugs.Preferably, but not necessarily, drugs are already considered safe and effective for human or animal use by appropriate government or regulatory agencies.For example, drugs approved for human use are listed by the FDA under 21 CFR §§ 330.5, 331-361 and 440-460 (incorporated herein by reference); drugs for veterinary use are listed by the FDA under 21 CFR §§ 500-589 (incorporated herein by reference).

[0086] A "protein," "peptide," or "polypeptide" includes a polymer of amino acid residues linked together by peptide bonds. This term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein is at least three amino acids in length. A protein may refer to an individual protein or a collection of proteins. Proteins of the present invention preferably contain only natural amino acids, although unnatural amino acids (i.e., compounds that do not occur in nature but can be incorporated into polypeptide chains) and / or amino acid analogs, as known in the art, may alternatively be used. One or more amino acids within a protein may also be modified, for example, by chemical modifications such as sugar groups, hydroxyl groups, phosphate groups, farnesyl groups, isofarnesyl groups, fatty acid groups, the addition of linkers for conjugation or functionalization, or other modifications. A protein may be a single molecule or a multimolecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination thereof.

[0087] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, usually beneficial, effect. For example, a therapeutic agent is one that can treat, ameliorate, and / or prevent a disease. A therapeutic agent can be a biologic or a small molecule therapeutic agent, as disclosed herein.

[0088] The term "E3 ubiquitin ligase" or "E3 ligase" refers to any protein that recruits an E2 ubiquitin-conjugating enzyme that is loaded with ubiquitin, recognizes a protein substrate, and assists in or directly catalyzes the transfer of ubiquitin from the E2 protein to the protein substrate. For E3 ubiquitin ligases, exemplary sequences in GenBank: ACH72645.1 (Homo sapiens) include: mesggrpslc qfillgttsv vtaalysvyr qkarvsqelk gakkvhlged lksilseapg kcvpyavieg avrsvketln sqfvenckgv iqrltlqehk mvwnrtthlw ndcskiihqr tntvpfdlvp hedgvdvavr vlkpldsvdl gletvyekfh psiqsftdvi ghyisgerpk giqeteemlk vgatltgvge lvldnnsvrl qppkqgmqyy lssqdfdsll qrqessvrlw kvlalvfgfa tcatlffilr kqylqrqerl rlkqmqeefq Examples include eheaqllsra kpedreslks acvvclssfk scvflecghv csctecyral pepkkcpicr qaitrvippy ns (SEQ ID NO: 1). For E3 ubiquitin ligases, exemplary sequences in GenBank: AAP47175.1 (Homo sapiens) include: meegnnneev ihlnnfhchr gqewinlrdg pitisdssde eripmlvtpa pqqheeedld ddviltetnk pqrsrpnlik paaqwqdlkr lgeerpkksr aafesdkssy fsvcnnplfd sgaqddsedd ygefldlgpp giseftkpsg qterepkpgp shnqaandiv nprseqkvii leegsllyte sdpletqnqs sedsetells nlgesaalad dqaieedcwl dhpyfqslnq qpreitnqvv pqerqpeael grllfqhefp gpafprpepq qggisgpssp qpahplgefe dqqlasddee pgpafpmqesqepnleniwg qeaaevdqel vellvketea rfpdvangfi eeiihfknyy dlnvlcnfll enpdypkred riiinpsssl lasqdetklp kidffdyskl tpldqrcfiq aadllmadfk vlssqdikwa lhelkghyai trkalsdaik kwqelspets gkrkkrkqmn qysyidfkfe qgdikiekrm flenkrrhc rsydrrallp avqqeqefye qkikemaehe dfllalqmne eqyqkdgqli ecrccygefp feeltqcada hlfckeclir yaqeavfgsg klelscmegs ctcsfptsel ekvlpqtily kyyerkaeee vaaayadelv rcpscsfpal Examples include ldsdvkrfsc pnphcrketc rkcqglwkeh ngltceelae kddikyrtsi eekmtaarir kchkcgtgli ksegcnrmsc rcgaqmcylc rvsingydhf cqhprspgap cqecsrcslw tdpteddekl ieeiqkeaee eqkrkngent fkrigpplek pvekvqrvea lprpvpqnlp qpqmppyafa hppfplppvr pvfnnfplnm gpipapyvpp lpnvrvnydf gpihmplehn lpmhfgpqpr hrf (SEQ ID NO: 2). For E3 ubiquitin ligases, exemplary sequences in GenBank: AAP47174.1 (Homo sapiens) include: meegnnneev ihlnnfhchr gqewinlrdg pitisdssde eripmlvtpa pqqheeedld ddviltedds eddygefldl gppgiseftk psgqterepk pgpshnqaan divnprseqk viileegsll ytesdpletq nqssedsete llsnlgesaa laddqaieed cwldhpyfqs lnqqpreitn qvvpqerqpe aelgrllfqh efpgpafprp epqqggisgp sspqpahplgefedqqlasd deepgpafpm qesqepnlen iwgqeaaevd qelvellvke tearfpdvan gfieeiihfk nyydlnvlcn fllenpdypk redriiinps ssllasqdet klpkidffdy skltpldqrc fiqaadllma dfkvlssqdi kwalhelkgh yaitrkalsd aikkwqelsp etsgkrkkrk qmnqysyidf kfeqgdikie krmfflenkr rhcrsydrra llpavqqeqe fyeqkikema ehedfllalq mneeqyqkdg qliecrccyg efpfeeltqc adahlfckec liryaqeavf gsgklelscm egsctcsfpt selekvlpqt ilykyyerka eeevaaayad Examples include elvrcpscsf palldsdvkr fscpnphcrk etcrkcqglw kehngltcee laekddikyr tsieekmtaa rirkchkcgt gliksegcnr mscrcgaqmc ylcrvsingy dhfcqhprsp gapcqecsrc slwtdptedd eklieeiqke aeeeqkrkng entfkrigpp lekpvekvqr vealprpvpq nlpqpqmppy afahppfplp pvrpvfnnfp lnmgpipapy vpplpnvrvn ydfgpihmpl ehnlpmhfgp qprhrf (SEQ ID NO: 3).

[0089] The term "binder" refers to a compound that binds to a protein. A binder binds to a protein with a K of less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d Combine with.

[0090] The term "proteasome" refers to a multi-subunit enzyme complex that plays a key role in regulating proteins that control cell cycle progression and apoptosis. The proteasome carries out the proteolysis of selected proteins.

[0091] The term "DOT1L" or "Disruptor of telomeric silencing 1-like histone H3K79 methyltransferase" refers to the enzyme encoded by the DOT1L gene. DOT1L is a histone methyltransferase that methylates lysine-79 of histone H3. DOT1L is inactive on free core histones but exhibits significant histone methyltransferase activity on nucleosomes. [Brief explanation of the drawings]

[0092] [Figure 1] FIG. 1 shows CRBN-induced degradation of targeted proteins, which involves ubiquitination of the protein followed by degradation by the proteasome. [Figure 2]2A-2C show the degradation of DOT1L using an exemplary DOT1L degrader compound. FIG. 2A shows a crystal structure of the interaction between a DOT1L protein and an exemplary DOT1L degrader compound. FIG. 2B shows a closer view of the crystal structure of the interaction between a DOT1L protein and an exemplary DOT1L degrader compound. FIG. 2C shows a detailed description of the parts of an exemplary DOT1L degrader compound. [Figure 3] Figure 3 shows the design principles behind exemplary CRBN-based DOT1L degrader compounds. [Figure 4] Figures 4A-4F show exemplary DOT1L degrader compounds. Figure 4A shows an exemplary DOT1L degrader compound (dDOT1L-1). Figure 4B shows an exemplary DOT1L degrader compound (dDOT1L-2). Figure 4C shows an exemplary biotinylated probe compound (dDOT1L-3). Figure 4D shows an exemplary DOT1L degrader compound (dDOT1L-4). Figure 4E shows an exemplary DOT1L degrader compound (dDOT1L-5). Figure 4F shows an exemplary DOT1L degrader compound. [Figure 5] Figure 5 shows the DOT1L fluorescence polarization (FP) shift assay of exemplary DOT1L degrader compounds, inhibitor derivatives, and negative and positive control compounds tested at different concentrations [M] (measured by mP [M]). The compounds tested include exemplary DOT1L degrader compounds DOT1L-1, DOT1L-2, DOT1L-4, DOT1L-5, DOT1L-6, DOT1L-7, an inhibitor derivative (DOT1L-11), negative control compounds EPZ4777, EPZ5676, and CC006, and a positive control, lenalidomide. Compounds EPZ4777, EPZ5676, and CC006 have the structures shown below: [ka] (EPZ4777); [ka] (EPZ5676); and [ka] (CC006). This is another exemplary negative control compound: [ka] [Figure 6] 6 shows CRBN binding assays of exemplary DOT1L degrader compounds, inhibitor derivatives, and positive control compounds at different concentrations [M] (expressed relative to mP [M]). The compounds include exemplary DOT1L degrader compounds DOT1L-1, DOT1L-2, DOT1L-4, DOT1L-5, DOT1L-6, and DOT1L-7; an inhibitor derivative (DOT1L-11); and the positive control lenalidomide. [Figure 7] FIG. 7 shows a docking model of the interaction between an exemplary DOT1L degrader compound and DOT1L protein with CRBN protein. [Figure 8] 8 shows a 6-hour IKZF-GFP degradation assay of exemplary DOT1L degrader compounds, inhibitor derivatives, negative control compounds, and positive control compounds at different concentrations [M], expressed as compound concentration relative to normalized levels. These exemplary compounds include exemplary DOT1L degrader compounds DOT1L-1, DOT1L-2, DOT1L-4, DOT1L-5, DOT1L-6, and DOT1L-7; inhibitor derivative DOT1L-11; negative control compounds EPZ4777, EPZ5676, and CC006; and positive control lenalidomide. [Figure 9]Figures 9A-9B show acute myeloid leukemia cells (Molm13 PA) treated with the indicated concentrations of DOT1L-1 for the indicated amounts of time. Cells were immunoblotted with DOT1L(D402T), actin, and H3K79me2. Figure 9A shows cells treated with the indicated concentrations of DOT1L-1 (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24 and 48 hours). Figure 9B shows repeated treatments in which cells were treated with the indicated concentrations of DOT1L-1 (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24, 48, and 72 hours). [Figure 10] Figures 10A-10B show murine MLL-AF9 PA (mixed lineage leukemia (MLL)-AF9 leukemia) cells treated with the indicated concentrations of DOT1L-1 for the indicated amounts of time. Cells were immunoblotted with DOT1L(D402T), actin, and H3K79me2. Figure 10A shows experiment 1, in which cells were treated with the indicated concentrations of DOT1L-1 (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24 hours, 48 ​​hours, and 72 hours). Figure 10B shows experiment 2, in which cells were treated with the indicated concentrations of DOT1L-1 (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24 hours and 48 hours). [Figure 11] Figure 11 shows Molm13 PA cells treated with DOT1L-4 at the indicated concentrations (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24 h, 48 h, and 72 h). Cells were immunoblotted with DOT1L(D402T), actin, and H3K79me2. These cells demonstrate DOT1L degradation. [Figure 12]Figures 12A-12E show the relative cell proliferation (%) of acute myeloid leukemia cells as demonstrated by treatment of Molm13 PA cells, Molm13 RE cells, and HL60 (as a negative control) cells with various concentrations of exemplary thalidomide-based DOT1L degrader compounds for 10 days. Figure 12A shows the results for cells treated with the exemplary DOT1L degrader DOT1L-1. Figure 12B shows the results for cells treated with the exemplary DOT1L degrader DOT1L-2. Figure 12C shows the results for cells treated with the exemplary DOT1L degrader DOT1L-4. Figure 12D shows the results for cells treated with the exemplary DOT1L degrader DOT1L-5. Figure 12E shows the results for cells treated with the negative control compound EPZ5676. [Figure 13] Figure 13 shows the MLL-rearranged leukemia (mixed lineage leukemia-rearranged leukemia) gene. MLL-rearranged leukemia accounts for 10% of adult leukemias and 70% of infant leukemias. The prognosis is generally poor, and MLL patients often suffer early relapse after treatment with currently used therapies. Rearrangement of the MLL gene, located at 11q23, is a common chromosomal abnormality associated with acute leukemia. [Figure 14] Figure 14A shows wild-type MLL (mixed lineage leukemia) containing a SET domain histone methyltransferase at its C-terminus that catalyzes methylation at lysine 4 of histone 3 (H3K4). Figure 14B shows MLL-rearranged forms with the C-terminal portion replaced by over 70 known fusion patterns, e.g., AF4, AF9, AF6, AF10, ELL, ENL, etc. Such fusion partners recruit DOT1L, which methylates lysine 79 of histone 3 (H3K79). H3K79me2 is a mark associated with active transcriptional elongation. [Figure 15] FIG. 15 shows that DOT1L promotes MLL-r (mixed lineage leukemia-rearranged) leukemia through aberrant H3K79 methylation, which leads to inappropriately increased expression of genes critical for hematopoietic differentiation and leukemogenesis. [Figure 16]Figures 16A-16C show exemplary first-round degraders. Figure 16A shows exemplary linker lengths for exemplary first-round degraders. Figure 16B shows exemplary linker positions on the CRBN-binding side of first-round degraders. Figure 16C shows exemplary degraders with PEG linkers and exemplary degraders with alkyl linkers. [Figure 17] Figures 17A-17D show exemplary DOT1L degraders with different combinations of PEG or alkyl groups, various linker lengths, and linker positions on the CRBN binding site in iMiD. Figure 17A shows exemplary DOT1L degraders with alkyl linkers and PEG linkers, respectively. Figure 17B shows exemplary DOT1L degraders, including one with a linker length of 11. Figure 17C shows exemplary DOT1L degraders with different linker positions on the CRBN binding site. Figure 17D shows exemplary DOT1L degrader JQ-DD6. [Figure 18] Figure 18 shows a DOT1L fluorescence polarization (FP) shift assay of exemplary DOT1L degrader compounds and control compounds tested at different concentrations [M] (measured by mP [M]). Tested compounds include exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JD-DD4, JD-DD5, and JD-DD6, as well as the positive control thalidomide and the negative control EPZ5676. These exemplary compounds demonstrate binding to DOT1L and CRBN, respectively. [Figure 19] 19 shows CRBN binding assays of exemplary DOT1L degrader compounds, negative control compounds, and positive control compounds at different concentrations [M] (expressed relative to mP [M]). The compounds include exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5; JQ-DD6; as well as the positive control thalidomide and the negative control EPZ5676. [Figure 20]Figure 20 shows a biochemical assay to examine the dimerization of CRBN with DOT1L induced by degraders. This new assay examines whether exemplary compounds can induce the dimerization of CRBN and DOT1L under the conditions set by the biochemical assay. Figure 20 shows that exemplary compounds can simultaneously bind to both proteins. JQ-DD6 produced the strongest signal, indicating that it dimerized the proteins very well. JQ-DD6 also performed very well in these cells. [Figure 21] Figure 21 shows EOL1 cells treated with exemplary DOT1L degrader compounds JQ-DD6, JQ-DD7, and JQ-DD8 at the indicated concentrations for 24 hours and immunoblotted for DOT1L, Myc, H3K79me2, and actin. EOL1 (an acute myeloid (eosinophilic) leukemia cell line) has the highest DOT1L levels among all cell lines, and JQ-DD6 demonstrated robust degradation. JQ-DD7 and JQ-DD8 also demonstrated degradation in the EOL1 cell line. JQ-DD8 demonstrated potential toxicity at 24 hours in EOL1. [Figure 22] Figure 22 shows EOL1 cells treated with exemplary DOT1L degrader compounds JQ-DD2, JQ-DD4, JQ-DD6, JQ-DD7, and JQ-DD8 at the indicated concentrations for 48 hours and immunoblotted with DOT1L, H3K79me2, Myc, actin, and H3. [Figure 23] Figure 23 shows EOL1 cells treated with exemplary DOT1L degrader compounds JQ-DD2, JQ-DD4, JQ-DD6, JQ-DD7, and JQ-DD8 at the indicated concentrations for the indicated times and immunoblotted with DOT1L, Myc, H3K79me2, and actin. This shows the time course of DOT1L degradation. For JQ-DD6, this degradation occurred at 16 hours. Maximum degradation occurred at 24 hours. [Figure 24]Figure 24 shows EOL1 cells treated with exemplary DOT1L degrader compounds JQ-DD6, JQ-DD7, and JQ-DD8 at the indicated concentrations for the indicated times and immunoblotted with DOT1L, Myc, H3K79me2, and actin. The structures of compounds JQ-DD6 (JQDD6), JQ-DD7 (JQDD7), and JQ-DD8 (JQDD8) are shown in Table 1 below. Figure 24 shows the time course of DOT1L degradation. Treatment with JQ-DD6 demonstrates degradation. Treatment with JQ-DD7 and JQ-DD8 also demonstrates degradation in the EOL1 cell line. Treatment with JQ-DD8 demonstrates potential toxicity at 24 hours in EOL1. [Figure 25] Figure 25 shows the development of a DOT1L degradation reporting cell line using DOT1L-tagged GFP and mcherry, which can directly report targeted protein degradation (see Sievers et al., Science, 2018). [Figure 26] Figure 26 shows DOT1L degradation using the eGFP-mCherry reporting cell line assay for tested exemplary DOT1L degrader compounds, as well as negative and positive control compounds, at different concentrations [M] (measured by mP [M]) after 24 hours of treatment as indicated. Tested compounds include exemplary DOT1L degrader compounds JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, JQ-DD7, and JQ-DD8, negative control EPZ5676, and positive controls thalidomide and lenalidomide. The eGFP-mCherry reporting cell line was able to report sufficient degradation within 24 hours. The exemplary compound JQ-DD6 showed the strongest signal for DOT1L degradation. [Figure 27]Figure 27 shows IKZF degradation using the eGFP-mCherry report cell line assay for exemplary DOT1L degrader compounds tested at different concentrations [M] (measured by mP [M]) over 24 hours of treatment as indicated. Tested compounds include exemplary DOT1L degrader compounds JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, JQ-DD7, and JQ-DD8, as well as the negative control EPZ5676 and the positive controls thalidomide and lenalidomide. Exemplary DOT1L degrader compounds also degrade IKZF1, a neo-substrate, when immunomodulatory imide drugs (IMiDs) bind to CRBN. [Figure 28] Figures 28A-28B show the antiproliferative effects of tested DOT1L degraders in MOLM13 and THP1 MLL-rearranged leukemia cell lines. Figure 28A shows a 7-day treatment assay of MOLM13 with different concentrations [M] (measured by mP [M]) of tested exemplary DOT1L degrader compounds and a positive control compound. Tested compounds include exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, and JQ-DD7, the negative control EPZ5676, and the positive control thalidomide. Figure 28B shows a 7-day treatment assay of THP1 (human monocytic leukemia cells) with different concentrations [M] (measured by mP [M]) of tested exemplary DOT1L degrader compounds and a positive control compound. The compounds tested include exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, and JQ-DD7, the negative control EPZ5676, and the positive control thalidomide. The exemplary DOT1L degrader compounds generally exhibit better antiproliferative effects than the inhibitor EPZ5676. The exemplary DOT1L degrader compounds exhibit better antiproliferative effects in cell lines that are DOT1L-dependent but unresponsive to inhibitors. Figures 28A-28B show that DOT1L is eliminated. [Figure 29]Figures 29A-29B show the antiproliferative effects of exemplary DOT1L degraders compared to inhibitors and iMiDs in different cell lines. Figure 29A shows a 7-day treatment assay with NOMO1 (a cancer cell line) of tested exemplary DOT1L degrader compounds, inhibitors, and positive control iMiD compounds at different concentrations [M] (measured as mP [M]), as well as the percentage of viable cells after treatment for the indicated amount of time. Tested compounds include exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, and JQ-DD7, the negative control EPZ5676, and the positive control thalidomide. Figure 29B shows cell proliferation assays in the EOL1 cell line for exemplary DOT1L degrader compounds, inhibitors, and positive control iMiD compounds tested at different concentrations [M] (measured by mP [M]), as well as the percentage of viable cells after treatment for the indicated amount of time. Tested compounds include exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3(old), JQ-DD3(new), JQ-DD4, JQ-DD5, and JQ-DD6, negative control EPZ5676, positive control thalidomide, and control PCK82. [Figure 30] Figures 30A-30E show the percentage (%) of viable cells (in the indicated cancer cell lines) in EOL1 cells, NOMO1 cells, MOLM13 cells, MOLM14 (human acute myeloid leukemia cells), and MOLM14 crbnKO cells following 3-day treatment with various concentrations of exemplary DOT1L degraders JQ-DD6, EPZ5676, and thalidomide. Figure 30A shows results for EOL1 cells. Figure 30B shows results for NOMO1 cells. Figure 30C shows results for MOLM13 cells. Figure 30D shows results for MOLM14 cells. Figure 30E shows results for MOLM14 crbnKO (CRBN knockout) cells. [Figure 31]Figures 31A-31E show the percentage of viable acute myeloid leukemia cells in EOL1, NOMO1, MOLM13, MOLM14, and MOLM14 crbnKO cells following 7-day treatment with various concentrations of exemplary DOT1L degraders JQ-DD6, EPZ5676, and thalidomide. Figure 31A shows results for EOL1 cells. Figure 31B shows results for NOMO1 cells. Figure 31C shows results for MOLM13 cells. Figure 31D shows results for MOLM14 cells. Figure 31E shows results for MOLM14 crbnKO cells. DETAILED DESCRIPTION OF THE INVENTION

