Synthesis and in vitro characterization of proteolytic targeting chimera (PROTACS) for degradation of DNA methyltransferase 1 (DNMT1)

Abstract

Disclosed is a bifunctional compound (degradation agent) comprising a [targeting ligand]-[linker]-[degrader] adduct, the targeting ligand comprising a substituted pyridine compound, the bifunctional compound targeting an epigenetic writing protein desoxyribonucleic acid methyltransferase 1 responsible for maintaining DNA methylation during cell proliferation, for degradation. Also disclosed are pharmaceutical compositions containing the compounds and methods of using the compounds in the treatment of diseases and disorders characterized or mediated by aberrant DNMT1 activity.

Description

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 523,993, filed June 29, 2023, which is incorporated by reference in its entirety. BACKGROUND

[0002] Deoxyribonucleic acid methyltransferase 1 (DNMT1) is an epigenetic writer protein responsible for maintaining DNA methylation during cell proliferation. DNA methylation is a well-studied epigenetic regulatory mechanism that influences the transcription of key genes and has been found to be associated with many human diseases, including cancer. Therefore, abnormal DNMT1 activity plays an important role in cancer development. Existing drugs for DNMT1 dysregulation, such as decitabine and 5-azacytidine, are highly toxic and cancer cells often develop resistance. SUMMARY

[0003] A first aspect of the present disclosure relates to a compound of Formula I, (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: the DNMT1-targeting ligand has the formula TL-1 or TL-2: wherein: R1is NR3R4; R3is H or methyl, and R4is , or R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl, or R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl, which is further bound to the linker; R2is NH2or ; and R5and R6are independently H, optionally substituted alkyl, or ; wherein is a bond between the DNMT1-targeting ligand and the linker, with the proviso that there is only one bond between the DNMT1-targeting ligand and the linker; the linker represents a moiety covalently linking the degron and the targeting ligand; and the degron has the formula D1, D2, or D3: wherein Q is CH2or C(O); and X1is O, NH, CH2, or CºC; R7is H or optionally substituted C1-C3alkyl, or R7and R8together with the carbon atom to which they are attached form a cyclopropyl; R8is H, methyl or ; R9is C(O)CR 10 R 11 R 12 、 ; R 10 and R 11 are each H, or R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl; R 12 is H, fluoro, cyano, or NMe2; and Y is H, , , or ; wherein is a bond between the degron and the linker, with the proviso that there is only one bond between the degron and the linker.

[0004] Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0005] In another aspect of the present disclosure, methods of making the compounds are provided.

[0006] A further aspect of the present disclosure relates to a method of treating a disease or disorder associated with (characterized by or mediated by) abnormal DNMT1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0007] Without intending to be bound by any particular theory of operation, it is believed that the compounds of Formula I (also referred to herein as PROTACs or degraders) facilitate the degradation of DNMT1 through the ubiquitin / proteasome system of the cell, a system whose function is to routinely identify and remove damaged proteins. After the DNMT1 protein molecules are destroyed, the degrader is released and continues to be effective. Thus, by hitching and utilizing the body’s own natural protein disposal system, the compounds of the present disclosure can represent a potential improvement over existing small molecule DNMT1 inhibitors. As a result, the effective intracellular concentration of the degraders can be significantly lower than small molecule DNMT1 inhibitors. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 Figure 1 is a Western blot showing degradation of DNMT1 in HL60 cells by compounds 1-4 at the indicated concentrations.

[0009] Figure 2 Figure 2 is a Western blot showing degradation of DNMT1 in HL60 cells by compounds 5-8 at the indicated concentrations.

[0010] Figure 3 Figure 3 is a Western blot showing degradation of DNMT1 in HL60 cells by compounds 9-12 at the indicated concentrations.

[0011] Figure 4 Figure 4 is a Western blot showing degradation of DNMT1 in HL60 cells by compounds 13-16 at the indicated concentrations.

[0012] Figure 5 Figure 5 is a Western blot showing degradation of DNMT1 in HL60 cells by compounds 17-19 at the indicated concentrations.

[0013] Figure 6 Figure 6 is a Western blot showing degradation of DNMT1 in HL60 cells by compounds 20-23 at the indicated concentrations.

[0014] Figure 7 Figure 7 is a Western blot showing degradation of DNMT1 in HL60 cells by compound 20 at the indicated concentrations.

[0015] Figure 8 Figure 8 is a Western blot showing degradation of DNMT1 in Jurkat cells by compound 20 at the indicated concentrations.

[0016] Figure 9 Figure 9 is a Western blot showing degradation of DNMT1 in A172 cells by compound 20 at the indicated concentrations.

[0017] Figure 10is a western blot showing compound 20 (which contains a cereblon (CRBN) targeted degrader) degrades DNMT1 in MOLM13 ch2.2 (left). The extent of degradation of DNMT1 relative to MOLM13 CRBN KO (right) cells indicates that the degradation is CRBN-dependent.

[0018] Figure 11 is a western blot showing compound 20 (3 µM) degrades DNMT1 in HL60 cells at the indicated time points.

[0019] Figure 12 is a western blot showing compounds 26 and 27 degrade DNMT1 in HL60 cells at the indicated concentrations. DETAILED DESCRIPTION

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs. As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural objects unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, and the like.

[0021] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural objects unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, and the like.

[0022] The term "about," unless otherwise indicated, means ±10% (e.g., ±5%, ±2%, or ±1%) of the particular value modified by the term "about."

[0023] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. When used in the context of the number of heteroatoms in a heterocyclic structure, it means a heterocyclic group of the minimum number of heteroatoms. In contrast, the transitional phrase "consisting of restricts any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s) of the disclosed subject matter."

[0024] With respect to the compounds of the disclosure, and in further describing them, the following definitions apply, as the terms are used herein.

[0025] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. In some embodiments, the alkyl group is a C1-C6 group. In some embodiments, and unless otherwise disclosed for any one or more groups of a compound of formula (I), the alkyl group is a C0-C6, C0-C5, C0-C3, C1-C6, C1-C5, C1-C4, or C1-C3 group (where C0 alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. In some embodiments, the alkyl group is a C1-C3 alkyl group. In some embodiments, the alkyl group is a C1-C2 alkyl group. In some embodiments, the alkyl group is methyl.

[0026] As used herein, the term "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain in which the remainder of a molecule is attached to a group, consisting only of carbon and hydrogen, without unsaturation, and having 1 to 18 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain can be attached to the remainder of the molecule via single bonds as well as to the group via single bonds. In some embodiments, the alkylene contains 1 to 15 carbon atoms (C1-C5). 15 Alkylene). In some embodiments, the alkylene contains 1 to 12 carbon atoms (C1-C1). 12 Alkylene). In some embodiments, the alkylene contains 1 to 10 carbon atoms (C1-C1). 10 Alkylenes. In some embodiments, the alkylene contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene contains 1 carbon atom (C1 alkylene).

[0027] As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon double bond. Alkenyl groups include groups having "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, the alkenyl group is C2-C. 18group. In some embodiments, and unless otherwise disclosed for any one or more groups of compounds of Formula (I), alkenyl is a C2-C8, C2-C6, or C2-C3group. Examples include ethenyl or vinyl, prop-1 -enyl, prop-2-enyl, 2-methylprop-1 -enyl, but-1 -enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl. 15 , C2-C 12 , C2-C 10 , C2-C8, C2-C6, or C2-C3group. Examples include ethenyl or vinyl, prop-1 -enyl, prop-2-enyl, 2-methylprop-1 -enyl, but-1 -enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl.

[0028] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In some embodiments, alkynyl is a C2-C 18 group. In some embodiments, and unless otherwise disclosed for any one or more groups of compounds of Formula (I), alkynyl is a C2-C 15 , C2-C 12 , C2-C 10 , C2-C8, C2-C6, or C2-C3. Examples include ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, and but-3-ynyl.

[0029] The term "alkoxyl" or "alkoxy" as used herein refers to an alkyl group as defined above having an oxyl group attached thereto and as the point of attachment. In some embodiments, alkoxyl is methoxyl, ethoxyl, propoxyl, or tert-butoxyl. An "ether" is two hydrocarbon groups covalently linked by an oxygen atom. Thus, the substituent of an alkyl group that makes the alkyl group an ether is or is analogous to an alkoxyl, e.g., can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0030] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0031] As used herein, the term "cyclyl" refers broadly to any group, used alone or as part of a larger moiety, containing a saturated, partially saturated, or aromatic ring system, such as carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl. Cyclyl groups can have one or more (e.g., fused) ring systems. Thus, for example, a cyclyl group can contain one or more carbocyclic, heterocyclic, aryl, or heteroaryl groups.