[0093] Detailed Description of Some Specific Embodiments of the Invention The bifunctional compounds described herein interact with E3 ubiquitin ligase and the target protein DOT1L. As described herein, without wishing to be bound by any particular theory, the therapeutic effect may be the result of the degradation, modulation, or binding of the E3 ubiquitin ligase (e.g., cereblon) and the target protein DOT1L by the compounds described herein. For example, the therapeutic effect may be the result of the recruitment of the E3 ubiquitin ligase (e.g., cereblon) by modulation, targeting, binding, or modification of the E3 ubiquitin ligase, thereby inducing the ubiquitination of the target protein DOT1L and subsequent degradation by the proteasome. In certain embodiments, the therapeutic effect is brought about by the binding or modification of the E3 ubiquitin ligase, thereby inducing the ubiquitination of the target protein DOT1L and subsequent degradation of DOT1L.

[0094] A compound for use in any composition, kit or method described herein may be provided as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof.

[0095] In certain embodiments, the E3 ubiquitin ligase binding portion of the bifunctional compound of Formula (I') is an E3 ubiquitin ligase binding portion of a bifunctional compound described in U.S. patent application Ser. Nos. 15 / 148,253, filed May 6, 2016, 14 / 707,930, filed May 8, 2015, 62 / 096,318, filed December 23, 2014, 62 / 128,457, filed March 4, 2015, and 62 / 149,170, filed April 17, 2015, each of which is incorporated herein by reference (an immunomodulatory imide-based drug (e.g., a derivative of lenalidomide or thalidomide or lenalidomide-based).

[0096] In one embodiment, a compound of formula (I'): [ka] During the ceremony: R 8 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 9 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 10’ is hydrogen, optionally substituted alkyl, or -N(R 10A )2; Each R 10A are independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 11 is halogen or optionally substituted alkyl; Each R 12 are independently hydrogen or oxygen protecting groups; R 13 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Each R 14 are independently hydrogen, halogen, or optionally substituted alkyl; or optionally, R 14 One of the entities in R 10’one of the entities taken together with the intervening atoms forms a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; or optionally, R 14 One of the entities in R 10A one of the entities taken together with the intervening atoms forms a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; Or optionally, [ka] The part [ka] and; W is an optionally substituted -CH2- or -N(R W )-, where R W is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Z is -(optionally substituted carbocyclyl)- or optionally substituted -CH-; L is a linker; D1 is the E3 ubiquitin ligase binding moiety, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0097] In certain embodiments, for compounds of formula (I'): R 8 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 9 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 10’ is hydrogen, optionally substituted alkyl, or —N(R 10A )2; Each R 10Aare independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 11 is halogen or optionally substituted alkyl; Each R 12 are independently hydrogen or oxygen protecting groups; R 13 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Each R 14 are independently hydrogen, halogen, or optionally substituted alkyl; or optionally, R 14 One of the entities in R 10A one of the entities taken together with the intervening atoms forms a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; Or optionally, [ka] The part [ka] and; W is -CH2- or -N(R W )-, where R W is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Z is -(optionally substituted carbocyclyl)- or -CH2-; L is a linker; D1 is the E3 ubiquitin ligase binding site.

[0098] In certain embodiments, the compound of formula (I') is a compound of formula (I).

[0099] In one embodiment, a compound of formula (I): [ka] During the ceremony: R8 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 9 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 10 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R 11 is halogen or optionally substituted alkyl; Each R 12 are independently hydrogen or oxygen protecting groups; L is a linker; D1 is the E3 ubiquitin ligase binding moiety, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0100] D group In certain embodiments, D1 is an E3 ubiquitin ligase binding moiety. D1 encompasses any moiety that binds or can bind to any E3 ubiquitin ligase. For example, in certain embodiments, D1 is capable of binding to an E3 ubiquitin ligase, such as cereblon. In certain embodiments, D1 is capable of binding to multiple different E3 ubiquitin ligases. In certain embodiments, D1 binds to cereblon. In certain embodiments, D1 is based on an immunomodulatory imide drug. In certain embodiments, D1 is derived from lenalidomide. In certain embodiments, D1 is derived from thalidomide.

[0101] Human cereblon (CRBN) is a 442-amino acid protein with an apparent molecular weight of approximately 51 kDa (GenBank: AAH17419). (For the CRBN protein sequence, see Higgins et al., Neurology. 2004, 63, 1927–31. For further information on the CRBN structure, see Hartmann et al., PLoS One. 2015, 10, e0128342.) Human CRBN contains the N-terminal portion (237 amino acids from 81 to 317) of the ATP-dependent Lon protease domain, lacking the conserved Walker A and Walker B motifs, 11 casein kinase II phosphorylation sites, 4 protein kinase C phosphorylation sites, 1 N-linked glycosylation site, and 2 myristoylation sites. CRBN is widely expressed in the testis, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocytes, colon, brain, and retina. CRBN is also present in the cytoplasm, nucleus, and superficial membranes. (Chang et al., Int. J. Biochem. Mol. Biol. 2011, 2, 287-94)

[0102] Cereblon is an E3 ubiquitin ligase that forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex also ubiquitinates several other proteins. Through a mechanism that is not fully understood, cereblon-mediated ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 further regulates several developmental processes, such as limb and otic vesicle formation.

[0103] In certain embodiments, D1 is a modulator, binder, inhibitor, or ligand of cereblon. In certain embodiments, D1 is a modulator of cereblon. In certain embodiments, D1 is a binder of cereblon. In certain embodiments, D1 is an inhibitor of cereblon. In certain embodiments, D1 is a ligand of cereblon. In certain embodiments, D1 is any modulator, binder, inhibitor, or ligand of cereblon disclosed in U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, U.S. Patent Application No. 14 / 707,930, filed May 8, 2015, and International Patent Application No. PCT / US2013 / 054663, filed August 13, 2013 (each of which is incorporated herein by reference). In certain embodiments, D1 is a modulator, binder, inhibitor, or ligand of a cereblon variant. In certain embodiments, D1 is a modulator, binder, inhibitor, or ligand of a cereblon isoform.

[0104] In certain embodiments, D1 comprises a heteroaryl ring. In certain embodiments, D1 comprises a fused bicyclic heteroaryl ring. In certain embodiments, D1 comprises a fused bicyclic heteroaryl ring and a heterocyclic ring. In certain embodiments, D1 comprises a fused bicyclic heteroaryl ring and a heterocyclic ring, wherein the heterocyclic ring comprises at least one nitrogen. In certain embodiments, D1 comprises a fused bicyclic heteroaryl ring and a heterocyclic ring, wherein the fused bicyclic heteroaryl ring and the heterocyclic ring each comprise at least one nitrogen. In certain embodiments, D1 comprises a fused bicyclic heteroaryl ring and a heterocyclic ring, wherein the fused bicyclic heteroaryl ring and the heterocyclic ring each comprise one nitrogen. In certain embodiments, D1 comprises a phthalimido group or an analog or derivative thereof. In certain embodiments, D1 comprises a phthalimido-glutarimido group or an analog or derivative thereof.

[0105] In certain embodiments, D1 is represented by the formula (EI): [ka] It is of During the ceremony: Ring A is a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; Each R 1A are independently halogen, —OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3’ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl; m is 0, 1, 2 or 3; n is 1 or 2.

[0106] In certain embodiments, Formula (EI) is derived from an immunomodulatory imide drug (e.g., derived from lenalidomide or thalidomide). In certain embodiments, Formula (EI) is of Formula (IA) or Formula (IB).

[0107] In certain embodiments, D1 is represented by formula (IA): [ka] It is of During the ceremony: X A is C(O) or C(R 3A )2; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; R 3A is H or C1-C3 alkyl; Each R 3’ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl or halogen; m is 0, 1, 2 or 3; n is 0, 1 or 2; a1 is 0 or 1.

[0108] In certain embodiments, D1 is represented by formula (IA-a): [ka] It is of During the ceremony: X A is C(O) or C(R 3A )2; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl; m is 0, 1, 2 or 3.

[0109] In certain embodiments, D1 is represented by formula (IA-b): [ka] It is of During the ceremony: X A is C(O) or C(R 3A )2; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl.

[0110] In certain embodiments, D1 is selected from the group consisting of formula (IA-c): [ka] It is of During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl.

[0111] In certain embodiments, D1 is represented by formula (IA-d): [ka] It is of During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4Atogether with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl.

[0112] In certain embodiments, D1 is represented by formula (IB): [ka] It is of During the ceremony: -X 1 -X 2 - is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; R 3A is H or C1-C3 alkyl; Each R 3’ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl or halogen; m is 0, 1, 2 or 3; n is 0, 1 or 2; a1 is 0 or 1.

[0113] In certain embodiments, D1 is represented by formula (IB-a): [ka] It is of During the ceremony: X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R 1A are independently halogen, —OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl; m is 0, 1, 2 or 3.

[0114] In certain embodiments, D1 is represented by formula (IB-b): [ka] It is of During the ceremony: X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl.

[0115] In certain embodiments, D1 is represented by formula (IB-c): [ka] It is of During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R 5A is H, C1-C3 alkyl, F or Cl.

[0116] Formulas (IA), (IA-a) and (IA-b) are defined as follows: A In certain embodiments, X A is C(O). In certain embodiments, X A is C(R 3A )2.

[0117] Formulas (IB), (IB-a) and (IB-b) are each a substituent -X 1 -X 2 In certain embodiments, -X 1 -X 2 - is C(R 3A )=N. In certain embodiments, -X 1 -X 2 - is C(H)=N. In certain embodiments, -X 1 -X 2 - is C(C1-C3 alkyl)=N. In certain embodiments, -X 1 -X 2 - is C(R 3A )2-C(R 3A )2. In certain embodiments, -X 1 -X 2 - is C(H)2-C(H)2. In certain embodiments, -X 1 -X2 - is C(H)2-C(C1-C3 alkyl)2. In certain embodiments, -X 1 -X 2 - is C(H)2-C(C1-C3 alkyl)2. In certain embodiments, -X 1 -X 2 - is C(C1-C3 alkyl)2-C(H)2-. In certain embodiments, -X 1 -X 2 - is C(C1-C3 alkyl)2-C(C1-C3 alkyl)2.

[0118] In formulas (IB), (IB-a) and (IB-b), in some particular embodiments, [ka] The part [ka] In some particular embodiments, [ka] The part [ka] In some particular embodiments, [ka] The part [ka] In some particular embodiments, [ka] The part [ka] In some particular embodiments, [ka] The part [ka] In some particular embodiments, [ka] The part [ka] In some particular embodiments, [ka] The part [ka] Alkyl In some particular embodiments, [ka] The part [ka] is.

[0119] Formula (EI) includes ring A. In certain embodiments, ring A is a substituted or unsubstituted heterocyclyl ring. In certain embodiments, ring A is a substituted or unsubstituted heterocyclyl ring, which is a 3-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, ring A is a substituted or unsubstituted heteroaryl ring. In certain embodiments, ring A is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom, wherein the aromatic ring system has 1-4 ring heteroatoms, each of which is independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, ring A is a substituted or unsubstituted heterocyclyl ring, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom, wherein the aromatic ring system has 1-4 ring heteroatoms, each of which is independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, ring A is a substituted or unsubstituted pyrrolidin-2-one. In certain embodiments, ring A is a substituted or unsubstituted pyrrolidine-2,5-dione. In certain embodiments, Ring A is a substituted or unsubstituted 5,6-dihydropyrimidin-4(3H)-one. In certain embodiments, Ring A is a substituted or unsubstituted tetrahydropyrimidin-4(1H)-one.

[0120] Formulas (EI), (IA-a), (IA), (IB) and (IB-a) are each a substituent R 1A In certain embodiments, R 1A is independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy. 1A At least one of the entities is a halogen (e.g., F, Cl, Br, or I). In certain embodiments, R 1A At least one of the entities is OH. In certain embodiments, R 1A At least one of the entities is C1-C6 alkyl (e.g., methyl, ethyl). 1AIn certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.

[0121] Formulas (EI), (IA), (IB), (IB-a) and (IB-b) are defined as groups each containing a substituent R 3A In certain embodiments, R 3A is H. In certain embodiments, R 3A is C1-C3 alkyl (e.g., methyl, ethyl). In certain embodiments, R 3’ At least one of the entities is C1-C3 alkyl (e.g., methyl, ethyl). 3’ At least one of the entities is methyl. In certain embodiments, R 3’ In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0122] Formulas (EI), (IA-a), (IA-b), (IA-c), (IA-d), (IA), (IB), (IB-a), (IB-b) and (IB-c) are defined as groups each containing a substituent R 5A In certain embodiments, R 5A is H. In certain embodiments, R 5A is deuterium. In certain embodiments, R 5A is C1-C3 alkyl. In certain embodiments, R 5A is a halogen (e.g., F, Cl, Br, or I).

[0123] In certain embodiments, a1 is 0. In certain embodiments, a1 is 1.

[0124] Formulas (EI), (IA-a), (IA-b), (IA-c), (IA-d), (IA), (IB), (IB-a), (IB-b) and (IB-c) are defined as groups each containing a substituent R4A In certain embodiments, R 4A At least one of the entities is H. In certain embodiments, R 4A At least one of the entities is C1-C3 alkyl (e.g., methyl, ethyl). In certain embodiments, two R 4A are taken together with the carbon atoms to which they are attached to form a C(O), a C-C carbocycle, or a 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O. In certain embodiments, two R 4A However, together with the carbon atom to which they are attached, they form C(O).

[0125] In certain embodiments, m and n are both 0; R 3A is H; two R 4A together with the carbon atom to which they are attached form C(O); R 5A is H.

[0126] In certain embodiments, a1 is 1; m and n are both 0; and R 3A is H; two R 4A together with the carbon atom to which they are attached form C(O); R 5A is H;X A is C(O). In certain embodiments, a1 is 1; m and n are both 0; and R 3A is H; two R 4A together with the carbon atom to which they are attached form C(O); R 5A is H;X A is C(R 3A )2. In certain embodiments, two R 4A together with the carbon atom to which they are attached form C(O); R 5A is H;X A is C(O). In certain embodiments, two R 4A together with the carbon atom to which they are attached form C(O); R 5A is H;XA is C(R 3A )2. In certain embodiments, two R 4A together with the carbon atom to which they are attached form C(O); R 5A is H. In certain embodiments, X A is C(O). In certain embodiments, X A is -CH2-.

[0127] In certain embodiments, -X 1 -X 2 - is C(R 3A )=N;R 3A is H; two R 4A together with the carbon atom to which they are attached form C(O). In certain embodiments, -X 1 -X 2 - is C(R 3A )2-C(R 3A )2;R 3A is H; two R 4A together with the carbon atom to which they are attached form C(O). In certain embodiments, -X 1 -X 2 - is C(R 3A )=N;R 5A is H; two R 4A together with the carbon atom to which they are attached form C(O). In certain embodiments, -X 1 -X 2 - is C(R 3A )2-C(R 3A )2;R 5A is H; two R 4A However, together with the carbon atom to which they are attached, they form C(O).

[0128] In certain embodiments, D1 is thalidomide, lenalidomide, pomalidomide, CC-885 (Matyskiela et al., Nature 2016, 535, 252-257), 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione or an analog or derivative thereof. In certain embodiments, D1 is thalidomide. In certain embodiments, D1 is lenalidomide.

[0129] In certain embodiments, D1 is: [ka] is.

[0130] In certain embodiments, D1 is: [ka] is.

[0131] In certain embodiments, D1 is [ka] is.

[0132] In certain embodiments, D1 is of the formula: [ka] It is of the type.

[0133] In certain embodiments, the E3 ligase binding moiety binds an E3 ubiquitin ligase to a K of less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d Combine with.

[0134] In certain embodiments, the E3 ligase binding moiety binds cereblon to a K of less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM or less than 1 nM. d Combine with.

[0135] In certain embodiments, the E3 ligase binding moiety selectively binds an E3 ubiquitin ligase over another protein. In some embodiments, the E3 ligase binding moiety selectively binds cereblon over another protein. In some embodiments, the E3 ligase binding moiety selectively binds cereblon over another E3 ubiquitin ligase. In certain embodiments, the selectivity is about 2-fold to about 5-fold. In certain embodiments, the selectivity is about 5-fold to about 10-fold. In certain embodiments, the selectivity is about 10-fold to about 20-fold. In certain embodiments, the selectivity is about 20-fold to about 50-fold. In certain embodiments, the selectivity is about 50-fold to about 100-fold. In certain embodiments, the selectivity is about 100-fold to about 200-fold. In certain embodiments, the selectivity is about 200-fold to about 500-fold. In certain embodiments, the selectivity is about 500-fold to about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.

[0136] Substituent R 10’ , R 10A , R 13 and R 14 The compounds of formula (I') are bifunctional compounds that bind to the target protein DOT1L and bind to E3 ligase. For the compounds of formula (I'), the DOT1L binding moiety is the substituent R 8 , R 9 , R 10’ , R 10A , R 11 , R 12 , R 13 and R 14 Includes:

[0137] Substituent R 8 , R 9 , R 10 , R 11 and R 12 are listed below.

[0138] In certain embodiments, R 10’ are independently hydrogen, optionally substituted alkyl, or —N(R10A )2; where each R 10A are independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group. 10’ is hydrogen. In certain embodiments, R 10’ is optionally substituted alkyl. In certain embodiments, R 10’ -N(R 10A )2;R 14 One of the entities in R 10A one of the entities R together with the intervening atoms forms a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring, and the other R 10A is hydrogen, an optionally substituted alkyl, or a nitrogen protecting group. 10’ -N(R 10A )2;R 14 One of the entities in R 10A one of the entities R together with the intervening atoms forms a substituted or unsubstituted 6- to 14-membered heterocyclic ring or a substituted or unsubstituted heteroaryl ring, and the other R 10A is hydrogen, an optionally substituted alkyl, or a nitrogen protecting group. 10’ -N(R 10A )2;R 14 One of the entities in R 10A and one of the entities R together with the intervening atoms form a substituted or unsubstituted 5-14 membered heterocyclic ring or a substituted or unsubstituted 5-14 membered heteroaryl ring. 10’ -N(R 10A )2;R 14 One of the entities in R 10Aand one of the entities R together with the intervening atoms form a substituted or unsubstituted 5-6 membered heterocyclic ring or a substituted or unsubstituted 5-6 membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring contains 0-2 heteroatoms selected from the group consisting of N and O. In certain embodiments, R 14 One of the entities in R 10’ and one of the entities R together with the intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. 14 One of the entities in R 10’ and one of the entities R together with the intervening atoms form a substituted or unsubstituted 5- to 14-membered heterocyclic ring or a substituted or unsubstituted 5- to 14-membered heteroaryl ring. 14 One of the entities in R 10’ together with the intervening atoms form a substituted or unsubstituted 5- to 6-membered heterocyclic ring or a substituted or unsubstituted 5- to 6-membered heteroaryl ring.

[0139] In certain embodiments, R 10’ -N(R 10A )2;R 10A At least one of the entities is R as described herein. 10 is.

[0140] In certain embodiments, R 10A In certain embodiments, at least one of the R 10A At least one of the entities is optionally substituted alkyl (e.g., optionally substituted C 1~6 In certain embodiments, R 10A At least one of the entities is optionally substituted methyl or optionally substituted ethyl. In certain embodiments, R 10AAt least one of the entities is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0141] In certain embodiments, R 13 is hydrogen. In certain embodiments, R 13 is optionally substituted alkyl (e.g., optionally substituted C 1~6 In certain embodiments, R 13 is optionally substituted methyl or optionally substituted ethyl. In certain embodiments, R 13 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0142] In certain embodiments, R 14 In certain embodiments, at least one of the R 14 In certain embodiments, both entities of R 14 At least one of the entities is optionally substituted alkyl (e.g., optionally substituted C 1~6 In certain embodiments, R 14 At least one of the entities is optionally substituted methyl or optionally substituted ethyl. In certain embodiments, R 14is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, [ka] The part [ka] is.

[0143] In certain embodiments, R 10’ is hydrogen, [ka] The part [ka] is.

[0144] In certain embodiments, W is optionally substituted —CH— or —N(R W )-, where R W is hydrogen, an optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, W is —CH— or —N(R W )-, where R W is hydrogen, an optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, W is an optionally substituted -CH-, which is optionally substituted with halogen, -CN, -NO, -SO, acyl (e.g., -C(=O)(alkyl)), or -NH). In certain embodiments, W is unsubstituted -CH-. In certain embodiments, W is -N(R W )-, where R W is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.

[0145] In certain embodiments, R 10’ is hydrogen, [ka] The part [ka] and W is -N(R W )-, where R W is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R 10’ is hydrogen, [ka] The part [ka] and W is -NH-.

[0146] In certain embodiments, Z is -(optionally substituted carbocyclyl)-. In certain embodiments, Z is -(optionally substituted C 3~10 In certain embodiments, Z is -(optionally substituted C 3~6 In certain embodiments, Z is -(optionally substituted cyclobutyl)-. In certain embodiments, Z is optionally substituted methylene (-optionally substituted -CH-). In certain embodiments, Z is optionally substituted -CH-, which is optionally substituted with halogen, -CN, -NO, -SO, acyl (e.g., -C(=O)(alkyl)), or -NH). In certain embodiments, Z is unsubstituted -CH-. In certain embodiments, [ka] The part [ka] W is -NH-; and Z is -CH2-.