[0032] As used herein, the term "carbocyclo" (and "carbocyclyl") refers to a radical, alone or as part of a larger moiety, containing a saturated, partially unsaturated, or aromatic ring system having from 3 to 12 carbon atoms, which is either alone or part of a larger moiety (e.g., an alkylcarbocyclyl). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In one embodiment, a carbocyclyl group includes 3 to 10 carbon atoms (C3-C10). In one embodiment, a carbocyclyl group includes 3 to 6 carbon atoms (C3-C6). In one embodiment, a carbocyclyl group includes 5 to 6 carbon atoms (C5-C6). In some embodiments, a carbocyclyl group as a bicyclic ring includes C6-C10. In another embodiment, a carbocyclyl group as a spiro system includes C5-C10. Representative examples of monocyclic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and phenyl; bicyclic carbocyclyl groups having 7 to 11 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spiro carbocyclyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term carbocyclyl includes aromatic ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi-, or spiro carbocyclyl). The term carbocyclyl also includes carbocyclic rings fused to one or more (e.g., 1, 2, or 3) distinct cyclic groups (e.g., aromatic or heterocyclic rings), where the linkage is through a carbon on the carbocyclic ring. 10 ) In one embodiment, a carbocyclyl group includes 3 to 6 carbon atoms (C3-C6). In one embodiment, a carbocyclyl group includes 5 to 6 carbon atoms (C5-C6). In some embodiments, a carbocyclyl group as a bicyclic ring includes C6-C 10 ) In another embodiment, a carbocyclyl group as a spiro system includes C5-C 11 ) In another embodiment, a carbocyclyl group as a spiro system includes C5-C c Representative examples of monocyclic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and phenyl; bicyclic carbocyclyl groups having 7 to 11 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spiro carbocyclyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term carbocyclyl includes aromatic ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi-, or spiro carbocyclyl). The term carbocyclyl also includes carbocyclic rings fused to one or more (e.g., 1, 2, or 3) distinct cyclic groups (e.g., aromatic or heterocyclic rings), where the linkage is through a carbon on the carbocyclic ring.

[0033] Thus, the term carbocyclo also includes carbocyclylalkyl, which as used herein, refers to a radical of the formula --R c -carbocyclyl, wherein R c is an alkylene chain. The term carbocyclo also includes carbocyclylalkoxy, which as used herein, refers to a radical bonded through an oxygen atom of the formula --O--R c -carbocyclyl, wherein R c is an alkylene chain.

[0034] As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl", wherein the terminal carbon atom of the alkyl group is the point of attachment, such as benzyl; "aralkoxy", wherein the oxygen atom is the point of attachment; or "aryloxyalkyl", wherein the point of attachment is on the aryl group) refers to groups including monocyclic, bicyclic or tricyclic carbocyclic ring systems, including fused rings, wherein at least one ring in the system is aromatic. In some embodiments, the aralkoxy group is benzyloxy. The term "aryl" can be used interchangeably with the term "aromatic ring". In one embodiment, aryl groups include groups having from 6 to 12 carbon atoms. In another embodiment, aryl groups include groups having from 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, and the like, which can be substituted or independently substituted with one or more substituents described herein. A particular aryl group is phenyl. In some embodiments, aryl groups include aryl rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the linkage or point of attachment is on the aryl ring.

[0035] Thus, the term aryl includes aralkyl groups (e.g., benzyl), which, as disclosed above, refers to groups of the formula --R c - a group of the formula --R c is an alkylene chain, such as methylene or ethylene. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl also includes aralkoxy groups, which, as used herein, refers to groups bonded through an oxygen atom of the formula --O—R c - a group of the formula --R c is an alkylene chain, such as methylene or ethylene.

[0036] As used herein, the term "heterocyclyl" refers to "carbocyclyl" used alone or as part of a larger moiety, containing a saturated, partially unsaturated, or aromatic ring system in which one or more (e.g., 1, 2, 3, 4, or 5) carbon atoms have been replaced with a heteroatom or a heteroatom-containing group (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, as well as combinations thereof. In some embodiments, heterocyclyl refers to 3- to 12-membered heterocyclic ring systems. In some embodiments, heterocyclyl refers to saturated ring systems, such as 3- to 12-membered saturated heterocyclic ring systems. In some embodiments, heterocyclyl refers to heteroaromatic ring systems, such as 5- to 12-membered heteroaromatic ring systems. The term heterocyclyl also includes C2-C8heterocycloalkyl groups, which are saturated or partially unsaturated monocyclic, bicyclic, or spiro ring systems containing 2-8 carbons and one or more (e.g., 1, 2, or 3) heteroatoms.

[0037] In some embodiments, heterocyclyl includes 3-12 ring atoms, and includes monocyclic, bicyclic, tricyclic, and spirocyclic systems, wherein the ring atoms are carbon, and 1-5 ring atoms are heteroatoms, such as nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyl includes a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from O, N, and S. In some embodiments, heterocyclyl includes a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from O, N, and S. In some embodiments, heterocyclyl includes a 3-membered monocyclic ring. In some embodiments, heterocyclyl includes a 4-membered monocyclic ring. In some embodiments, heterocyclyl includes a 5- to 6-membered monocyclic ring. In some embodiments, heterocyclyl includes 0-3 double bonds. In any one of the foregoing embodiments, heterocyclyl includes 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom can optionally be oxidized (e.g., NO, SO, S02), and any nitrogen heteroatom can optionally be substituted (e.g., methyl, isopropyl) and / or quaternized (e.g., [NR4] + Cl - , [NR4] + OH -oxazepinyl, diazepinyl, thiazepinyl, oxazepinyl, triazepinyl, dithiazepinyl, imidazoline, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-onyl, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyl groups containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms are thiazolyl (e.g., thiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl), oxazolyl (e.g., oxazol-2-yl), and oxadiazolyl (e.g., 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl).Examples of 5-membered heterocyclyl groups containing 2 to 4 nitrogen atoms include imidazolyl (e.g., imidazol-2-yl), triazolyl (e.g., 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl, and 1,2,4-triazol-5-yl), and tetrazolyl (e.g., 1H-tetrazol-5-yl). Representative examples of benzo-fused 5-membered heterocyclyl groups include benzoxazol-2-yl, benzothiazol-2-yl, and benzoimidazol-2-yl. Examples of 6-membered heterocyclyl groups containing 1 to 3 nitrogen atoms and optionally containing a sulfur or oxygen atom are pyridyl (e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl and pyrimidin-4-yl), triazinyl (e.g., 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl), pyridazinyl (e.g., pyridazin-3-yl), and pyrazinyl. In some embodiments, heterocyclyl groups include heterocycles that are fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic or heterocyclic), where the linkage or point of attachment is on the heterocyclic group, and in some embodiments, where the point of attachment is a heteroatom contained in the heterocyclic group.

[0038] Thus, the term heterocyclyl includes N-heterocyclyl, as used herein, which refers to a heterocyclyl group containing at least one nitrogen atom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, 1-pyrazolidinyl, 1-imidazolinyl, and 1-imidazolidinyl. The term heterocyclyl also includes C-heterocyclyl, as used herein, which refers to a heterocyclyl group containing at least one heteroatom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl groups include 2- or 3-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocyclyl also includes heterocyclylalkyl, as disclosed above, which refers to a group of the formula -R c -heterocyclyl, wherein R c is an alkylene chain. The term heterocyclyl also includes heterocyclylalkoxy, as used herein, which refers to a group bonded through an oxygen atom of the formula -O-R c -heterocyclyl, wherein R c is an alkylene chain.

[0039] As used herein, the term "heteroaryl," used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also referred to as "heteroaralkyl") or "heteroarylalkoxy" (also referred to as "heteroaralkoxy")), refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms are O, N, or S. Representative examples of heteroaryl include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, imidazopyridyl, pyrazinyl, pyridazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, and 1,2,3-triazol-5-yl. The term "heteroaryl" also includes groups in which the heteroaryl is fused to one or more rings (e.g., carbocyclyl or heterocyclyl), where the linkage is through a ring atom of the heteroaryl ring. Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic or tricyclic. In some embodiments, the heteroaryl includes a heteroaromatic ring fused to one or more (e.g., 1 or 2) different ring groups (e.g., carbocyclic or heterocyclic), where the linkage is through a ring atom of the heteroaromatic ring, and in some embodiments, where the point of attachment is a heteroatom contained in the heterocyclic ring.

[0040] Thus, the term heteroaryl includes N-heteroaryl, as used herein, which refers to a heteroaryl group as defined above containing at least one nitrogen and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl also includes C-heteroaryl, as used herein, which refers to a heteroaryl group as defined above and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also includes heteroaralkyl, as disclosed above, which refers to a group of the formula -R c- a group bound through an oxygen atom of a heteroaryl group, wherein R c is an alkylene chain as defined above. The term heteroaryl also includes heteroaralkoxy (or heteroarylalkoxy), as used herein, which refers to a group of the formula -O-R c - a group bound through an oxygen atom of a heteroaryl group, wherein R c is an alkylene chain as defined above.