[0147] Substituent R 8 , R 9 , R 10 , R 11 and R 12 The compounds of formula (I') and (I) are bifunctional compounds that bind to the target protein DOT1L and bind to E3 ligase. For the compounds of formula (I') and (I), the DOT1L binding moiety is the substituent R 8 , R 9 , R 10 , R 11 and R 12 Includes:

[0148] In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is optionally substituted alkyl (e.g., optionally substituted C 1~6 In certain embodiments, R 8 is optionally substituted methyl or optionally substituted ethyl. In certain embodiments, R 8 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0149] In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is optionally substituted alkyl (e.g., optionally substituted C 1~6 In certain embodiments, R 9is optionally substituted methyl or optionally substituted ethyl. In certain embodiments, R 9 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0150] In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is optionally substituted alkyl (e.g., optionally substituted C 1~6 In certain embodiments, R 10 is optionally substituted methyl or optionally substituted ethyl. In certain embodiments, R 9 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0151] In certain embodiments, R 10 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0152] In certain embodiments, R 11 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R 11 is optionally substituted alkyl (e.g., optionally substituted C 1~6 In certain embodiments, R 11is optionally substituted C 1~6 In certain embodiments, R 11 is optionally substituted methyl or optionally substituted ethyl. In certain embodiments, R 11 is optionally substituted propyl. In certain embodiments, R 11 is optionally substituted butyl. In certain embodiments, R 11 is optionally substituted t-butyl. In certain embodiments, R 11 is unsubstituted t-butyl.

[0153] In certain embodiments, R 12 In certain embodiments, at least one of the R 12 is an oxygen protecting group (e.g., methyl, methoxylmethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl-thexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts)). In certain embodiments, R 12 Both of these entities are hydrogen.

[0154] In certain embodiments, the compound of formula (I') is of formula (I).

[0155] In certain embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0156] In certain embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0157] In certain embodiments, the compound of formula (I') has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0158] In certain embodiments, the compound of formula (I') has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0159] In certain embodiments, the compound of formula (I') has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0160] Linker L In formula (I), L represents a D1 group. [ka] In formula (I), L is a divalent moiety that links to the D group (i.e., the DOT1L linking moiety). [ka] is covalently linked to the moiety.

[0161] In formula (I'), L represents a D1 group. [ka] In formula (I), L is a divalent moiety that links to the D group (i.e., the DOT1L linking moiety). [ka] is covalently linked to the moiety.

[0162] In formula (I'), L is a divalent moiety. In certain embodiments, L is a divalent moiety that is [ka] The permuted or unpermuted C that has the shortest number of paths between parts of 1~50 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L is a substituted or unsubstituted alkyl, or a nitrogen protecting group. [ka] The permuted or unpermuted C that has the shortest number of paths between parts of 1~50 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L is a substituted or unsubstituted alkyl, or a nitrogen protecting group. [ka] The permuted or unpermuted C that has the shortest number of paths between parts of 1~50 and optionally, one or more atoms in the hydrocarbon chain are independently selected from the group consisting of —C(═O)—, —O—, —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups.

[0163] In formula (I'), L is a divalent moiety. In certain embodiments, L is a divalent moiety that is [ka] The permuted or unpermuted C that has the shortest number of paths between parts of 1~50 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L is a substituted or unsubstituted alkyl, or a nitrogen protecting group. [ka] The permuted or unpermuted C that has the shortest number of paths between parts of 1~50 and optionally, one or more atoms in the hydrocarbon chain are independently selected from the group consisting of —C(═O)—, —O—, —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups.

[0164] In certain embodiments, L is a substituted or unsubstituted linear C 1~30 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R bare independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups.

[0165] In certain embodiments, L is substituted or unsubstituted C 1~30 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L is an unsubstituted C 1~30 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L is a substituted or unsubstituted C 1~26 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L is an unsubstituted C 1~26 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6In certain embodiments, L is any "L" group or "Linker" group described in U.S. Patent Application No. 14 / 707,930, filed May 8, 2015, which is incorporated herein by reference. In certain embodiments, L is any "L" group described in U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, which is incorporated herein by reference.

[0166] In certain embodiments, the chain of linker L is a chain of up to 50 consecutive covalently bonded atoms, D1 and [ka] The atoms between the portions have a length that is the shortest path number excluding hydrogen atoms and substituents.

[0167] In certain embodiments, the chain of linker L is a chain of up to 50 consecutive covalently bonded atoms, D1 and [ka] The atoms between the portions have a length that is the shortest path number excluding hydrogen atoms and substituents.

[0168] In certain embodiments, the chain of linker L comprises a length of up to 50 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 46 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 45 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 40 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 35 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 32 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 30 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 25 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 25 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 23 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 20 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 14 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 15 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 12 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 10 consecutively covalently bonded atoms (excluding hydrogen atoms and substituents), hi certain embodiments, L comprises a length of up to 9 consecutively covalently bonded atoms (excluding hydrogen atoms and substituents).In certain embodiments, L comprises a length of up to 6 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 5 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents). In certain embodiments, L comprises a length of up to 3 consecutive covalently bonded atoms (excluding hydrogen atoms and substituents).

[0169] In certain embodiments, any of the atoms in L may be substituted. In certain embodiments, none of the atoms in the linker L are substituted. In certain embodiments, none of the carbon atoms in the linker are substituted.

[0170] In certain embodiments, L is an asymmetric carbon / stereocenter, i.e., an sp 3 In certain embodiments, the compound containing such an L group is enantiomerically enriched or substantially enantiomerically enriched. In certain embodiments, the compound containing such an L group is racemic.

[0171] In certain embodiments, L is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, or a combination thereof. In certain embodiments, L is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene. In certain embodiments, L is a linker selected from the group consisting of the following divalent moieties: substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof.

[0172] References to L being a combination of at least two instances of a divalent moiety described herein indicate that the linker is comprised of at least one instance of a first divalent moiety and at least one instance of a second divalent moiety, where the first and second divalent moieties are the same or different and are included within the scope of the divalent moieties described herein, and where the first and second divalent moiety instances are contiguously covalently bonded to each other. For example, when L is a combination of an alkylene linker and a heteroalkylene linker, examples include -alkylene-heteroalkylene-, -alkylene-(heteroalkylene)-, - ... )2 - and -heteroalkylene-alkylene-heteroalkylene- are all included within the scope of L, where each alkylene entity in any one of the linkers can be the same or different, and each heteroalkylene entity in any one of the linkers can be the same or different.

[0173] In certain embodiments, L is at least one substituted or unsubstituted alkylene entity, such as substituted or unsubstituted C1~6 Alkylene, substituted or unsubstituted C 1~2 Alkylene, substituted or unsubstituted C 2~3 Alkylene, substituted or unsubstituted C 3~4 Alkylene, substituted or unsubstituted C 4~5 Alkylene, substituted or unsubstituted C 5~6 Alkylene, substituted or unsubstituted C 3~6 Alkylene or substituted or unsubstituted C 4~6 Exemplary alkylene groups include unsubstituted alkylene groups, such as methylene (-CH-), ethylene (-(CH)-), n-propylene (-(CH)-), n-butylene (-(CH)-), n-pentylene (-(CH)-), and n-hexylene (-(CH)-).

[0174] In certain embodiments, L is at least one of a substituted or unsubstituted alkenylene entity, such as a substituted or unsubstituted C 2~6 Alkenylene, substituted or unsubstituted C 2~3 Alkenylene, substituted or unsubstituted C 3~4 Alkenylene, substituted or unsubstituted C 4~5 Alkenylene or substituted or unsubstituted C 5~6 Includes alkenylene.

[0175] In certain embodiments, L is at least one substituted or unsubstituted alkynylene entity, such as substituted or unsubstituted C 2~6 Alkynylene, substituted or unsubstituted C 2~3 Alkynylene, substituted or unsubstituted C 3~4 Alkynylene, substituted or unsubstituted C 4~5 Alkynylene or substituted or unsubstituted C 5~6 Includes alkynylene.

[0176] In certain embodiments, L is at least one substituted or unsubstituted heteroalkylene entity, such as a substituted or unsubstituted heteroC 1~6 Alkylene, substituted or unsubstituted hetero C1~2 Alkylene, substituted or unsubstituted hetero C 2~3 Alkylene, substituted or unsubstituted hetero C 3~4 Alkylene, substituted or unsubstituted hetero C 4~5 Alkylene or substituted or unsubstituted hetero C 5~6 Exemplary heteroalkylene groups include unsubstituted heteroalkylene groups, such as -(CH2)2-O(CH2)2-, -OCH2-, -CHO-, -O(CH2)2-, -(CH2)2O-, -O(CH2)3-, -(CH2)3O-, -O(CH2)4-, -(CH2)4O-, -O(CH2)5-, -(CH2)5O-, -O(CH2)6-, and -O(CH2)6O-, and amide groups (e.g., -NH-C(=O)- and -C(=O)NH-).

[0177] In certain embodiments, L is at least one substituted or unsubstituted heteroalkenylene entity, such as a substituted or unsubstituted heteroC 2~6 Alkenylene, substituted or unsubstituted hetero C 2~3 Alkenylene, substituted or unsubstituted hetero C 3~4 Alkenylene, substituted or unsubstituted hetero C 4~5 Alkenylene or substituted or unsubstituted hetero C 5~6 Includes alkenylene.

[0178] In certain embodiments, L is at least one substituted or unsubstituted heteroalkynylene entity, such as a substituted or unsubstituted heteroC 2~6 Alkynylene, substituted or unsubstituted hetero C 2~3 Alkynylene, substituted or unsubstituted hetero C 3~4 Alkynylene, substituted or unsubstituted hetero C 4~5 Alkynylene or substituted or unsubstituted hetero C 5~6 Includes alkynylene.

[0179] In certain embodiments, L is at least one of a substituted or unsubstituted carbocyclylene entity, such as a substituted or unsubstituted C 3~6Carbocyclylene, substituted or unsubstituted C 3~4 Carbocyclylene, substituted or unsubstituted C 4~5 Carbocyclylene or substituted or unsubstituted C 5~6 Includes carbocyclylene.

[0180] In certain embodiments, L comprises at least one substituted or unsubstituted heterocyclylene entity, such as substituted or unsubstituted 3- to 6-membered heterocyclylene, substituted or unsubstituted 3- to 4-membered heterocyclylene, substituted or unsubstituted 4- to 5-membered heterocyclylene, or substituted or unsubstituted 5- to 6-membered heterocyclylene.

[0181] In certain embodiments, L comprises at least one substituted or unsubstituted arylene entity, such as substituted or unsubstituted phenylene. In certain embodiments, L comprises at least one substituted or unsubstituted heteroarylene entity, such as substituted or unsubstituted 5-6 membered heteroarylene.

[0182] In certain embodiments, each R b are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting group, or optionally R b and the two entities R together with the intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. b In certain embodiments, at least one of the R b At least one of the entities is substituted or unsubstituted C 1~6 alkyl (e.g., substituted or unsubstituted methyl or ethyl). In certain embodiments, R bAt least one of the entities is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0183] In certain embodiments, L is selected from D1 and [ka] The unsubstituted C 1~45 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups.

[0184] In certain embodiments, L is selected from D1 and [ka] The unsubstituted C 1~45 a hydrocarbon chain, optionally wherein one or more atoms within the hydrocarbon chain are independently —C(═O)—, —O—, or —NR b - or cyclic moiety, R b are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups.

[0185] In certain embodiments, L is a hydrocarbon chain in which one or more atoms in the chain are independently —O— or —NR b - Unsubstituted C replaced by 1~30 In certain embodiments, L is an unsubstituted C, wherein at least one atom in the hydrocarbon chain is independently replaced with -O-. 1~30In certain embodiments, L is a hydrocarbon chain, wherein one or more atoms in the hydrocarbon chain are independently —O— or —NR b - Unsubstituted C replaced by 1~26 In certain embodiments, L is a hydrocarbon chain, wherein one or more atoms in the hydrocarbon chain are independently —O— or —NR b - Unsubstituted C replaced by 5~26 In certain embodiments, L is a hydrocarbon chain, wherein one or more atoms in the hydrocarbon chain are independently —O— or —NR b - Unsubstituted C replaced by 5~20 In certain embodiments, L is a hydrocarbon chain, wherein one or more atoms in the hydrocarbon chain are independently —O— or —NR b - Unsubstituted C replaced by 5~15 In certain embodiments, L is a hydrocarbon chain, wherein one or more atoms in the hydrocarbon chain are independently —O— or —NR b - Unsubstituted C replaced by 15~20 In certain embodiments, L is a hydrocarbon chain, wherein one or more atoms in the hydrocarbon chain are independently —O— or —NR b - Unsubstituted C replaced by 20~25 In certain embodiments, L is a substituted or unsubstituted C 1~45 In certain embodiments, L is a substituted or unsubstituted C 5~40 In certain embodiments, one or more atoms in the hydrocarbon chain of L are independently —C(═O)—, —O—, —S—, —NR b In certain embodiments, one or more atoms in the hydrocarbon chain of L are independently replaced with -, -N=, or -N-. b -, where R b are independently hydrogen, substituted or unsubstituted C 1~6In certain embodiments, L is an unsubstituted C alkyl, wherein at least one atom in the hydrocarbon chain is independently replaced with -O-. 1~26 It is a hydrocarbon chain.

[0186] In certain embodiments, L is selected from D1 and [ka] The shortest path length between the two carbon atoms is the shortest, excluding hydrogen atoms and substituents. 1~45 In certain embodiments, L is a hydrocarbon chain. [ka] The shortest path length between the two carbon atoms is the shortest, excluding hydrogen atoms and substituents. 1~30 In certain embodiments, L is a hydrocarbon chain. [ka] The shortest path length between the two carbon atoms is the shortest, excluding hydrogen atoms and substituents. 1~26 It is a hydrocarbon chain.

[0187] In certain embodiments, L is selected from D1 and [ka] The shortest path length between the two carbon atoms is the shortest, excluding hydrogen atoms and substituents. 1~45 In certain embodiments, L is a hydrocarbon chain. [ka] The shortest path length between the two carbon atoms is the shortest, excluding hydrogen atoms and substituents. 1~30 In certain embodiments, L is a hydrocarbon chain. [ka] The shortest path length between the two carbon atoms is the shortest, excluding hydrogen atoms and substituents. 1~26 It is a hydrocarbon chain.