[0041] Unless otherwise indicated, and unless further defined for any particular group in a compound of Formula (I), any group described herein can be substituted or unsubstituted. Representative examples of substituents can include alkyl (e.g., Ci-C6, Ci-Cs, Ci-C4, Ci-C3, Ci-C2, Ci), substituted alkyl (e.g., substituted Ci-C6, Ci-Cs, Ci-C4, Ci-C3, Ci-C2, Ci), alkoxy (e.g., Ci-C6, Ci-Cs, Ci-C4, Ci-C3, Ci-C2, Ci), substituted alkoxy (e.g., substituted Ci-C6, Ci-Cs, Ci-C4, Ci-C3, Ci-C2, Ci), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-Cs, C2-C4, C2-C3, C2), substituted alkenyl (e.g., substituted C2-C6, C2-Cs, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-Cs, C2-C4, C2-C3, C2), substituted alkynyl (e.g., substituted C2-C6, C2-Cs, C2-C4, C2-C3, C2), cycloalkyl (e.g., C3-C6, C3-C5, C3-C4), substituted cycloalkyl (e.g., substituted C3-C6, C3-C5, C3-C4), carbocyclyl (e.g., C3-C6, C3-C5, C3-C4), substituted carbocyclyl (e.g., substituted C3-C6, C3-C5, C3-C4), heterocyclyl (e.g., 3- to 12-membered, 5- to 6-membered), substituted heterocyclyl (e.g., substituted 3- to 12-membered, 5- to 6-membered), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or substituted phenyl), heteroaryl (e.g., pyridinyl or pyrimidinyl), substituted heteroaryl (e.g., substituted pyridinyl or substituted pyrimidinyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C6, C6), substituted aryloxy (e.g., substituted C6-C6, C6), alkylthio (e.g., Ci-C6), substituted alkylthio (e.g., substituted Ci-C6), arylthio (e.g., C6-C6, C6), substituted arylthio (e.g., substituted C6-C6, C6), amino, substituted amino, nitro, cyano, oxo, carboxyl, carboxyalkyl, acyl, acyloxy, aldehyde, ketone, ester, silyl, silyloxy, sulfonyl, sulfonylalkyl, sulfonamide, sulfamide, phosphonyl, phosphonylalkyl, phosphoramidite, phosphoramidite alkyl, phosphine, phosphine alkyl, and / or the like, unless otherwise indicated. 12 12 12 12 12 12 12 12 ​​​​​​​, C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide. Terminal substituents can include C1-C6 alkyl, halo, hydroxyl, cyano, amino, or amido.

[0042] The term“bind” when referring to the interaction between a compound of Formula (I) and a targeted protein (in the present disclosure, DNMT1) via the DNMT1 targeting ligand, generally refers to a molecular interaction that can be preferential (also referred to herein as“selective”), in that the binding of the compound of Formula (I) to other proteins present in the cell is significantly lower and can be functionally insignificant. The compounds of the present invention preferentially bind and recruit DNMT1 for targeted degradation.

[0043] The term“bind” when referring to the interaction between a degron and an E3 ubiquitin ligase, generally refers to a molecular interaction that can or can not exhibit a level of affinity equal to or exceeding that between the compound and DNMT1, but is still sufficient to achieve E3 ubiquitin ligase recruitment to DNMT1.

[0044] Broadly speaking, the compounds of the present disclosure have a structure represented by Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof: (I), wherein: The DNMT1 targeting ligand has the formula TL-1 or TL-2: wherein: R1is NR3R4; R3is H or methyl, and R4is , or R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl, or R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl, which is also bound to the linker; R2is NH2or ; each R5is independently H, optionally substituted alkyl, or ; wherein is a bond between the DNMT1 targeting ligand and the linker, provided that there is only one bond between the DNMT1 targeting ligand and the linker; the linker represents a moiety that covalently links the degrader and the targeting ligand; and the degrader represents a moiety that binds an E3 ubiquitin ligase.

[0045] Targeting Ligand In some embodiments, the DNMT1 targeting ligand has the formula TL-1 and R2 is NH2.

[0046] In some embodiments, R1 is NR3R4, wherein R3 is H and R4 is , R2 is NH2 and the formula TL-1 has TL-1a: (TL-1a).

[0047] Accordingly, in some embodiments, the compound has a structure represented by the formula I-1a: (I-1a), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0048] In some embodiments, R1 is NR3R4, wherein R3 is Me and R4 is , R2 is NH2 and the formula TL-1 has TL-1b: (TL-1b).

[0049] Accordingly, in some embodiments, the compound has a structure represented by the formula I-1b: (I-1b), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0050] In some embodiments, R1 is NR3R4, wherein R3 and R4, together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered heterocyclyl group, which is also bound to the linker, and R2 is NH2.

[0051] In some embodiments, R1 is NR3R4, wherein R3 and R4, together with the nitrogen atom to which they are attached, form a piperidinyl group, and the formula TL-1 has TL-1c: (TL-1c).

[0052] Accordingly, in some embodiments, the compound has a structure represented by the formula I-1c: (I-1c), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0053] In some embodiments, R1is NR3R4, wherein R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl. In some embodiments, R3and R4together with the nitrogen atom to which they are attached form an optionally substituted piperidinyl. In some embodiments, the piperidinyl is substituted with amino.

[0054] In some embodiments, R1is NR3R4, wherein R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl. In some embodiments, R3and R4together with the nitrogen atom to which they are attached form an optionally substituted piperidinyl. In some embodiments, the piperidinyl is substituted with amino. , and Formula TL-1 has TL-1d: (TL-1d).

[0055] Thus, in some embodiments, the compound has a structure represented by Formula I-1d: (I-1d), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0056] In some embodiments, the DNMT1 -targeting ligand has Formula TL-2, R5is and R6is H.

[0057] Thus, in some embodiments, the compound has a structure represented by Formula I-2a: (I-2a), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0058] In some embodiments, the DNMT1 -targeting ligand has Formula TL-2, R5is H or optionally substituted alkyl, and R6is .

[0059] Thus, in some embodiments, the compound has a structure represented by Formula I-2b: (I-2b), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0060] Linker The linker (“L”) provides a covalent linkage between the targeting ligand and the degron.

[0061] In some embodiments, the linker has Formula L0: (L0), or a stereoisomer thereof, wherein p1is an integer selected from 0 to 6; p2is an integer selected from 0 to 12; p3is an integer selected from 0 to 12; each W is independently absent, CH2, O, S, NR 13 or C(O)NR 13 ; each R 13 is independently hydrogen or C1-C6 alkyl; W1and W2are independently absent, (CH2) 1-3 , O, NH or C(O)NR 13 ; and Z1and Z2are independently absent, -O-, -S-, -N(R 13 )-, -CºC-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR 13 )-, -C(O)N(R 13 )-, -C(O)N(R 13 )C(O)-, -C(O)N(R 13 )C(O)N(R 13 )-, -N(R 13 )C(O)-, -N(R 13 )C(O)N(R 13 )-, -N(R 13 )C(O)O-, -OC(O)N(R 13 )-, -C(NR 13 )-, -N(R 13 )C(NR 13 )-, -C(NR 13 )N(R 13 )-, -N(R 13 )C(NR 13 )N(R 13 )-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R 13 )S(O)2-, -S(O)2N(R 13 )-, -N(R 13 )S(O)-, -S(O)N(R 13 )-, -N(R 13 )S(O)2N(R 13 )-, -N(R 13 )S(O)N(R 13 )- C3-C 12 carbon cycloalkylene, 3- to 12-membered heterocycloalkylene, or 5- to 12-membered heteroarylene; wherein the linker is covalently bonded to the degron through the immediately adjacent to W2, and to the effector through the immediately adjacent to W1. covalently bonded to a targeting ligand, or the linker is through W1 covalently bonded to a degrading moiety, and through W2 covalently bonded to a targeting ligand.

[0062] In some embodiments, pi is an integer selected from 0 to 4. In some embodiments, pi is an integer selected from 0 to 2. In some embodiments, pi is an integer selected from 1 to 3.

[0063] In some embodiments, p2 is an integer selected from 0 to 8. In some embodiments, p2 is an integer selected from 0 to 6. In some embodiments, p2 is an integer selected from 0 to 4. In some embodiments, p2 is an integer selected from 1 to 4.

[0064] In some embodiments, p3 is an integer selected from 0 to 10. In some embodiments, p3 is an integer selected from 0 to 8. In some embodiments, p3 is an integer selected from 0 to 6. In some embodiments, p3 is an integer selected from 0 to 4. In some embodiments, p3 is an integer selected from 1 to 8. In some embodiments, p3 is an integer selected from 1 to 6. In some embodiments, p3 is an integer selected from 1 to 4.

[0065] In some embodiments, each W is CH2. In some embodiments, each W is O.

[0066] In some embodiments, each R 10 is independently hydrogen or methyl.

[0067] In some embodiments, W1 and W2 are independently absent, CH2, (CH2)2, (CH2)3, NH, C(O)NH, or C(O)NMe.

[0068] In some embodiments, Z1 and Z2 are independently absent, -O-, -N(R 13 )-, -C(O)-, -C(O)N(R 13 )-, -N(R 13 )C(O)-, C5-C6 carbocyclylene, 5- to 6-membered heterocyclylene, or 5- to 6-membered heteroarylene.

[0069] In some embodiments, Formula L0 has Formulae L0a-L0j: wherein TL represents a targeting ligand.

[0070] In some embodiments, the linker comprises an alkylene chain (e.g., having 1-18 alkylene units). In other embodiments, the linker can comprise an alkylene chain or a divalent alkylene chain, either of which can be interrupted and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(O)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, C3-C12 carbocycloalkylene, 3- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein R' is H or C1-C6 alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different. 12 C3-C12 carbocycloalkylene, 3- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein R' is H or C1-C6 alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different.

[0071] In some embodiments, the linker comprises an alkylene chain having 1-18 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(0)NH-, -C(0)N(Me)-, C6 carbocyclylene, 6-membered heterocyclylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-12 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(0)NH-, -C(0)N(Me)-, C6 carbocyclylene, 6-membered heterocyclylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-6 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(0)NH-, -C(0)N(Me)-, C6 carbocyclylene, 6-membered heterocyclylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-3 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(0)NH-, -C(0)N(Me)-, C6 carbocyclylene, 6-membered heterocyclylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-18 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1-12 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1-6 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1-3 alkylene units.

[0072] "Carbocyclylene" means a divalent carbocyclic ring, which is optionally substituted.

[0073] "Heterocyclylene" means a divalent heterocyclic ring, which can be optionally substituted.