[0188] In certain embodiments, L is [ka] and g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In certain embodiments, L is [ka] and g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In certain embodiments, L is a bond. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6. In certain embodiments, g is 7. In certain embodiments, g is 8. In certain embodiments, g is 9. In certain embodiments, g is 10. In certain embodiments, g is 11. In certain embodiments, g is 12. In certain embodiments, g is 13. In certain embodiments, g is 14. In certain embodiments, g is 15. In certain embodiments, L comprises a -NHC(=O)- moiety. In certain embodiments, L comprises a -NH- moiety.

[0189] In certain embodiments, L is a group of the formula: [ka] is of; l R indicates the bonding point with D1, and l A But, the formula [ka] n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, or 6; n3 is 1, 2, 3, 4, 5, or 6; n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24; n5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0190] In certain embodiments, L is a group of the formula: [ka] is of; l R indicates the bonding point with D1, and l A But, the formula [ka] n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, or 6; n3 is 1, 2, 3, 4, 5, or 6; n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; n5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0191] In certain embodiments, n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In certain embodiments, n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In certain embodiments, n4' is n4. In certain embodiments, n4' is 1. In certain embodiments, n4' is 2. In certain embodiments, n4' is 3. In certain embodiments, n4' is 4. In certain embodiments, n4' is 5. In certain embodiments, n4' is 6. In certain embodiments, n4' is 7. In certain embodiments, n4' is 8. In certain embodiments, n4' is 9. In certain embodiments, n4' is 10. In certain embodiments, n4' is 11. In certain embodiments, n4' is 12. In certain embodiments, n4' is 13. In certain embodiments, n4' is 14. In certain embodiments, n4' is 15. In certain embodiments, n4' is 16. In certain embodiments, n4' is 17. In certain embodiments, n4' is 18. In certain embodiments, n4' is 19. In certain embodiments, n4' is 20. In certain embodiments, n4' is 21. In certain embodiments, n4' is 22. In certain embodiments, n4' is 23. In some certain embodiments, n4' is 24.

[0192] In certain embodiments, L is a group of the formula: [ka] wherein: l R indicates the bonding point with D1, and l A is the expression: [ka] and g is 1, 2, 3, 4, 5, or 15. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n2 is 1. In certain embodiments, n2 is 2. In certain embodiments, n2 is 3. In certain embodiments, n2 is 3. In certain embodiments, n2 is 4. In certain embodiments, n2 is 5. In certain embodiments, n2 is 6. In certain embodiments, n4 is 1. In certain embodiments, n4 is 2. In certain embodiments, n4 is 3. In certain embodiments, n4 is 4. In certain embodiments, n4 is 5. In certain embodiments, n4 is 6. In certain embodiments, n4 is 7. In certain embodiments, n4 is 8. In certain embodiments, n4 is 9. In certain embodiments, n4 is 10. In certain embodiments, n4 is 11. In certain embodiments, n4 is 12. In certain embodiments, n5 is 1. In certain embodiments, n5 is 2. In certain embodiments, n5 is 3. In certain embodiments, n5 is 4. In certain embodiments, n5 is 5. In certain embodiments, n5 is 6. In certain embodiments, n5 is 7. In certain embodiments, n5 is 8. In certain embodiments, n5 is 9. In certain embodiments, n5 is 10. In certain embodiments, n5 is 11. In certain embodiments, n5 is 12. In certain embodiments, g is 1. In certain embodiments, g is 2.In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6. In certain embodiments, g is 7. In certain embodiments, g is 8. In certain embodiments, g is 9. In certain embodiments, g is 10. In certain embodiments, g is 11. In certain embodiments, g is 12. In certain embodiments, g is 13. In certain embodiments, g is 14. In certain embodiments, g is 15.

[0193] In certain embodiments, L is a group of the formula: [ka] It is of the type.

[0194] In certain embodiments, L is a group of the formula: [ka] It is of the type.

[0195] In certain embodiments, L is a group of the formula: [ka] wherein n1 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In certain embodiments, L is of the formula: [ka] wherein: n1 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some particular embodiments, n1 is 4. In some particular embodiments, n1 is 5. In some particular embodiments, n1 is 6. In some particular embodiments, g is 3. In some particular embodiments, g is 5. In some particular embodiments, g is 6. In some particular embodiments, g is 12. In some particular embodiments, g is 6. In some particular embodiments, g is 13. In some particular embodiments, L is of the formula: [ka] It is of the type.

[0196] In certain embodiments, L is a group of the formula: [ka] wherein: n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, or 6; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n2 is 3. In certain embodiments 6s, n2 is 4. In certain embodiments, n2 is 5. In certain embodiments, n2 is 6. In certain embodiments, n2 is 2. In certain embodiments, n2 is 3. In certain embodiments, n2 is 4. In certain embodiments, g is 3. In certain embodiments, g is 5. In certain embodiments, g is 6.

[0197] In certain embodiments, L is a group of the formula: [ka] It is of the type.

[0198] In certain embodiments, L is a group of the formula: [ka] wherein: n1 is 1, 2, 3, 4, 5, or 6; and n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n4' is 3. In certain embodiments, n4' is 4. In certain embodiments, n4' is 5. In certain embodiments, n4' is 6. In certain embodiments, n4' is 7. In certain embodiments, n4' is 8. In certain embodiments, n4' is 9. In certain embodiments, n4' is 10. In certain embodiments, n4' is 11. In certain embodiments, n4' is 12. In certain embodiments, n4' is 13. In certain embodiments, n4' is 14. In certain embodiments, n4' is 15. In certain embodiments, n4' is 16. In certain embodiments, n4' is 17. In certain embodiments, n4' is 18.

[0199] In certain embodiments, L is a group of the formula: [ka] wherein n1 is 1, 2, 3, 4, 5, or 6; and n4 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n4 is 8. In certain embodiments, n4 is 9. In certain embodiments, n4 is 10. In certain embodiments, n4 is 11. In certain embodiments, n4 is 12. In certain embodiments, L is of the formula: [ka] It is of the type.

[0200] In certain embodiments, L is a group of the formula: [ka] It is of the type.

[0201] In certain embodiments, L is a group of the formula: [ka] wherein: n1 is 1, 2, 3, 4, 5, or 6; n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; and n5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, n5 is 1. In certain embodiments, n4 is 2. In certain embodiments, n5 is 3. In certain embodiments, n5 is 4. In certain embodiments, n5 is 5. In certain embodiments, n5 is 6. In certain embodiments, n5 is 7. In certain embodiments, n5 is 8. In certain embodiments, n5 is 9. In certain embodiments, n5 is 10. In certain embodiments, n5 is 11. In certain embodiments, n5 is 12. In certain embodiments, n1 is 4; n4' is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; and n5 is 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, L is a group of the formula: [ka] It is of the type.

[0202] In certain embodiments, L is a group of the formula: [ka] wherein: n1 is 1, 2, 3, 4, 5, or 6; n4 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and n5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, n5 is 1. In certain embodiments, n4 is 2. In certain embodiments, n5 is 3. In certain embodiments, n5 is 4. In certain embodiments, n5 is 5. In certain embodiments, n5 is 6. In certain embodiments, n5 is 7. In certain embodiments, n5 is 8. In certain embodiments, n5 is 9. In certain embodiments, n5 is 10. In certain embodiments, n5 is 11. In certain embodiments, n5 is 12. In certain embodiments, n1 is 4; n4 is 5, 6, 7, 8, 9, 10, 11, or 12; and n5 is 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, L is a group of the formula: [ka] It is of the type.

[0203] In certain embodiments, L is a group of the formula: [ka] wherein: n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, or 6; and n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n2 is 2. In certain embodiments, n1 is 3. In certain embodiments, n2 is 4. In certain embodiments, n2 is 5. In certain embodiments, n2 is 6. In certain embodiments, n4' is 3. In certain embodiments, n4' is 4. In certain embodiments, n4' is 5. In certain embodiments, n4' is 6. In certain embodiments, n4' is 7. In certain embodiments, n4' is 8. In certain embodiments, n4' is 9. In certain embodiments, n4' is 10. In certain embodiments, n4' is 11. In certain embodiments, n4' is 12. In certain embodiments, n4' is 13. In certain embodiments, n4' is 14. In certain embodiments, n4' is 15. In certain embodiments, n4' is 16. In certain embodiments, n4' is 17. In some certain embodiments, n4' is 18.

[0204] In certain embodiments, L is a group of the formula: [ka] It is of the type.

[0205] In certain embodiments, L is a group of the formula: [ka] [ka] It is of the type.

[0206] Compound of formula (I') In certain embodiments, the compound of formula (I') has the formula: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0207] In certain embodiments, the compound of formula (I') has the formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0208] In certain embodiments, the compound of formula (I') has the formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0209] In certain embodiments, the compound of formula (I') has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0210] In certain embodiments, the compound of formula (I') has the formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0211] In certain embodiments, the compound of Formula (I') includes a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, the compound of Formula (I') includes a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I') selectively binds DOT1L over another protein. In certain embodiments, this selectivity is about 2-fold to about 5-fold. In certain embodiments, this selectivity is about 5-fold to about 10-fold. In certain embodiments, this selectivity is about 10-fold to about 20-fold. In certain embodiments, this selectivity is about 20-fold to about 50-fold. In certain embodiments, this selectivity is about 50-fold to about 100-fold. In certain embodiments, this selectivity is about 100-fold to about 200-fold. In certain embodiments, this selectivity is about 200-fold to about 500-fold. In certain embodiments, this selectivity is about 500-fold to about 1000-fold. In certain embodiments, this selectivity is at least about 1000-fold.

[0212] In some embodiments, compounds of Formula (I') selectively degrade DOT1L over other proteins in the proteome. In certain embodiments, this selectivity is about 2-fold to about 5-fold. In certain embodiments, this selectivity is about 5-fold to about 10-fold. In certain embodiments, this selectivity is about 10-fold to about 20-fold. In certain embodiments, this selectivity is about 20-fold to about 50-fold. In certain embodiments, this selectivity is about 50-fold to about 100-fold. In certain embodiments, this selectivity is about 100-fold to about 200-fold. In certain embodiments, this selectivity is about 200-fold to about 500-fold. In certain embodiments, this selectivity is about 500-fold to about 1000-fold. In certain embodiments, this selectivity is at least about 1000-fold.

[0213] In some embodiments, a compound of Formula (I') selectively binds an E3 ligase over another protein. In certain embodiments, this selectivity is about 2-fold to about 5-fold. In certain embodiments, this selectivity is about 5-fold to about 10-fold. In certain embodiments, this selectivity is about 10-fold to about 20-fold. In certain embodiments, this selectivity is about 20-fold to about 50-fold. In certain embodiments, this selectivity is about 50-fold to about 100-fold. In certain embodiments, this selectivity is about 100-fold to about 200-fold. In certain embodiments, this selectivity is about 200-fold to about 500-fold. In certain embodiments, this selectivity is about 500-fold to about 1000-fold. In certain embodiments, this selectivity is at least about 1000-fold.

[0214] In certain embodiments, the compounds of formula (I') induce up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% degradation of the target protein DOT1L at concentrations of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 30,000 nM or less, 40,000 nM or less, 50,000 nM or less, 60,000 nM or less, 70,000 nM or less, 80,000 nM or less, 9 ... Induction occurs at concentrations of 00nM or less, 10,000nM or less, 5,000nM or less, 3,500nM or less, 2,500nM or less, 1,000nM or less, 900nM or less, 800nM or less, 700nM or less, 600nM or less, 500nM or less, 400nM or less, 300nM or less, 200nM or less, 100nM or less, 90nM or less, 80nM or less, 70nM or less, 60nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, or 1nM or less.

[0215] In certain embodiments, the compound of formula (I') inhibits the degradation rate of the target protein DOT1L by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100%, up to 100,000 nM or less, up to 50,000 nM or less, up to 20, The concentration of 000nM or less, 10,000nM or less, 5,000nM or less, 3,500nM or less, 2,500nM or less, 1,000nM or less, 900nM or less, 800nM or less, 700nM or less, 600nM or less, 500nM or less, 400nM or less, 300nM or less, 200nM or less, 100nM or less, 90nM or less, 80nM or less, 70nM or less, 60nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less or 1nM or less.

[0216] Pharmaceutical Compositions, Kits and Administration The present disclosure provides a pharmaceutical composition comprising a compound of formula (I') or a pharmaceutically acceptable salt thereof, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of formula (I') or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0217] In certain embodiments, the compound of Formula (I') is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to treat a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to treat cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to reduce the risk of developing a disease (e.g., a proliferative disease or cancer) in a subject in need thereof.

[0218] In certain embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mouse and transgenic pig). In certain embodiments, the subject is a fish or a reptile.

[0219] In certain embodiments, an effective amount is an amount effective to induce degradation of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the target protein DOT1L in cells. In certain embodiments, an effective amount is an amount effective to induce degradation of the target protein DOT1L in cells to a range between one of the percentages described in this paragraph and another percentage described in this paragraph, inclusive.

[0220] The present disclosure provides a pharmaceutical composition comprising a compound that interacts with an E3 ubiquitin ligase (e.g., cereblon) and a target protein DOT1L, for use in treating a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the composition is for use in treating cancer. In certain embodiments, the composition is for use in treating multiple myeloma, lymphoma, leukemia (e.g., acute myeloid leukemia (e.g., acute myeloid leukemia with a mutation in the nucleophosmin (NPM1) gene; acute myeloid leukemia with a mutation in the DNMT3A gene), mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia), or proteasome inhibitor-resistant cancer. In certain embodiments, the composition is for use in treating multiple myeloma. In certain embodiments, the composition is for use in treating lymphoma. In certain embodiments, the composition is for use in treating leukemia. In certain embodiments, the composition is for use in treating acute myeloid leukemia. In certain embodiments, the composition is for use in treating acute myeloid leukemia associated with a mutation in the nucleophosmin (NPM1) gene. In certain embodiments, the composition is for use in treating acute myeloid leukemia associated with a mutation in the DNMT3A gene. In certain embodiments, the composition is for use in treating mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia. In certain embodiments, the composition is for use in treating acute myeloid eosinophilic leukemia. In certain embodiments, the composition is for use in treating cancer resistant to proteasome inhibitors. In certain embodiments, the composition is for use in treating cancer resistant to bortezomib. In certain embodiments, the composition is for use in treating cancer resistant to carfilzomib. In certain embodiments, the composition is for use in treating multiple myeloma.

[0221] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as single unit doses and / or multiple single unit doses. A "unit dose" is a discrete amount of pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the active ingredient is generally the same as the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage, e.g., one-half or one-third of such a dosage.

[0222] The relative amounts of active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the subject being treated, its size and / or condition, and also on the route by which the composition is administered. The compositions may contain from 0.1% to 100% (w / w) of the active ingredient.

[0223] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface-active and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents and perfuming agents may also be present in the compositions.

[0224] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar and mixtures thereof.

[0225] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood-derived products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0226] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glycerin monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acids, and the like. Esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glycerol monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters ( For example, polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and Solutol®), sucrose fatty acid ester, polyethylene glycol fatty acid ester (e.g., Cremophor®), polyoxyethylene ether (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate,Examples of suitable oleic acid preservatives include sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0227] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0228] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0229] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0230] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0231] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0232] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0233] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0234] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0235] Exemplary buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0236] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0237] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, blackcurrant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grapeseed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, and ritzel. Oils of acbeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ are included. Exemplary synthetic oils include, but are not limited to, butyl stearate, glyceryl tricaprylate, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0238] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters and their mixtures.In addition to inert diluents, oral compositions can also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and perfumes. In certain embodiments for parenteral administration, the conjugates described herein are mixed with a solubilizing agent, such as Cremophor®, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0239] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and USP standard isotonic sodium chloride solution. Sterile fixed oils are also commonly used as solvents or suspending media. For this purpose, any non-irritating fixed oil, such as synthetic mono- or diglycerides, can be used. Fatty acids, such as oleic acid, are also used in the preparation of injectable preparations.

[0240] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0241] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance that is poorly soluble in water. In this case, the absorption rate of the drug depends on its dissolution rate, which may further depend on the size and crystalline form of the crystals. Alternatively, the drug can be dissolved or suspended in an oil vehicle to delay absorption of a parenterally administered drug form.

[0242] Compositions for rectal or vaginal administration are typically suppositories, which may be prepared by mixing the conjugates described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active ingredient.

[0243] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) a humectant, such as glycerol; and (d) a disintegrant, such as agar, calcium carbonate. , potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents.

[0244] Solid compositions of a similar type can be used as fillers for pre-filled soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. These can optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, or preferentially, the active ingredient(s) in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers for pre-filled soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0245] The active ingredient may be microencapsulated with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may, as is customary, contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may contain a buffering agent, which may optionally contain an opacifying agent and may be of a composition that releases only the active ingredient(s), or the active ingredient(s), preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that may be used include polymeric substances and waxes.

[0246] Dosage forms for topical and / or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any necessary preservatives and / or buffers, if needed. Furthermore, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in a suitable medium. Alternatively or additionally, the rate can be controlled by either providing a rate-controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0247] Suitable devices for use in delivering the intradermal pharmaceutical compositions described herein include short-needle devices. Intradermal compositions can be administered using devices with limited needle penetration length into the skin. Alternatively or additionally, conventional syringes can be used in traditional Mantoux intradermal administration. Jet injection devices are also suitable, delivering liquid formulations to the dermis via a liquid jet injector and / or via a needle that pierces the stratum corneum and generates a jet stream that reaches the dermis. Ballistic powder / particle delivery devices are also suitable, using compressed gas to accelerate powder-form compounds from the outer layer of the skin into the dermis.

[0248] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may contain, for example, about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more of the additional ingredients described herein.

[0249] The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in formulations suitable for pulmonary administration via the buccal cavity. Such formulations may comprise dry particles comprising the active ingredient and having diameters ranging from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a propellant stream can be directed to disperse the powder, and / or using a self-propelling solvent / powder dispenser, e.g., a sealed container, comprising the active ingredient dissolved and / or suspended in a low-boiling propellant. Such powders comprise particles in which at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as a carbohydrate and are conveniently provided in a unit dose form.

[0250] Low-boiling propellants generally include liquid propellants having a boiling point below 65°F at atmospheric pressure. Generally, the propellant may comprise 50 to 99.9% (w / w) of the composition, and the active ingredient may comprise 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional components, such as a liquid nonionic surfactant and / or a solid anionic surfactant and / or a solid diluent (which may have a particle size similar to that of the particles comprising the active ingredient).

[0251] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as optionally sterile aqueous and / or dilute alcoholic solutions and / or suspensions containing the active ingredient, and may be conveniently administered using any nebulization and / or atomization device. Such formulations may further include one or more additional ingredients, including, but not limited to, flavoring agents, such as saccharin sodium, volatile oils, buffers, surfactants, and / or preservatives, such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter ranging from about 0.1 to about 200 nanometers.

[0252] Formulations described herein that are useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered by rapid inhalation through the nasal passage from a container of the powder held close to the nostrils.

[0253] Formulations for nasal administration can contain, for example, as little as about 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may optionally contain one or more additional ingredients described herein. The pharmaceutical compositions described herein can also be prepared, packaged, and / or sold in formulations for buccal administration. Such formulations can be, for example, in the form of tablets and / or lozenges made using conventional methods and can contain, for example, 0.1-20% (w / w) of the active ingredient, with the remainder comprising a composition that dissolves and / or disintegrates in the oral cavity, and optionally one or more additional ingredients described herein. Alternatively, formulations for buccal administration can comprise a powder and / or an aerosolized and / or atomized solution and / or suspension containing the active ingredient. Such powdered, aerosolized and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range of about 0.1 to about 200 nanometers and may further comprise one or more additional ingredients described herein.

[0254] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and veterinary pharmacologists of ordinary skill in the art will be able to design and / or implement such modifications with routine experimentation.

[0255] The compound provided herein is typically formulated into unit dosage form for easy administration and uniform dosage.However, it is understood that the total daily use amount of the compositions described herein is determined by a doctor within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, such as the severity of the disease and disorder to be treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and the excretion rate of the specific active ingredient used; the duration of treatment; the drug used in combination with the specific active ingredient used or simultaneously; and similar factors well known in the medical field.

[0256] The compounds and compositions provided herein can be administered by any route, for example, enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, interdermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream and / or drops), transmucosal, nasal, buccal, sublingual; intratracheal instillation, bronchial instillation and / or inhalation; and / or oral spray, nasal spray and / or aerosol.Specifically envisioned routes are oral administration, intravenous administration (e.g., systemic intravenous injection), localized administration via blood and / or lymphatic supply and / or direct administration to the affected site.Generally, the most appropriate administration route depends on various factors, such as the properties of the drug (e.g., stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the eye of a subject.

[0257] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general health, the severity of side effects or disorders, the identity of the specific compound, the mode of administration, etc. An effective amount may be contained in a single dose (e.g., a single oral dose) or in multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses in the multiple doses contain different or substantially the same amount of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency with which the multiple doses are administered to the subject or applied to the biological sample, tissue, or cell is three times a day, twice a day, once a day, once every other day, once every three days, once every week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the frequency of administering repeated doses to a subject or applying repeated doses to biological samples, tissues or cells is one dose per day.In certain embodiments, the frequency of administering repeated doses to a subject or applying repeated doses to biological samples, tissues or cells is two doses per day.In certain embodiments, the frequency of administering repeated doses to a subject or applying repeated doses to biological samples, tissues or cells is three doses per day.In certain embodiments, when administering repeated doses to a subject or applying repeated doses to biological samples, tissues or cells, the period between the first and last doses of repeated doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years or the lifetime of the subject, biological samples, tissues or cells. In certain embodiments, the period between the first and last dose of the repeated doses is 3 months, 6 months, or 1 year. In certain embodiments, the period between the first and last dose of the repeated doses is the lifetime of the subject, biological sample, tissue, or cell.In certain embodiments, the doses described herein (e.g., any dose in a single dose or multiple doses) independently include 0.1 μg to 1 μg, 0.001 mg to 0.01 mg, 0.01 mg to 0.1 mg, 0.1 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g (inclusive) of a compound described herein. In certain embodiments, the doses described herein independently include 1 mg to 3 mg (inclusive) of a compound described herein. In certain embodiments, the doses described herein independently include 3 mg to 10 mg (inclusive) of a compound described herein. In certain embodiments, the doses described herein independently include 10 mg to 30 mg (inclusive) of a compound described herein. In certain embodiments, the doses described herein independently include 30 mg to 100 mg (inclusive) of a compound described herein.

[0258] The dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount to be administered to a child or adolescent can be determined by a physician or person skilled in the art and may be less than or the same as the amount administered to an adult.

[0259] The compound or composition described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically active agents and / or prophylactically active agents).The compound or composition can be administered in combination with an additional pharmaceutical agent that improves its activity (e.g., the activity (e.g., efficacy and / or effectiveness) of treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, inducing the degradation of target protein, and / or reducing the risk of developing a disease in a subject in need thereof), improves bioavailability, improves the ability to cross the blood-brain barrier, improves safety, reduces drug resistance, and / or modifies metabolism, inhibits excretion, and / or modifies distribution in a subject, biological sample, tissue, or cell.It will also be recognized that the treatments used can achieve the desired effect on the same disorder, and / or can achieve different effects. In certain embodiments, pharmaceutical compositions described herein that comprise a compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is not present in pharmaceutical compositions that comprise one of the compound and the additional pharmaceutical agent, but not both.

[0260] The compound or composition can be administered in parallel with one or more additional pharmaceutical agents, for example, in combination therapy, before or after the additional pharmaceutical agent. The pharmaceutical agents include therapeutically active agents. The pharmaceutical agents can also include prophylactically active agents. The pharmaceutical agents can include small organic compounds, such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as set forth in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agents are pharmaceutical agents useful for the treatment and / or prevention of diseases (e.g., proliferative diseases). Each of the additional pharmaceutical agents can be administered at a dose and / or time schedule determined for the pharmaceutical agent. In addition, the additional pharmaceutical agents can be administered together with each other and / or with the compounds or compositions described herein in a single dose, or can be administered separately in different doses.The specific combination to be used in the regimen will take into consideration the compatibility of the compounds described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or preventive effects to be obtained.Generally, it is expected that the additional pharmaceutical agent(s) in combination will be used at a level that does not exceed the level that is used individually.In some embodiments, the level that is used in combination is lower than the level that is used individually.

[0261] The additional pharmaceutical agent includes, but is not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, analgesics, and combinations thereof.In some specific embodiments, the additional pharmaceutical agent is an antiproliferative agent (e.g., anticancer agent).In some specific embodiments, the additional pharmaceutical agent is an anti-leukemia agent.In some specific embodiments, the additional pharmaceutical agent is an anti-lymphoma agent.In some specific embodiments, the additional pharmaceutical agent is an anti-multiple myeloma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, adriamycin RDF (doxorubicin hydrochloride), ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Erwinia chrysanthemi-derived asparaginase), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX (anticoagulant ... PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATELPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (peguaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuxinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib) or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORI (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 Tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRONA (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticles), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR 200mg / mL (prescription only), ABRAXANE (albumin-stabilized nanoparticles), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR 200mg / mL (prescription only), ABRAXANE (albumin-stabilized nanoparticles), ABRAXANE (albumin-stabilized nanoparticles), ABRAXANE (prescription only ...DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEXPFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposomal), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONEHYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plelixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacytidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESI D (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacytidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium-223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992(TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647 and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is a protein kinase inhibitor (e.g., a tyrosine protein kinase inhibitor). In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic agents (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), protein stability modulators (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein may be administered in combination with anti-cancer treatments, such as, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0262] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). The kits provided may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe and / or a dispenser package or other suitable container). In some embodiments, the kits provided may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound provided in the first container and the second container are combined to form a single unit dosage form.

[0263] Therefore, in one aspect, a kit is provided, comprising a first container with the compound or pharmaceutical composition described herein.In some specific embodiments, the kit is useful for treating disease (for example, proliferative disease) in a subject in need thereof.In some specific embodiments, the kit is useful for preventing disease (for example, proliferative disease) in a subject in need thereof.

[0264] In certain embodiments, the kits described herein further comprise instructions for use of the compound or pharmaceutical composition included in the kit. The kits described herein may also comprise information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide treatment of a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kit and instructions provide prevention of a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kit and instructions provide induction of degradation of the target protein DOT1L in a subject, biological sample, tissue, or cell. The kits described herein may also comprise one or more additional pharmaceutical agents described herein as separate compositions.

[0265] Treatment Methods and Uses The compounds described herein can bind (e.g., reversibly or irreversibly bind) an E3 ubiquitin ligase (e.g., cereblon) and a target protein DOT1L, thereby inducing degradation of the target protein DOT1L. Thus, the present disclosure also provides methods for inducing degradation of the target protein DOT1L in a subject, biological sample, tissue, or cell. The present disclosure further provides methods for treating a disease, such as a proliferative disease, in a subject in need thereof.

[0266] In some specific embodiments, the present application provides a method for promoting the degradation of target protein DOT1L by binding to ubiquitin receptor RPN13.In another aspect, the present disclosure provides a method for inducing the degradation of target protein DOT1L in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.In another aspect, the present disclosure provides a method for inducing the degradation of target protein DOT1L in a biological sample, tissue or cell, comprising contacting the biological sample, tissue or cell with an effective amount of a compound or pharmaceutical composition described herein.

[0267] In certain embodiments, the present application provides a method for binding an E3 ubiquitin ligase (e.g., cereblon) and a target protein DOT1L to induce degradation of the target protein DOT1L. In certain embodiments, the binder of the target protein DOT1L has the formula: [ka] It is of the type.

[0268] In certain embodiments, the binder of the target protein DOT1L has the formula: [ka] It is of the type.

[0269] The use of bifunctional compounds that bind an E3 ubiquitin ligase (e.g., cereblon) and a target protein, DOT1L, provides a strategy for treating diseases associated with DOT1L (e.g., proliferative diseases) as a research tool for investigating the role of DOT1L in cells or for investigating diseases associated with DOT1L (e.g., proliferative diseases).