[0074] "Heteroarylene" means a divalent heteroaryl group, which can be optionally substituted.

[0075] Representative examples of linkers that can be suitable for use in the present disclosure include alkylene chains: (L1), wherein n is an integer from 1-12 ("of" is meant to be inclusive), such as 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, 9-10, and 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, examples of which include: Alkylene chains ending with various functional groups (as described above) are, for example, as follows: Alkylene chains interrupted by various functional groups (as described above) are actually as follows: Hybridized subcyclic groups, for example (L4) Discontinuous or terminated alkylene chains, where m and n are independent integers from 0 to 10, examples of which include: Examples of alkylene chains interrupted by amide, heterocyclic, and / or aryl groups include: Examples of alkylene chains interrupted by heterocyclic groups, aryl groups, and heteroatoms include: as well as heteroatoms such as N, O or B, for example (L7) Interrupted and / or terminated alkylene chains, wherein each n is independently an integer from 1 to 10, such as 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, 9-10 and 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, and R is H or C1 to C4 alkyl, examples of which are (L7-a).

[0076] In some embodiments, the linker can include a polyethylene glycol (PEG) chain that can be terminated at either or both ends with at least one of: -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -R'C(O)N(R')R'-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C 3-12 carbon cycloalkylene, 3- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein R' is H or C1-C6 alkyl, wherein the one or two terminating groups can be the same or different.

[0077] In some embodiments, the linker includes a polyethylene glycol chain having 1-10 PEG units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof. In some embodiments, the linker includes a polyethylene glycol chain having 1-6 PEG units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof. In some embodiments, the linker includes a polyethylene glycol chain having 1-2 PEG units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof. In some embodiments, the linker includes a polyethylene glycol chain having 1-10 PEG. In some embodiments, the linker includes a polyethylene glycol chain having 1-6 PEG units. In some embodiments, the linker includes a polyethylene glycol chain having 1-2 PEG units.

[0078] Examples of linkers including a polyethylene glycol chain include: (L8), wherein n is an integer from 2-10, examples of which include: .

[0079] In some embodiments, the linker containing the polyethylene glycol chain can be terminated with a functional group, for example as follows: (L9-e).

[0080] In some implementations, the connector is represented by any of the following structures: and .

[0081] In some embodiments, the compounds of this disclosure may be represented by any of the following structures: , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0082] Degradon The ubiquitin-proteasome pathway (UPP) is an important cellular pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is important for multiple cellular processes. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases include over 500 different proteins and are classified into multiple categories defined by structural elements of their E3 functional activity.

[0083] The degrader can bind to an E3 ligase that is cereblon (CRBN) or von Hippel Lindau (VHL) tumor suppressor.

[0084] In some embodiments, the degrader that binds to cereblon is represented by D1: (D1), or a stereoisomer thereof; wherein, Q is CH2or C(O); and X1is O or NH.

[0085] In some embodiments, Q is CH2.

[0086] In some embodiments, Q is C=O.

[0087] In some embodiments, X1is O.

[0088] In some embodiments, X1is NH.

[0089] In some embodiments, X1is CH2.

[0090] In some embodiments, X1is C≡C.

[0091] In some embodiments, Q is CH2and X1is O. In some embodiments, Q is CH2and X1is NH. In some embodiments, Q is CH2and X1is CH2. In some embodiments, Q is CH2and X1is C≡C.

[0092] In some embodiments, Q is C(O) and X1is O. In some embodiments, Q is C(O) and X1is NH. In some embodiments, Q is C(O) and X1is CH2. In some embodiments, Q is C(O) and X1is C≡C.

[0093] In some embodiments, Formula D1 has the formula D1a-D1p: .

[0094] Thus, in some embodiments, the compounds of the disclosure can be represented by any of the following structures: , , , , , , , , , , , , , , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Q is CH2or C(O). In some embodiments, the linker comprises an alkylene chain having 1-12 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6carbocyclylene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-6 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6carbocyclylene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-3 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6carbocyclylene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-12 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1-6 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1-3 alkylene units. In some embodiments, the linker comprises a polyethylene glycol chain having 1-6 PEG units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof. In some embodiments, the linker comprises a polyethylene glycol chain having 1-2 PEG units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof. In some embodiments, the linker comprises a polyethylene glycol chain having 1-6 PEG units. In some embodiments, the linker comprises a polyethylene glycol chain having 1-2 PEG units.

[0095] In some embodiments, the degron can bind to an E3 ligase, which is the von Hippel-Lindau (VHL) tumor suppressor and is represented by D2 or D3: (D2) or (D3), or a stereoisomer thereof, wherein: R7is H or optionally substituted C1-C3alkyl, or R8and R9together with the carbon atom to which they are attached form a cyclopropyl; R8is H, methyl or ; R9is C(O)CR 10 R 11 R 12 , ; R 10 and R 11 are each H, or R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl group; R 12 is H, fluoro, cyano, or NMe2; and Y is H, , , or ; wherein is a bond between the degron and the linker, with the proviso that there is only one bond between the degron and the linker.

[0096] In some embodiments, the degron is of Formula D2.

[0097] In some embodiments, R7is H and R8is .

[0098] In some embodiments, R7and R8are each H.

[0099] In some embodiments, R7is H and R8is methyl.

[0100] In some embodiments, R7is optionally substituted C1-C3alkyl and R8is H.

[0101] In some embodiments, R7is optionally substituted C1-C3alkyl and R8is methyl.

[0102] In some embodiments, R7and R8together with the carbon atom to which they are attached form a cyclopropyl group.

[0103] In some embodiments, Y is H.

[0104] In some embodiments, Y is , , or .

[0105] In some embodiments, R9is .

[0106] In some embodiments, R9is C(O)CR 10 R 11 R 12 In some embodiments, R 10 , R 11 , and R 12is H. In some embodiments, R6and R7together with the carbon atom to which they are attached form a cyclopropyl group and R8is H, fluoro, cyano, or NMe2. In some embodiments, R8is fluoro, cyano, or NMe2.

[0107] In some embodiments, R7is H, R8is and Y is H.

[0108] In some embodiments, R7is H, R8is , Y is H, and R9is C(O)CR 10 R 11 R 12 wherein R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl group and R 12 is fluoro, cyano, or NMe2.

[0109] In some embodiments, Y is , , or and R7and R8are H.

[0110] In some embodiments, Y is , , or , R7and R8are H, and R9is C(O)CR 10 R 11 R 12 wherein R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl group and R 12 is fluoro, cyano, or NMe2.

[0111] In some embodiments, R9is , Y is H, and R7and R8are H.

[0112] In some embodiments, R9is , Y is H, R7is H, and R8is methyl.

[0113] In some embodiments, R9is , Y is H, R7is optionally substituted C1-C3alkyl, and R8is H.

[0114] In some embodiments, R9is , Y is H, R7is optionally substituted C1-C3alkyl, and R8is H.

[0115] In some embodiments, R9is Y is H, and R7and R8together with the carbon atom to which they are attached form a cyclopropyl.

[0116] In some embodiments, Formula D2 has Formulae D2a-D2o: , or a stereoisomer thereof.

[0117] In some embodiments, the degrader has Formula D3.

[0118] In some embodiments, the degrader of Formula D3 has Formulae D3a-D3g: , or a stereoisomer thereof, Thus, in some embodiments, the compounds of the present disclosure can be represented by any of the following structures: , , , , , or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the linker comprises an alkylene chain having 1-12 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6 carbocyclylene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-6 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6 carbocyclylene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-3 alkylene units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6 carbocyclylene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1-12 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1-6 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1-3 alkylene units. In some embodiments, the linker comprises a polyethylene glycol chain having 1-6 PEG units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof. In some embodiments, the linker comprises a polyethylene glycol chain having 1-2 PEG units and is interrupted and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof. In some embodiments, the linker comprises a polyethylene glycol chain having 1-6 PEG units. In some embodiments, the linker comprises a polyethylene glycol chain having 1-2 PEG units.

[0119] In some embodiments, the compounds of the present disclosure are represented by any one of the following structures: or a pharmaceutically acceptable salt or stereoisomer thereof.

[0120] The compounds of the present disclosure can be in the form of a free acid or a free base or a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the compounds of the present disclosure can be formed, for example, by reaction of a suitable free base of a compound of the present disclosure with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, e.g., Gould, P. L., "Salt selection for basic drugs," International Journal of Pharmaceutics, 33 : 201-217 (1986); Bastin, R. J., et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4 : 427-435 (2000); and Berge, S. M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66 : 1-19, (1977).

[0121] The compounds of the present disclosure can have at least one chiral center and therefore can exist as stereoisomers, which as used herein, include all isomers that differ only in their atomic spatial orientation. The term stereoisomers includes mirror image isomers (enantiomers, which include compounds having either the (R- ) or (S-) configuration), mixtures of mirror image isomers (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of compounds, and isomers of compounds having more than one chiral center that are not mirror images of one another (diastereomers). The chiral centers of the compounds can undergo epimerization in vivo; thus, for these compounds, administration of a compound in the (R-) form is considered equivalent to administration of a compound in the (S-) form. Thus, the compounds of the present disclosure can be prepared and used in the form of each isomer and substantially free of other isomers, or as mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0122] In some embodiments, a compound of Formula (I) is an isotopically-labeled derivative, because one or more of its atoms are replaced by an atom having an atomic mass or mass number that is substantially the same as the atomic mass or mass number of the atoms which they replace. In one embodiment, the compound includes one or more deuterium atoms. As used herein, the term "compound" includes isotopically-labeled derivatives.

[0123] The compounds of Formula (I) can also exist in N-oxide forms, in crystalline forms (also known as polymorphs), co-crystals, active metabolites, prodrugs, tautomers, and unsolvated as well as solvated forms (for example, hydrated forms) with pharmaceutically acceptable solvents such as water, ethanol, and the like. As used herein, the term "compound" includes all such forms.

[0124] The compounds of Formula (I) can be prepared by crystallization under different conditions and can exist as one polymorph or a combination of polymorphs of the compound. For example, different polymorphs can be recrystallized using different solvents or different solvent mixtures, identified and / or prepared by crystallization at different temperatures or by using various cooling regimes ranging from very fast to very slow cooling during crystallization, by heating or melting the compound followed by gradual or fast cooling. The existence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction patterns, and / or other known techniques.

[0125] In some embodiments, the pharmaceutical composition comprises a co-crystal of the compound of Formula (I). The term "co-crystal" as used herein refers to a stoichiometric multi-component system comprising the compound of Formula (I) and a co-crystal former, wherein the compound of Formula (I) and the co-crystal former are connected by non-covalent interactions. The term "co-crystal former" as used herein refers to a compound that can form intermolecular interactions with the compound of Formula (I) and co-crystallize with it. Representative examples of co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydrobenzoic acid, glycolic acid, trans-4-hydroxy cinnamic acid, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroquinone, isoniazid, theophylline, adenine, theobromine, acetophenetidin, dimethylphenylpyrazolone, ethoxytheophylline, and phenobarbital. - 2-hexanoic acid, 2-hydroxyhexanoic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picrolic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine, p- aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, m-pyrogallol, hydroquinone, isoniazid, theophylline, adenine, theobromine, acetophenetidin, dimethylphenylpyrazolone, ethoxytheophylline, and phenobarbital.

[0126] Synthetic Methods In some embodiments, the present disclosure relates to methods for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. Broadly, the compounds, or pharmaceutically acceptable salts or stereoisomers thereof, can be prepared by any method known to be applicable to the preparation of a chemically related compound. The compounds of the present disclosure will be better understood in connection with the synthetic schemes described in the various working examples that illustrate non-limiting methods by which the compounds of the present disclosure can be prepared.

[0127] Pharmaceutical Composition Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as known in the art refers to a pharmaceutically-acceptable material, composition or vehicle, which is suitable for administering a compound of the present disclosure to a mammal. Suitable carriers can include, for example, liquids (both aqueous and non-aqueous, as well as combinations thereof), solids, encapsulating materials, gases and combinations thereof (e.g., semi-solids), and gases, which serve to carry or transport the compound from one organ, or portion of the body, to another organ, or portion of the body. The carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and the formulation is not deleterious to the subject or patient in the manner in which it is to be administered. Depending on the type of formulation, the composition can further include one or more pharmaceutically acceptable excipients.

[0128] Broadly speaking, the compounds of Formula (I) and pharmaceutically acceptable salts and stereoisomers thereof can be formulated into compositions in accordance with conventional pharmaceutical practice, e.g., conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes (see, e.g., Remington: The Science and Practice of Pharmacy, 20th ed., ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and The Science and Practice of Pharmacy (20thed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology , eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York), each incorporated herein by reference in their entirety. The type of formulation depends on the mode of administration, which can include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous ( s.c. ), intravenous ( i.v. ), intramuscular ( i.m. ) and intrasternal injection or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intracerebroventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation and inhalation) and topical (e.g., transdermal).

[0129] Generally speaking, the most appropriate route of administration will depend on a variety of factors, including, for example, the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). For example, parenteral (e.g., intravenous) administration can also be advantageous in that the compound can be administered relatively quickly, e.g., in the case of single dose therapy and / or acute conditions.

[0130] In some embodiments, the compounds are formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0131] Thus, the compounds of Formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets and suppositories), liquid compositions (e.g., solutions in which the compounds are dissolved, suspensions in which solid particles of the compounds are dispersed, emulsions and solutions containing liposomes, micelles or nanoparticles, syrups and elixirs); semi-solid compositions (e.g., gels, suspensions and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid, intermediate or extended release.

[0132] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with a carrier, e.g., sodium citrate or dicalcium phosphate, and other carriers or excipients, such as a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, e.g., paraffin; f) absorption accelerators, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other coatings, shells, which protect such dosage forms from the atmosphere and / or moieties in the gastrointestinal tract that break down such dosage forms. They can also further contain opacifying agents, and can also be of a composition that they release the active compound(s) only, or preferentially, in a particular segment of the gastrointestinal tract, as in a targeted drug delivery system. They can also contain agents to delay the absorption of the active compound(s) from the gastrointestinal tract.

[0133] In some embodiments, the compounds of Formula (I) can be formulated in hard or soft gelatin capsules. Representative excipients that can be used include pregelatine starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose, and croscarmellose sodium. Gelatin shells can include gelatin, titanium dioxide, iron oxide, and colorants.

[0134] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups, and elixirs. In addition to the subject compound, the liquid dosage forms can contain inert carriers, e.g., water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylen glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions can also include excipients, e.g., wetting agents, suspending agents, coloring, sweetening, flavoring, and perfuming agents.

[0135] Injectable preparations for parenteral administration include sterile aqueous and oleaginous suspensions. They can be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable forms can also be aqueous or oleaginous solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable formulations 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 prior to use. The effects of the compounds can be prolonged by slowing their absorption, which can be accomplished by the use of a liquid suspension or a crystalline or amorphous material having poor water solubility. Prolonged absorption of a compound from a parenteral administration can also be accomplished by suspending the compound in an oil vehicle.

[0136] In certain embodiments, the compounds of Formula (I) can be administered in a local rather than systemic manner, for example, via injection directly into an organ, typically in a depot formulation or slow release formulation. In particular embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming a matrix consisting of the compound in a biodegradable polymer, for example, polylactic acid- polyglycolic acid, poly(orthoesters) and poly(anhydrides). The rate of release of the compound can be controlled by varying the ratio of the compound to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues. In other embodiments, the compounds are delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to the organ and are selectively taken up by the organ.

[0137] Compositions can be formulated for buccal or sublingual administration, examples of which include tablets, lozenges and gels.

[0138] The compounds of Formula (I) can be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists, or powders. The pharmaceutical compositions can be used in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichloromonofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, the dosage unit for a pressurized aerosol can be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0139] The compounds of Formula (I) can be formulated for topical administration, which as used herein, refers to intradermal administration by injection of a formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0140] Representative examples of vehicles that can be used to formulate the compounds for topical application include solvents (e.g., alcohols, polyols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline). For example, creams can be formulated using saturated or unsaturated fatty acids, such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl alcohol, or oleyl alcohol. Creams can also contain non-ionic surfactants, such as polyoxyl-40-stearate.

[0141] In some embodiments, the topical formulation can also include an excipient, an example of which is a penetration enhancer. These agents are capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in enhancing the rate of penetration of drugs through the skin. See, e.g., Percutaneous Penetration Enhancers , Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al. , Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery SystemsRepresentative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe vera compositions (e.g., aloe vera gel), ethanol, isopropyl alcohol, octyl phenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glyceryl monooleate, and propylene glycol monooleate), and N-methyl pyrrolidone.

[0142] Representative examples of other excipients that can be included in topical, as well as other forms of, formulations to the extent that they are compatible, include preservatives, antioxidants, humectants, emollients, buffering agents, solubilizing agents, skin-protective agents, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents such as EDTA and citric acid. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffering agents include citric acid, hydrochloric acid, and lactic acid buffers. Suitable solubilizing agents include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin-protective agents include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0143] Transdermal formulations generally use transdermal delivery devices and transdermal delivery patches in which the compound is dispensed in a lipophilic emulsion or buffered aqueous solution, which is dissolved and / or dispersed in a polymer or adhesive. The patch can be constructed to deliver the medicament continuously, pulsed, or on demand. Transdermal delivery of the compound can be achieved by means of iontophoresis patches. Transdermal patches can provide controlled delivery of the compound, in which the rate of absorption is slowed by the use of a rate-controlling membrane or by embedding the compound in a polymer matrix or gel. Absorption enhancers can be used to increase absorption, examples of which include absorbable, pharmaceutically acceptable solvents that aid in passage through the skin.

[0144] Ophthalmic formulations include eye drops.

[0145] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which can contain conventional suppository formulations, such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. Compositions for rectal or vaginal administration can also be formulated as suppositories, which can be prepared by mixing the compound with a suitable non-irritating carrier and excipient such as cocoa butter, a fatty acid glyceride mixture, a polyethylene glycol, a suppository wax, and the like, all of which melt at body temperatures and thus exit the body rectally or vaginally.

[0146] Dose As used herein, the term "therapeutically effective amount" means an amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, effective to produce the desired therapeutic response in a particular patient in need thereof. Thus, the term "therapeutically effective amount" includes an amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, which when administered induces a positive improvement of the disease or condition to be treated, or is sufficient to prevent development or progression of the disease or condition, or to alleviate to some extent one or more symptoms of the disease or condition being treated in a subject, or simply to kill diseased (e.g., cancer, autophagy-dependent disease (e.g., neurodegenerative disorder)) cells or inhibit their growth, or reduce the amount of DNMT1 in diseased cells.