[0270] The disclosure also provides a compound of formula (I') or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug, or composition thereof, for use in treating a disease, e.g., a proliferative disease, in a subject in need thereof.

[0271] The disclosure also provides the use of a compound of formula (I') or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug or composition thereof in the manufacture of a medicament for treating a disease, e.g., a proliferative disease, in a subject in need thereof.

[0272] In some embodiments, the method of the present disclosure comprises administering to a subject an effective amount of a compound of Formula (I') or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, or a composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0273] In certain embodiments, the subject to be treated is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject to be treated is a human. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0274] Some specific methods described herein may include administering one or more additional pharmaceutical agents in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered simultaneously with the compound of formula (I'), or may be administered at different times from the compound of formula (I'). For example, the compound of formula (I') and any additional pharmaceutical agent(s) may be on the same or different dosing schedules. All or a portion of the doses of the compound of formula (I') may be administered before all or a portion of the doses of the additional pharmaceutical agent, after all or a portion of the doses of the additional pharmaceutical agent, within the dosing schedule of the additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of formula (I') and the additional pharmaceutical agent may vary depending on the additional pharmaceutical agent.

[0275] In certain embodiments, the additional pharmaceutical agent comprises an agent useful for treating a disease, such as a proliferative disease, in a subject in need thereof. In certain embodiments, the additional pharmaceutical agent is useful for treating a proliferative disease. In certain embodiments, the additional pharmaceutical agent is useful for treating an inflammatory disease. In certain embodiments, the additional pharmaceutical agent is useful for treating a proliferative disease. In certain embodiments, the additional pharmaceutical agent is useful for treating multiple myeloma. In certain embodiments, the additional pharmaceutical agent is useful for treating leukemia. In certain embodiments, the additional pharmaceutical agent is useful for treating acute myeloid leukemia. In certain embodiments, the additional pharmaceutical agent is useful for treating mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia. In certain embodiments, the additional pharmaceutical agent is useful for treating acute myeloid leukemia associated with a mutation in the nucleophosmin (NPM1) gene. In certain embodiments, the additional pharmaceutical agent is useful for treating acute myeloid leukemia with mutation of DNMT3A gene.In certain embodiments, the additional pharmaceutical agent is useful for treating lymphoma.In certain embodiments, the additional pharmaceutical agent is useful for treating non-Hodgkin's lymphoma.In certain embodiments, the additional pharmaceutical agent is useful for treating cancer that is resistant to proteasome inhibitors (for example, resistant to bortezomib).

[0276] In another aspect, the disclosure provides a method for inducing degradation of DOT1L, comprising administering to a subject a compound of Formula (I') or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof, or composition thereof.

[0277] In another aspect, the present disclosure provides a method for binding to an E3 ubiquitin ligase and promoting the degradation and / or ubiquitination of DOT1L, comprising administering to a subject a compound of Formula (I') or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In certain embodiments, a method is provided for treating a cancer resistant to standard cancer treatments. In certain embodiments, a method is provided for treating a cancer resistant to proteasome inhibitors. In certain embodiments, a method is provided for treating a disease, e.g., a proliferative disease, in a subject in need thereof. In certain embodiments, the disease is a proliferative disease. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is leukemia. In certain embodiments, the leukemia is acute myeloid leukemia. In certain embodiments, the leukemia is mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia. In certain embodiments, the leukemia is acute myeloid leukemia with a mutation in the nucleophosmin (NPM1) gene. In certain embodiments, the leukemia is acute myeloid leukemia with a mutation in the DNMT3A gene. In certain embodiments, the leukemia is acute myeloid eosinophilic leukemia. In certain embodiments, the cancer is a lymphoma. In certain embodiments, the lymphoma is non-Hodgkin's lymphoma. In certain embodiments, the cancer being treated is resistant to a proteasome inhibitor (e.g., resistant to bortezomib). In certain embodiments, methods are provided for treating cancer that is resistant to a proteasome inhibitor (e.g., resistant to bortezomib).

[0278] In yet another aspect, the present disclosure provides pharmaceutical compositions as described herein for use in binding to an E3 ubiquitin ligase and DOT1L and promoting the degradation of DOT1L; inducing ubiquitination of DOT1L in a subject, biological sample, tissue or cell; and treating and / or preventing a proliferative disease. [Example]

[0279] Example In order that this disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are presented to illustrate the compounds, pharmaceutical compositions and methods provided herein, and are not to be construed as limiting the scope thereof in any way.

[0280] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures or methods known in the art. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are shown, it will be recognized that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0281] Compounds of formula (I') or (I) may be prepared using the synthetic schemes and procedures detailed below. [Example]

[0282] Example 1. Experimental Procedures for the Synthesis of Exemplary Compounds [ka] 1) (2R,3R,4S,5R)-2-(6-((4-aminobutyl)amino)-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol: To a solution of DOT1L-WX (15 mg, 0.019 mmol) in DCM (0.4 mL) was added TFA (0.1 mL). The reaction mixture was stirred at room temperature overnight, concentrated, and dried in vacuo to give crude LW-DOT1L-11, which was used in the next step without further purification.

[0283] (2) N-(4-((9-((2R,3R,4S,5R)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)amino)butyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propenamide To a solution of IM-3A (2.38 mg, 0.0050 mmol) and HATU (2.09 mg, 0.0055 mmol) in DMF (0.1 mL) was added DIPEA (3.23 mg, 0.0250 mmol) at room temperature. To a solution of LW-DOT1L-11 (0.0050 mmol) in DMF (0.1 mL) was added DIPEA (3.23 mg, 0.0250 mmol) at room temperature. The latter was added to the former, and the combined reaction mixture was stirred for 30 min. It was purified by HPLC (0.1% TFA / MeCN) to give LW-DOT1L-1 (2.13 mg) as a white solid. [Example]

[0284] Example 2. Biological Assay of Exemplary Compounds with DOT1L. DOT1L fluorescence polarization (FP) displacement assay DOT1L fluorescence polarization (FP) shift assays were performed on exemplary DOT1L degrader compounds, inhibitor derivatives, and negative and positive control compounds at different concentrations [M] (measured as mP [M]). Test compounds included exemplary DOT1L degrader compounds DOT1L-1, DOT1L-2, DOT1L-4, DOT1L-5, DOT1L-6, and DOT1L-7, an inhibitor derivative (DOT1L-11), negative control compounds EPZ4777, EPZ5676, and CC006, and a positive control, lenalidomide. The results of the assay are shown in Figure 5.

[0285] DOT1L fluorescence polarization (FP) displacement assays were performed on exemplary DOT1L degrader compounds and control compounds at different concentrations [M] (measured as mP [M]). Test compounds included exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JD-DD4, JD-DD5, and JD-DD6, as well as the positive controls thalidomide and EPZ5676. These exemplary compounds exhibit binding to DOT1L and CRBN, respectively. The results of the assay are shown in Figure 18.

[0286] CRBN binding assay CRBN binding assays were performed with exemplary DOT1L degrader compounds, inhibitor derivatives, negative control compounds, and positive control compounds at different concentrations [M] (expressed relative to mP [M]). The compounds included exemplary DOT1L degrader compounds DOT1L-1, DOT1L-2, DOT1L-4, DOT1L-5, DOT1L-6, and DOT1L-7; an inhibitor derivative (DOT1L-11); and the positive control lenalidomide. The results of the assay are shown in Figure 6.

[0287] CRBN binding assays were performed on exemplary DOT1L degrader compounds, negative control compounds, and positive control compounds at different concentrations [M] (expressed relative to mP [M]). The compounds included exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, and JQ-DD6, as well as controls thalidomide and EPZ5676. The results of the assay are shown in Figure 19. DOT1L eGFP-mCherry Report Cell Line Assay A new DOT1L degradation reporter cell line was developed using DOT1L-tagged GFP and mCherry. This reporter cell line can directly report targeted protein degradation (see Sievers et al., Science, 2018). DOT1L degradation using the eGFP-mCherry reporter cell line assay was performed for different concentrations [M] (measured as mP [M]) of exemplary DOT1L degrader compounds and control compounds. Test compounds included exemplary DOT1L degrader compounds JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, JQ-DD7, and JQ-DD8, as well as controls EPZ5676, thalidomide, and lenalidomide. The results of the assay are shown in Figure 26.

[0288] IKZF-GFP degradation assay IKZF-GFP degradation assay was performed using exemplary DOT1L degrader compounds, inhibitor derivatives, negative control compounds, and positive control compounds at different concentrations [M], where the compound concentration is expressed relative to the normalized level.These exemplary compounds include exemplary DOT1L degrader compounds DOT1L-1, DOT1L-2, DOT1L-4, DOT1L-5, DOT1L-6, and DOT1L-7; inhibitor derivative DOT1L-11; negative control compounds EPZ4777, EPZ5676, and CC006; and positive control lenalidomide.The results of the assay are shown in Figure 8.

[0289] An IKZF-GFP degradation assay using an eGFP-mCherry reporter cell line was performed on exemplary DOT1L degrader compounds and control compounds at different concentrations [M] (measured by mP [M]). Tested compounds included exemplary DOT1L degrader compounds JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, JQ-DD7, and JQ-DD8, as well as controls EPZ5676, thalidomide, and lenalidomide. These exemplary DOT1L degrader compounds degrade DOT1L and its neo-substrate, IKZF1, when the immunomodulatory imide drug (IMiD) binds to CRBN. The results of the assay are shown in Figure 27.

[0290] Degradation by dDOT1L-1 in Molm13 PA cell line Molm13PA (acute myeloid leukemia) cells were treated with 0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM dDOT1L-1 for 24 and 48 hours. Cell lysates were loaded onto SDS-PAGE and then immunoblotted for DOT1L (D4O2T), actin, H3K79me2, and total H3. Replicate treatments were performed at the same dDOT1L-1 concentrations at 24, 48, and 72 hours. The blots show that dDOT1L-1 inhibits acute myeloid leukemia cells (Molm13PA) (see Figures 9A-9B). Figure 9A shows cells treated with the indicated concentrations (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) of DOT1L-1 for the indicated amounts of time (24 and 48 hours). FIG. 9B shows repeated treatments in which cells were treated with DOT1L-1 at the indicated concentrations (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24 hours, 48 ​​hours, and 72 hours).

[0291] Degradation by dDOT1L-1 in mouse MLL-AF9 PA cell line Murine MLL-AF9 PA (mixed lineage leukemia (MLL)-AF9 leukemia) cells were treated with 0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM DOT1L-1 for 24, 48, and 72 hours. Cell lysates were loaded onto SDS-PAGE and then immunoblotted with DOT1L (DOT1L), actin, H3K79me2, and total H3. A second treatment was performed at 24 and 48 hours with DOT1L-1 concentrations of 0 μM, 0.01 μM, 0.1 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM. The blots show that the exemplary DOT1L degrader compound DOT1L-1 degrades murine MLL-AF9 PA (mixed lineage leukemia (MLL)-AF9 leukemia) cells (see Figures 10A-10B). Figure 10A shows experiment 1 in which cells were treated with DOT1L-1 at the indicated concentrations (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24 hours, 48 ​​hours, and 72 hours). Figure 10B shows experiment 2 in which cells were treated with DOT1L-1 at the indicated concentrations (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM) for the indicated amounts of time (24 hours and 48 hours).

[0292] Degradation by dDOT1L-4 in Molm13 PA cell line Molm13PA (acute myeloid leukemia) cells were treated with 0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM DOT1L-4 for 24, 48, and 72 hours. Cell lysates were loaded onto SDS-PAGE and then immunoblotted with DOT1L (D4O2T), actin, H3K79me2, and total H3. The blots show that DOT1L-4 degrades (mixed lineage leukemia (MLL)-AF9 leukemia) cells (see Figure 11).

[0293] Degradation by JQ-DD1-8 in EOL1 cell line EOL1 (acute myeloid (eosinophilic) leukemia cell line) cells were treated with exemplary DOT1L degrader compounds JQ-DD6, JQ-DD7, and JQ-DD8 at 0.5 μM, 1 μM, 3 μM, 5 μM, and 10 μM for 24 hours. Cell lysates were loaded onto SDS-PAGE and then immunoblotted with DOT1L, Myc, H3K79me2, and actin (see Figure 21).

[0294] EOL1 cells were treated with 1 μM, 5 μM, and 10 μM of exemplary DOT1L degrader compounds JQ-DD2, JQ-DD4, JQ-DD6, JQ-DD7, and JQ-DD8 for 48 hours. Cell lysates were immunoblotted with the indicated concentrations of DOT1L, H3K79me2, Myc, actin, and H3 for 48 hours (see FIG. 22).

[0295] EOL1 cells were treated with 1 μM and 10 μM of exemplary DOT1L degrader compounds JQ-DD2, JQ-DD4, JQ-DD6, JQ-DD7, and JQ-DD8 for 2, 4, 8, 16, and 24 hours. Cell lysates were immunoblotted with the indicated concentrations of DOT1L, Myc, H3K79me2, and actin for the indicated times (see FIG. 23).

[0296] EOL1 cells were treated with 1 μM and 10 μM of exemplary DOT1L degrader compounds JQ-DD6, JQ-DD7, and JQ-DD8 for 24 and 48 hours. Cell lysates were immunoblotted with the indicated concentrations of DOT1L, Myc, H3K79me2, and actin for the indicated times (see FIG. 24).

[0297] Relative Cell Proliferation in the Presence of Exemplary Thalidomide-Based DOT1L Degrader Compounds Molm13 PA (acute myeloid leukemia), Molm13 RE (acute myeloid leukemia), and HL60 (human leukemia) cells were treated with exemplary thalidomide-based DOT1L degrader compounds DOT1L-1, DOT1L-2, DOT1L-4, and DOT1L-5, and the negative control compound EPZ5676, at concentrations ranging from 0 to 10 μM. Relative cell proliferation of Molm13 PA, Molm13 RE, and HL60 cells was measured after 10 days. Results show that Molm13 leukemia cells and HL60 (human leukemia) cells treated with exemplary DOT1L degrader compounds exhibited reduced cell proliferation with increasing concentrations of the exemplary DOT1L degrader compounds (see Figures 12A-12E). [Example]

[0298] Example 3. Dimerization assay Biochemical dimerization assay A biochemical assay was performed to examine the dimerization of CRBN with DOT1L induced by degraders. This assay examines whether exemplary compounds can induce dimerization of CRBN and DOT1L under the conditions set by the biochemical assay. Figure 20 shows that exemplary compounds can simultaneously bind to both proteins. The strongest signal was obtained with JQ-DD6. The results of the assay are shown in Figure 20. [Example]

[0299] Example 4. Antiproliferative effects of DOT1L degraders A 7-day treatment assay of MOLM13 was performed with exemplary DOT1L degrader compounds and control compounds at different concentrations [M] (measured in mP [M]). Test compounds included exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, and JQ-DD7, as well as controls EPZ5676 and thalidomide (see Figure 28A).