[0147] The total daily dose and its use can be decided according to standard medical practice, e.g., by the attending physician using sound medical judgment. The specific therapeutically effective dose for any particular subject can depend upon many factors, including the disease or condition being treated and its severity (e.g., its current status); the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the compound; and like factors well known in the medical arts (see, e.g., Hardy and Driscoll, eds., A to Z of Goodman and Gilman's The Pharmacological Basis of Therapeutics , 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001), which is incorporated herein by reference in its entirety.

[0148] Method of Use In some aspects, the present disclosure relates to methods of treating a disease or disorder by reducing the level or activity of DNMT1. The methods entail administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0149] The disease or disorder is characterized or mediated by aberrant DNMT1 activity, e.g., elevated levels of DNMT1, or otherwise functionally abnormal DNMT1, e.g., mutant DNMT1 activity, relative to a non-pathological state. A "disease" is generally considered to be a state of health of a subject in which the subject is unable to maintain homeostasis, and in which the health of the subject continues to deteriorate if the disease is not ameliorated. In contrast, a "disorder" of a subject is a state of health of the subject in which the subject is able to maintain homeostasis, but in which the state of health of the subject is more adverse than it would be in the absence of the disorder. Without treatment, a disorder does not necessarily lead to further deterioration of the state of health of the animal.

[0150] The term "subject" (or "patient") as used herein includes all members of the animal kingdom that are susceptible to or afflicted with a specified disease or disorder. In some embodiments, the subject is a mammal, e.g., a human or a non-human mammal. The methods are also applicable to companion animals, e.g., dogs and cats. In accordance with the present disclosure, a subject who is in need of treatment "may be suffering from or suspected of suffering from" a particular disease or disorder, which can have been diagnosed definitively or otherwise exhibited a sufficient number of risk factors or a sufficient number or combination of signs or symptoms such that a medical professional is able to diagnose or suspect that the subject is suffering from the disease or disorder. Thus, subjects who are suffering from and suspected of suffering from a particular disease or disorder are not necessarily two distinct populations.

[0151] In some embodiments, the compounds of Formula (I) can be used to treat cell proliferative diseases and disorders. As used herein, the term "cell proliferative disease or disorder" refers to conditions characterized by dysregulated or abnormal or both cell growth, including non-cancerous conditions, e.g., neoplasms, precancerous conditions, benign tumors, and cancers.

[0152] In some embodiments, the methods of the present disclosure entail treating a subject having a cell proliferative disease or disorder of the blood system, liver, brain, colon, prostate, breast, and head and neck.

[0153] As used herein, "a cell proliferative disease or disorder of the blood system" includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplastic disorders, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, myeloid metaplasia of unknown cause, and essential thrombocythemia. Representative examples of blood system cancers can thus include leukemia, multiple myeloma, and lymphoma (including T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL). Examples of NHL include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), cutaneous T-cell lymphoma (CTCL) (including mycosis fungoides and Sezary syndrome), peripheral T-cell lymphoma (PTCL) (including anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, epithelial T-cell lymphoma, and gamma-delta T-cell lymphoma), germinal center B-cell-like diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, Burkitt's lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, refractory NHL, relapsed NHL, pediatric lymphoma, and small lymphocytic lymphoma. Examples of leukemia include childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, mast cell leukemia, myeloid neoplasms, and mast cell neoplasms.

[0154] As used herein, "a cell proliferative disease or disorder of the liver" includes all forms of cell proliferative disorders affecting the liver. Cell proliferative disorders of the liver can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatoblastoma), precancerous or pre-cancerous conditions of the liver, benign growths or lesions of the liver, and malignant growths or lesions of the liver, as well as metastatic lesions of tissues and organs in the body other than the liver. Cell proliferative disorders of the liver can include hyperplasia, metaplasia, and dysplasia of the liver.

[0155] As used herein, "a cell proliferative disease or disorder of the brain" includes all forms of cell proliferative disorders affecting the brain. Cell proliferative disorders of the brain can include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, and primitive neuroectodermal tumor (medulloblastoma)), precancerous or pre-cancerous conditions of the brain, benign growths or lesions of the brain, and malignant growths or lesions of the brain, as well as metastatic lesions of tissues and organs in the body other than the brain. Cell proliferative disorders of the brain can include hyperplasia, metaplasia, and dysplasia of the brain.

[0156] As used herein, a "cell proliferative disease or disorder of the colon" includes all forms of cell proliferative disorders affecting cells of the colon, including colon cancer, precancerous or pre-cancerous conditions of the colon, colonic adenomatous polyps, and colonic metaplastic lesions. Colon cancer includes sporadic and hereditary colon cancer, malignant colon tumors, carcinoma in situ, typical and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer can be associated with hereditary syndromes, such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis. Cell proliferative disorders of the colon can also be characterized by hyperplasia, metaplasia, or dysplasia of the colon.

[0157] As used herein, a "cell proliferative disease or disorder of the prostate" includes all forms of cell proliferative disorders affecting cells of the prostate. Cell proliferative disorders of the prostate can include prostate cancer, precancerous or pre-cancerous conditions of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, as well as metastatic lesions of tissues and organs in the body other than the prostate. Cell proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate.

[0158] As used herein, a "cell proliferative disease or disorder of the breast" includes all forms of cell proliferative disorders affecting cells of the breast. Cell proliferative disorders of the breast can include breast cancer, precancerous or pre-cancerous conditions of the breast, benign growths or lesions of the breast, and metastatic lesions of tissues and organs in the body other than the breast. Cell proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0159] These and other aspects of the present disclosure will become further apparent from the following examples, which are intended to illustrate certain specific embodiments of the disclosure, but not to limit its scope as defined by the claims. Examples

[0160] Example 1 : Synthesis of N-( 1 -(6-((2-amino-2-oxo- 1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanamide (1) 3,5-Dicyano-4-ethyl-6-hydroxypyridine-2-carboxylic acid ammonium salt 2,6-Dichloro-4-ethylpyridine-3,5-dicarbonitrile 2-Amino-2-oxo- 1 -phenylethyl methanesulfonate To a solution of 2-cyanoacetamide (28.6 g, 0.34 mol) in water (190 mL) was added ammonium hydroxide (25% aqueous solution, 10 mL) and propionaldehyde (10 g, 0.17 mol). The mixture was stirred at room temperature (rt) for 16 hours, then filtered. The filter cake was washed with cold methanol and dried under reduced pressure to obtain the title compound (12 g, 34.3%).

[0161] ( 1 -(6-((2-amino-2-oxo- 1 -phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4- yl)carbamic acid tert-butyl ester To a thick walled 75 mL reaction tube with a magnetic stir bar was added POCl3(10 mL). 3,5-Dicyano-4-ethyl-6-hydroxypyridine-2-carboxylic acid ammonium salt (1.26 g, 5.82 mmol) was carefully added while stirring. The tube was capped and heated at 150 °C for 30 hours. The reaction mixture was cooled to rt and the POCl3evaporated under a stream of nitrogen. The residue was poured into 150 mL of ice water. The resulting suspension was filtered and the filter cake was washed with water and dried under reduced pressure to obtain the title compound as a grey solid (1.03 g, 78.2 %). LCMS m / z = 206.31, 208.32, 226.38.

[0162] 2-((6-(4-Aminopiperidin- 1 -yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide To a solution of 2-hydroxy-2-phenylacetamide (0.90 g, 5.95 mmol) in acetonitrile (18 mL) was added triethylamine (1.20 g, 1.65 mL, 2 eq) and methanesulfonyl chloride (0.84 g, 0.52 mL, 1.23 eq). The reaction mixture was stirred at 40 °C for 5.5 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DCM (100 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (1.1 g, 80 %). LCMS m / z = 230.22.

[0163] N-( 1 -(6-((2-amino-2-oxo- 1 -phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4- yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide Example 2: Synthesis of N-( 1 -(6-((2-amino-2-oxo- 1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)propanamide (2) A suspension of 2,6-dichloro-4-ethylpyridine-3,5-dicarbonitrile (300 mg, 1.33 mmol) in EtOH (2 mL) was cooled to -20 °C. A solution of tert-butyl piperidin-4-yl carbonate (292 mg, 1.1 eq) in EtOH (2.5 mL) was added and the mixture was stirred at -20 °C for 30 minutes. Then potassium thioacetate (227 mg, 1.5 eq), triethylamine (0.46 mL) and ethanol (5 mL) were added and the mixture was stirred at rt for 17 hours. 2-Amino-2-oxo-1-phenylethyl methanesulfonate (608 mg, 2 eq) was added and the mixture was stirred at 40 °C for 3 hours and then cooled to rt. The mixture was filtered and the filter cake was washed with EtOH, water and diethyl ether and then dried under reduced pressure to obtain the title compound (0.283 g, 41.0 %). LCMS m / z = 521.55 [M+H] + .

[0164] Example 3: Synthesis of N-( 1 -(6-((2-amino-2-oxo- 1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)propanamide (3) Dioxane (0.3 mL) and 4M HCI in dioxane (0.3 mL) were added to 4-(6-((2-amino-2-oxo-l- phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperazine-l-carboxylate (51.96 mg, 0.1 mmol). The mixture was stirred at rt for 6 h and the solvent was removed under reduced pressure to obtain the title compound (45.1 mg, 100%). LCMS m / z = 422.48 [M+H] + .

[0165] ​ ​ ​ 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide (3.85 mg, 0.00915 mmol), 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (4.37 mg, 1.0 eq) and triethylamine (4.62 mg, 5.0 eq) were dissolved in DMF (0.2 mL). HATU (5.22 mg, 1.5 eq) was added and the solution was stirred at rt for 15 min. The reaction mixture was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-5% MeOH / DCM to obtain the title compound (3.18 mg, 39.5%). LCMS m / z = 880.78 [M+H] + .

[0166] ​ ​ ​ The compound 2 was prepared using a similar procedure to that used in Example 1 from 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid. LCMS m / z = 880.82 [M+H] + .

[0167] ​ N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanamide (4) Example 4: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanamide (4) Compound 3 was prepared using a similar procedure to that used in example 1 from 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)hexanoic acid. LCMS m / z = 790.72 [M+H] + .

[0168] Example 5: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)decanamide (5) Example 6: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)lauramide (6) Example 7: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxamide (7) Compound 4 was prepared using a similar procedure to that used in example 1 from 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)octanoic acid. LCMS m / z = 818.77 [M+H] + .

[0169] Example 8: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzamide (8) Example 9: Synthesis of N-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)-6-oxohexyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxamide (9) tert-Butyl 6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)-6-oxohexyl)carbamate Compound 5 was prepared using a similar procedure to that used in example 1 from 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)decanoic acid. LCMS m / z = 846.77 [M+H] + .

[0170] 6-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)hexanamide N-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)-6-oxohexyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxamide ​ Compound 6 was prepared using a similar procedure to that used in example 1 from 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 12-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)dodecanoic acid. LCMS m / z = 874.85 [M+H] + .

[0171] ​​ ​ Compound 7 was prepared using a similar procedure to that used in Example 1 from 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)cyclohexane-1-carboxylic acid. LCMS m / z = 802.77 [M+H] + .

[0172] ​ ​ ​ Compound 8 was prepared using a similar procedure to that used in Example 1 from 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)benzoic acid. LCMS m / z = 810.71 [M+H] + .

[0173] ​ ​ ​ ​ ​ 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide (20.7 mg, 0.0492 mmol), 6-((tert-butoxycarbonyl)amino)hexanoic acid (11.4 mg, 0.0492 mmol) and triethylamine (34.4 µL, 0.245 mmol) were dissolved in DMF (0.25 mL). HATU (28.1 mg, 0.0738 mmol) was added and the mixture was stirred at rt for 15 min. The solvent was removed under a stream of nitrogen and the residue was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with 0-4% MeOH / DCM to give the title compound (26.7 mg, 85.6%). LCMS m / z = 634.67 [M+H] + .

[0174] ​ ​ A solution of THF (0.2 mL) and 4 M HCl in dioxane (0.4 mL, 1.6 mmol) was added to tert-butyl carbamate (6-((1-(6-(((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)-6-oxohexyl)carbamate (11.9 mg, 0.0188 mmol). The mixture was stirred at rt for 13 hours. The solvent was removed under reduced pressure to obtain the title compound (9.84 mg, 98%). LCMS m / z = 535.53 [M+H] + .

[0175] ​ yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide Using a procedure similar to that used in Example 1, from 6-amino- N The title compound was prepared from 1-(6-(((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)hexanoamide and 4-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)cyclohexane-1-carboxylic acid. LCMS m / z = 915.74 [M+H] + .

[0176] Example 10: Synthesis of N-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5- dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)-6-oxohexyl)-4-(((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzamide (10) Example 11: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano- 4-ethylpyridin-2-yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethyl)piperazin-1-yl)propanamide (11) yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide Using a procedure similar to that used in Example 1, from 6-amino- N Compound 10 was prepared from 1-(6-(((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)hexanoamide and 4-(((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)benzoic acid. LCMS m / z = 923.79 [M+H] + .

[0177] yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide A mixture of 3-(4-(2-aminoethyl)piperazin-1-yl)propanoic acid methyl ester (100 mg, 0.464 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (128.3 mg, 0.464 mmol), diisopropylethylamine (405 µL, 2.32 mmol) and N - methylpyrrolidine (2.3 mL) was added to a microwave reaction tube. The tube was capped and microwaved at 100 °C for 1 hour. The mixture was cooled to rt and purified by column chromatography (Teledyne ISCO, 40 g silica gel column) eluting with a gradient of 0-5% MeOH / DCM to obtain the title compound (44.16 mg, 20.1%). LCMS m / z = 472.45 [M+H] + .

[0178] yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide yl)piperidin-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)piperazin-1-yl)propanamide A mixture of 3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)propanoic acid methyl ester (44.16 mg, 0.0937 mmol), 4 M HCl in dioxane (1.6 mL) and water (0.5 mL) was heated at 100 °C for 30 minutes. The solvent was removed by lyophilization to obtain the title compound. LCMS m / z = 458.69 [M+H] + .

[0179] ​ ​ ​ The title compound was prepared using a procedure similar to that used in Example 1 from 6-amino- N - (1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)hexanamide and 3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)propanoic acid. LCMS m / z = 860.64 [M+H] + .

[0180] ​ ​ ​ ​ ​ A mixture of methyl 3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethyl)piperazin-l-yl)propanoate (25.0 mg, 0.0531 mmol), 4 M HC1 in dioxane (1.0 mL) and water (0.25 mL) was heated at 100 °C for 30 min. The solvent was removed by lyophilization to obtain the title compound. LCMS m / z = 458.43 [M+H] N - methylpyrrolidine (2.0 mL) was added to a microwave reaction tube. The tube was capped and microwaved at 100 °C for 1 h. The mixture was cooled to rt and purified by column chromatography (Teledyne ISCO, 40 g silica gel column) eluting with a gradient of 0-15% MeOH / DCM to obtain the title compound (25.0 mg, 12.5%). LCMS m / z = 473.33 [M+H] + .

[0181] ​ ​ A mixture of methyl 3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethyl)piperazin-l-yl)propanoate (25.0 mg, 0.0531 mmol), 4 M HC1 in dioxane (1.0 mL) and water (0.25 mL) was heated at 100 °C for 30 min. The solvent was removed by lyophilization to obtain the title compound. LCMS m / z = 458.43 [M+H] + .

[0182] ​ ​ ​ The title compound was prepared using a procedure similar to that used in Example 1 from 6-amino- N The title compound was prepared using a procedure similar to that used in Example 1 from 6-amino- + .

[0183] ​ (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino Acetamide (13) Compound 13 was prepared from 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetamide and (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)glycine using a procedure similar to that used in Example 1. LCMS m / z = 734.49 [M+H] + .

[0184] Example 14: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethyl (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl) (14)amino)ethoxy)acetamide Compound 14 was prepared from 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetamide and 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)acetic acid using a procedure similar to that used in Example 1. LCMS m / z = 778.57 [M+H] + .

[0185] Example 15: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethyl (2,6-dioxopiperidin-3-yl)piperidin-4-yl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-) (15)amino)ethyl)benzamide Compound 15 was prepared from 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetamide and 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)amino)ethyl)benzoic acid using a procedure similar to that used in Example 1. LCMS m / z = 824.50 [M+H] + .

[0186] Example 16: Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethyl (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-6-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl) (16)amino)propyl)amino)nicotinamide 6-((3-((2-(2,6 - dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino Nicotinic acid Compound 13 was prepared from 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetamide and (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)glycine using a procedure similar to that used in Example 1. LCMS m / z = 734.49 [M+H] NA mixture of methylpyrrolidinone (0.1 mL) was stirred at 90 °C for 20 h. The mixture was cooled to rt and purified by column chromatography (Teledyne ISCO, 12 g silica gel column) eluting with a gradient of 0-12% MeOH / DCM to obtain the title compound (1.0 mg, 14.3%). LCMS m / z = 452.34 [M+H] + .

[0187] N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) Piperidin-4-yl)-6-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propyl) (amino)nicotinamide The title compound was prepared using a similar procedure to that used in Example 1 from 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide and 6-((3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)propyl)amino)nicotinic acid. LCMS m / z = 854.57 [M+H] + .

[0188] Example 17: Synthesis of (2S,4R)-1-((2S)-2-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)) (Thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)hexanoylamino)-3,3-dimethylbutyryl)- 4-Hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (17) tert-butyl 6-bromohexanoate 6-Bromohexanoic acid (390 mg, 2.0 mmol) and trifluoroacetic anhydride (1.11 mL, 8.0 mmol) were dissolved in THF (4 mL). The solution was stirred at rt for 1.5 h, then tert-butanol (2 mL, 34.5 mmol) was added. The solution was stirred at rt for 16 h, then quenched by slow addition of saturated aqueous NaHC03(15 mL). The mixture was extracted with EtOAc (3 x 20 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was filtered through a plug of silica gel, eluting with 50% EtOAc / hexanes (20 mL). The filtrate was concentrated in vacuo to obtain the title compound as a colorless oil (357.05 mg, 71.1%).

[0189] 6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) Piperidin-4-yl)amino)tert-butyl hexanoate 6-Amino- N-(1-(6-(((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)hexanoamide (5.0 mg, 0.0119 mmol) and DIPEA (10.4 µL, 0.0594 mmol) were dissolved in DMF (60 µL) and the solution was stirred at rt for 4 h. A DMF solution (50 µL) of tert-butyl 6-bromohexanoate (2.2 mg, 0.00893 mmol) was added and the mixture was stirred at rt for 16 h. Another portion of tert-butyl 6-bromohexanoate (0.88 mg, 0.0035 mmol) was added and the mixture was stirred for another 6 h. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) with a gradient elution of 0–6% MeOH / DCM to obtain the title compound (2.0 mg, 28.6%). LCMS m / z = 591.54 [M+H] + .