[0300] A 7-day THP1 treatment assay was performed with exemplary DOT1L degrader compounds and positive control compounds at different concentrations [M] (measured in mP [M]). Test compounds included exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, and JQ-DD7, as well as controls EPZ5676 and thalidomide (see Figure 28B).

[0301] A 7-day NOMO1 treatment assay was performed with exemplary DOT1L degrader compounds and control compounds at different concentrations [M] (measured in mP [M]). Test compounds included exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3, JQ-DD4, JQ-DD5, JQ-DD6, and JQ-DD7, as well as controls EPZ5676 and thalidomide (see Figure 29A).

[0302] EOL1 cell line cell proliferation assays were performed with exemplary DOT1L degrader compounds and control compounds at different concentrations [M] (measured by mP [M]). Test compounds included exemplary DOT1L degrader compounds JQ-DD1, JQ-DD2, JQ-DD3 (old), JQ-DD3 (new), JQ-DD4, JQ-DD5, and JQ-DD6, as well as controls EPZ5676, thalidomide, and PCK82 (see Figure 29B).

[0303] The percentage (%) of viable cells of exemplary cancer cells (e.g., acute myeloid leukemia cells) was examined in EOL1, NOMO1, MOLM13, MOLM14, and MOLM14 crbnKO cells after treating these cells with various concentrations of exemplary DOT1L degraders JQ-DD6, EPZ5676, and thalidomide for 3 days. The results of these assays are shown in Figures 30A-30E.

[0304] The percentage (%) of viable cells of exemplary cancer cells (e.g., acute myeloid leukemia cells) was examined in EOL1, NOMO1, MOLM13, MOLM14, and MOLM14 crbnKO cells after treating the cells with various concentrations of exemplary DOT1L degraders JQ-DD6, EPZ5676, and thalidomide for 7 days. The results of these assays are shown in Figures 31A-31E. [Example]

[0305] Example 5. Exemplary DOT1L Degrader Exemplary DOT1L degraders are shown below in Table 1. The compounds in Table 1 below were synthesized according to the exemplary procedure shown in the synthetic scheme in Example 1. Table 1. Exemplary DOT1L degraders [Table 1-1] [Table 1-2] [Table 1-3]

[0306] Equivalents and their scope In the claims, articles such as "a," "an," and "the" may mean one or more than one unless indicated otherwise or clear from the context. Claims and descriptions including "or" between one or more members of a group should be construed as fulfilling the condition that one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless indicated otherwise or clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0307] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms of one or more of a recited claim are introduced into another claim. For example, any claim that depends on another claim may be amended to include one or more limitations found in any other claim that depends on the same base claim. Where elements are presented as lists, e.g., in Markush-style groups, each subgroup of the elements is also disclosed, and any element(s) may be removed from the group. In general, when the disclosure or aspects described herein are described as comprising certain elements and / or features, it will be understood that some specific embodiments described herein or some specific aspects described herein consist of or consist essentially of such elements and / or features. For purposes of brevity, such embodiments have not been specifically set forth in these terms herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended, permitting the inclusion of additional elements or steps. When ranges are stated, both ends are inclusive. Furthermore, unless otherwise stated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​stated as ranges indicate that any specific value or subrange within the stated range can be assumed in different embodiments described herein, down to one-tenth of the unit of the lower limit of the range, unless expressly stated otherwise in the context.

[0308] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification will control. Additionally, any specific embodiment of the present disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, as it would be understood by one of ordinary skill in the art. Any specific embodiment described herein may be excluded from any claim for any reason, whether related to the existence of prior art or otherwise.

[0309] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above detailed description, but is instead as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit and scope of the present disclosure, as defined in the following claims.

Claims

1. Formula (I') or (I): 【Chemistry 1】 (In the formula: R ８ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R ９ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R １０ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R １０’ is hydrogen, optionally substituted alkyl, or —N(R １０Ａ ) ２ and Each R １０Ａ are independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R １１ is halogen or optionally substituted alkyl; Each R １２ are independently hydrogen or an oxygen protecting group; R １３ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Each R １４ is independently hydrogen, halogen, or optionally substituted alkyl; Or optionally, R １４ One of the and R １０’ together with the intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; Or optionally, R １４ One of the and R １０Ａ together with the intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; Or optionally, 【Chemistry 2】 The part 【Transformation 3】 and W is an optionally substituted —CH ２ - or -N(R Ｗ )—, where R Ｗ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group, Nitrogen protecting groups are -OH, -OR aa, -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc, C 1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl group; each instance of R aa is independently selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; each instance of R cc is independently selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; Each instance of R dd is independently halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff ) 2 , —N(R ff ) 3 + X − , —N(OR ee )R ff , —SH, —SR ee , —SSR ee , —C(═O)R ee , —CO 2 H, —CO 2 R ee , —OC(═O)R ee , —OCO 2 R ee , —C(═O)N(R ff ) 2 , —OC(═O)N(R ff ) 2 , —NR ff C(═O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee ) 2 , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 alkyl, hetero C 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 selected from carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents may be joined to form ═O or ═S;X − is a counter ion; each instance of R ee is independently selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; each instance of R ff is independently selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups; Each instance of R gg is independently halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X − , —NH(C 1-6 alkyl) 2 + X − , —NH 2 (C 1-6 alkyl) + X − , —NH 3 + X − , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C(═O)(C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 -C(═S)N(C 1-6 alkyl) 2 , C(═S)NH(C1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O)(OC 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg substituents may be joined to form =O or =S; X - is a counterion The oxygen protecting groups are -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 + X - , -P(OR cc ) 2 , -P(OR cc ) 3 + X - , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 and -P(=O)(N(R bb ) 2 ) 2 ; The entities of each R bb are independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O)(N(R cc ) 2 ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, or two R bb groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; and X − is a counterion; Z is -(optionally substituted carbocyclyl)- or -CH ２ - and; L is a linker; D1 is an E3 ubiquitin ligase binding moiety, and D1 is a moiety of Formula IA or IB: 【Transformation 6】 (In the formula: X Ａ is C(O) or C(R ３Ａ ) ２ and Each R １Ａ are independently halogen, OH, C １ ~C ６ Alkyl or C １ ~C ６ is alkoxy; Each R ３Ａ are independently H or C １ ~C ３ is alkyl; Each R ３’ is independently C １ ~C ３ is alkyl; Each R ４Ａ are independently H or C １ ~C ３ alkyl; or two R ４Ａ together with the carbon atoms to which they are attached, C(O), C ３ ~C ６ forming a carbocyclic or 4-, 5-, or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N and O; R ５Ａ is H, C １ ~C ３ is alkyl or halogen; m is 0, 1, 2 or 3; n is 0, 1 or 2; a1 is 0 or 1. or 【Transformation 7】 (In the formula: -X １ -X ２ - is C(R ３Ａ )=N or C(R ３Ａ ) ２ -C(R ３Ａ ) ２ and Each R １Ａ are independently halogen, OH, C １ ~C ６ Alkyl or C １ ~C ６ is alkoxy; R ３Ａ is H or C １ ~C ３ is alkyl; Each R ３’ is independently C １ ~C ３ is alkyl; Each R ４Ａ are independently H or C １ ~C ３ alkyl; or two R ４Ａ together with the carbon atoms to which they are attached, C(O), C ３ ~C ６ forming a carbocyclic or 4-, 5-, or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N and O; R ５Ａ is H, C １ ~C ３ is alkyl or halogen; m is 0, 1, 2 or 3; n is 0, 1 or 2; a1 is 0 or 1. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

2. The compound has the formula: 【Chemistry 4】 【change】 【change】 【change】 【change】 【change】 (In the formula: R ８ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R ９ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R １０ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; R １１ is halogen or optionally substituted alkyl; Each R １２ are independently hydrogen or an oxygen protecting group.

2. The compound of claim 1, wherein:

3. a1 is 1; or a1 is 1 and m is 0; or a1 is 1, m is 0, and n is 0; or R ３Ａ is hydrogen; or R ３Ａ is hydrogen and m is 0; or R ３Ａ is hydrogen, m is 0, and n is 0; or R ３Ａ is hydrogen, and two R ４Ａ together with the carbon atom to which they are attached form C(O); or R ３Ａ is hydrogen, and two R ４Ａ together with the carbon atom to which they are attached form C(O), and m is 0; or R ３Ａ is hydrogen, and two R ４Ａ together with the carbon atom to which they are attached form C(O), m is 0 and n is 0; or Two R's ４Ａ together with the carbon atom to which they are attached form C(O); or Two R's ４Ａ together with the carbon atom to which they are attached form C(O), and m is 0; or Two R's ４Ａ together with the carbon atom to which they are attached form C(O), m is 0 and n is 0; or X Ａ is C(O) or -CH ２ - is; or X Ａ is C(O) or -CH ２ - and m is 0; or X Ａ is C(O) or -CH ２ -, m is 0 and n is 0; or m is 0; or The compound of claim 1 , wherein n is 0.

4. D1 is a compound of the formula: 【Transformation 8】 2. The compound of claim 1, wherein

5. R ８ , R ９ , R １０ and R １３ is hydrogen, or R ９ and R １０ 10. The compound of claim 1, wherein each is hydrogen.

6. R １０’ -N (R １０Ａ ) ２ and R １４ One of the and R １０Ａ together with the intervening atoms form a substituted or unsubstituted 6- to 14-membered heterocyclic ring or a substituted or unsubstituted heteroaryl ring; or R １１ is optionally substituted C １～６ alkyl or unsubstituted t-butyl; or R １１ is optionally substituted C １～６ alkyl or unsubstituted t-butyl, R １２ are both hydrogen; or R １１ is optionally substituted C １～６ alkyl or unsubstituted t-butyl, R １２ are both hydrogen, 【Chemistry 14】 The part 【Chemistry 15】 is; or R １１ is optionally substituted C １～６ alkyl or unsubstituted t-butyl, R １２ are both hydrogen, 【Chemistry 14】 The part 【Chemistry 15】 and W is unsubstituted —CH ２ - or -NH-; or R １１ is optionally substituted C １～６ alkyl or unsubstituted t-butyl, R １２ are both hydrogen, 【Chemistry 14】 The part 【Chemistry 15】 and W is unsubstituted —CH ２ - or -NH-, and Z is -(optionally substituted cyclobutyl)- or -CH ２ The compound of claim 1, wherein

7. R １１ is optionally substituted C １～６ alkyl or unsubstituted t-butyl, R １２ are both hydrogen, 【Chemistry 14】 The part 【Chemistry 15】 and W is —NH— and Z is —CH ２ - is; or 【Chemistry 14】 The part 【Chemistry 15】 is; or W is unsubstituted —CH ２ - or -NH-; or Z is -(optionally substituted cyclobutyl)- or -CH ２ - is; or 【Chemistry 14】 The part 【Chemistry 15】 W is -NH-; Z is -CH ２ The compound of claim 1, wherein

8. L is unsubstituted C １～４５ a hydrocarbon chain, optionally wherein one or more atoms within said hydrocarbon chain are independently —C(═O)—, —O—, —NR ｂ - or cyclic moiety, R ｂ are independently hydrogen, substituted or unsubstituted C １～６ alkyl, or a nitrogen protecting group; or L is unsubstituted C １～３０ a hydrocarbon chain, optionally wherein one or more atoms within said hydrocarbon chain are independently —C(═O)—, —O—, —NR ｂ - or cyclic moiety, R ｂ are independently hydrogen, substituted or unsubstituted C １～６ alkyl, or a nitrogen protecting group; or L is unsubstituted C １～２６ a hydrocarbon chain, optionally wherein one or more atoms within said hydrocarbon chain are independently —C(═O)—, —O—, —NR ｂ - or cyclic moiety, R ｂ are independently hydrogen, substituted or unsubstituted C １～６ 10. The compound of claim 1, wherein the aryl group is an alkyl, or a nitrogen protecting group.

9. L [Chemistry 18] including the part L 【Chemistry 19】 having any one of the following structures: l Ｒ indicates the point of attachment to D1, and l Ａ But, the formula 【Chemistry 20】 indicates the point of attachment to the moiety; n1 is 1, 2, 3, 4, 5 or 6; n2 is 1, 2, 3, 4, 5 or 6; n3 is 1, 2, 3, 4, 5 or 6; n4' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; n5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; The compound of claim 8.

10. L 10. The compound of claim 9, wherein:

11. n1 is 4 or 6; n2 is 2, 3, or 12; n3 is 3; n4 is 10, 11 or 12; n4' is 3, 5, 6, 7 or 9; n5 is 8; 11. The compound of claim 9 or 10, wherein g is 3, 5 or 13.

12. L is of the formula: 【Chemistry 26-1】 【Chemistry 26-2】 Here, l R indicates the point of attachment to D1, and l A is a group represented by the formula [Chemical 90] indicates the point of attachment to the part; 2. The compound of claim 1, wherein

13. The compound has the formula: 【Chemistry 27-1】 【Chemistry 27-2】 【Chemistry 27-3】 【Chemistry 27-4】 10. The compound of claim 9, wherein:

14. The compound has the formula: 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 2. The compound of claim 1, wherein:

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof and optionally a pharmaceutically acceptable excipient.

16. 15. A pharmaceutical composition for treating a disease in a subject in need thereof, comprising a therapeutically effective amount of the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the disease is a proliferative disease, and the proliferative disease is a cancer selected from multiple myeloma, lymphoma, and leukemia.

17. 17. The pharmaceutical composition of claim 16, wherein the leukemia is acute myeloid leukemia, mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia, acute myeloid leukemia with a mutation in the nucleophosmin (NPM1) gene, acute myeloid leukemia with a mutation in the DNMT3A gene, or acute myeloid eosinophilic leukemia.

18. A pharmaceutical composition for inducing degradation of DOT1L in a cell, tissue or biological sample, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

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