[0190] 6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) Piperidin-4-yl)amino)hexanoic acid 6-((1-(6-(((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)tert-butyl hexanoate (2.0 mg, 0.00339 mmol) and TFA (5 µL, 0.0653 mmol) were dissolved in DCM (20 µL). The mixture was stirred at rt for 2 h, and then concentrated under vacuum to obtain the title compound. LCMS m / z = 535.45 [M+H] + .

[0191] (2S,4R)-1-((2S)-2-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano) (4-ethylpyridin-2-yl)piperidin-4-yl)amino)hexanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)hexanoic acid (2.0 mg, 0.00374 mmol) and (2 S 4 R )-1-(( S )-2-amino-3,3-dimethylbutyryl)-4-hydroxy- N -(( S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.8 mg, 0.00374 mmol) and triethylamine (2.62 μL, 0.0187 mmol) were dissolved in DMF (100 μL). To the solution was added HATU (2.1 mg, 0.00561 mmol) and the mixture was stirred at rt for 15 min, then purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-20% MeOH / DCM to give the title compound (0.62 mg, 17.2%). LCMS m / z = 961.80 [M+H] + .

[0192] Example 18: Synthesis of (2S,4R)-1-((2S)-2-(10-((1-(6-((2-amino-2-oxo-1- phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)dec anoyl amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (18) tert-Butyl 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)decanoate tert-Butyl 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)decanoate tert-Butyl 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)decanoate 10-Bromodecanoic acid (251.2 mg, 1 mmol) and trifluoroacetic anhydride (556 μL, 4.00 mmol) were dissolved in THF (2 mL) and the solution was stirred at rt for 2 h. Tert-butanol (1 mL) was added and the mixture was stirred for 16 h. The reaction was quenched slowly by the addition of saturated aqueous NaHCO3(10 mL). The mixture was extracted with EtOAc (3 x 10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.28 g, 92.6%).

[0193] (2S,4R)-1-((2S)-2-(10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)dec anoyl amino)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Example 19: Synthesis of (2S,4R)-1-((2S)-2-(16-((1-(6-((2-amino-2-oxo-1- phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)hexadec anoyl amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (19) 6-Amino- N -(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)hexanamide (10.0 mg, 0.0238 mmol) and DIPEA (20.8 μL, 0.119 mmol) were dissolved in DMF (50 μL) and the solution was stirred at rt for 2 h. A solution of tert-butyl 10-bromodecanoate (7.3 mg, 0.0238 mmol) in DMF (50 μL) was added and the mixture was stirred at rt for 16 h. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-5% MeOH / DCM to give the title compound (4.51 mg, 29.3%). LCMS m / z = 647.62 [M+H] + .

[0194] tert-Butyl 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)hexadecanoatetert-Butyl 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)hexadecanoate tert-Butyl 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)decanoate (4.51 mg, 0.00697 mmol) and TFA (5 µL) were dissolved in DCM (50 µL) and the solution was stirred at rt for 18 h, then concentrated in vacuo to obtain the title compound. LCMS m / z = 592.52 [M+H] + .

[0195] tert-Butyl 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)hexadecanoate (2S,4R)-1-((2S)-2-(16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)hexadec anoyl amino)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Example 20: Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5- dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)acetamide 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)decanoic acid (4.1 mg, 0.00697 mmol), (2 S ,4 R )-1-(( S )-2-amino-3,3-dimethylbutanoyl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (3.4 mg, 0.00697 mmol) and TEA (4.9 µL, 0.0349 mmol) were dissolved in DMF (50 µL). HATU (4.0 mg, 0.0105 mmol) was added and the mixture was stirred at rt for 1 h, then purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-15% MeOH / DCM to obtain the title compound (3.73 mg, 52.6%). LCMS m / z = 1017.85 [M+H] + .

[0196] ​ ​ ​ ​ Dissolve 16-bromohexadecanoic acid (335.3 mg, 1 mmol) and trifluoroacetic anhydride (556 µL, 4.00 mmol) in THF (2 mL) and stir the solution at rt for 2 hours, then add tert-butanol (1 mL) and stir the mixture for 16 hours. Quench the reaction by slow addition of saturated aqueous NaHCO3(10 mL). Extract the mixture with EtOAc (3 x 10 mL), and dry the combined organic layers over sodium sulfate, filter and concentrate in vacuo to obtain the title compound (0.39 g, 100%).

[0197] ​ ​ Dissolve 6-amino-1-phenylethanone (0.5 g, 3.19 mmol) and potassium tert- butoxide (0.5 g, 4.79 mmol) in DMSO (5 mL) and stir the solution at rt for 2 hours. Add 2-bromo-3,5-dicyano-4-ethylpyridine (0.7 g, 3.19 mmol) and stir the mixture at rt for 16 hours. Quench the reaction by slow addition of saturated aqueous NaHCO3(10 mL). Extract the mixture with EtOAc (3 x 10 mL), and dry the combined organic layers over sodium sulfate, filter and concentrate in vacuo to obtain the title compound (0.7 g, 100%). N Dissolve 6-amino-1-phenylethanone (0.5 g, 3.19 mmol) and potassium tert- butoxide (0.5 g, 4.79 mmol) in DMSO (5 mL) and stir the solution at rt for 2 hours. Add 2-bromo-3,5-dicyano-4-ethylpyridine (0.7 g, 3.19 mmol) and stir the mixture at rt for 16 hours. Quench the reaction by slow addition of saturated aqueous NaHCO3(10 mL). Extract the mixture with EtOAc (3 x 10 mL), and dry the combined organic layers over sodium sulfate, filter and concentrate in vacuo to obtain the title compound (0.7 g, 100%). + .

[0198] ​ ​ Dissolve 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)hexadecanoic acid (3.6 mg, 0.00536 mmol), (2 + .

[0199] ​ ​ ​ Dissolve 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)amino)hexadecanoic acid (3.6 mg, 0.00536 mmol), (2S 4 R )-1-(( S )-2-amino-3,3-dimethylbutyryl)-4-hydroxy- N -(( S 1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (2.6 mg, 0.00536 mmol) and TEA (3.8 µL, 0.0268 mmol) were dissolved in DMF (50 µL). HATU (3.1 mg, 0.00804 mmol) was added, and the solution was stirred at rt for 1 h. The solution was then purified by column chromatography (Teledyne ISCO, 4 g silica gel column) with a gradient elution of 0–15% MeOH / DCM to obtain the title compound (3.89 mg, 65.9%). LCMS m / z = 1101.99 [M+H] + .

[0200] ​ Ethylpyridin-2-yl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindole) (20)-P-(4-yl)amino)-N-methylhexanoamide (2-((6-chloro-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)(methyl)carbamate tert-methyl Butyl acetate 2,6-Dichloro-4-ethylpyridine-3,5-dicarboxynitrile (113 mg, 0.500 mmol) was dissolved in DMF (3 mL) and a DMF solution of methyl (2-(methylamino)ethyl)carbamate tert-butyl ester (112 mg, 0.595 mmol) (2 mL) was added, followed by triethylamine (70.1 µL, 0.500 mmol). The mixture was stirred at rt for 5 min, then diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (Teledyne ISCO, 12 g silica gel column) with a gradient elution of 0–28% EtOAc / hexane to obtain the title compound (152.43 mg, 80.7%). LCMS m / z = 378.31 [M+H] + .

[0201] (2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) (Methyl)amino)ethyl)(methyl)carbamate tert-butyl ester A mixture of tert-butyl (2-((6-chloro-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)(methyl)carbamate (69.79 mg, 0.184 mmol), potassium thioacetate (25.2 mg, 0.221 mmol) and DMF (0.9 mL) was stirred at rt for 30 min. 2-Amino-2-oxo-1-phenylethyl methanesulfonate (50.7 mg, 0.221 mmol) and triethylamine (51.6 µL, 0.368 mmol) were added and the mixture was stirred at rt for 15 h. Water (2 mL) was added to the reaction mixture and the mixture was filtered, and the filtered solid was re-dissolved in DCM. The solution was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with DCM to give the title compound (20.24 mg, 21.6%). LCMS m / z = 509.42 [M+H] + .

[0202] 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2-yl)thio)- 2-Phenylacetamide To tert-butyl (2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)(methyl)carbamate (20.24 mg, 0.0398 mmol) was added THF (0.1 mL) and 4M HCl in dioxane (0.1 mL) and the mixture was stirred at rt for 16 h, then concentrated in vacuo to give the title compound. LCMS m / z = 410.39 [M+H] + .

[0203] N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) (Methyl)amino)ethyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)amino)-N- Methylhexylamide Dissolve 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2- yl)thio)-2-phenylacetamide (5.0 mg, 0.0123 mmol), 6-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)hexanoic acid (4.7 mg, 0.0123 mmol), and TEA (8.6 µL, 0.0615 mmol) in DMF (50 µL) and DCM (50 µL). Add HATU (7.0 mg, 0.0185 mmol) and stir the mixture at rt for 15 min, then purify by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-2.5% MeOH / DCM to obtain the title compound (8.27 mg, 86.4%). LCMS m / z = 778.61 [M+H] + .

[0204] Example 21: Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- Ethylpyridin-2-yl)(methyl)amino)ethyl)-4-(((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindole) (21)P-4-yl)amino)methyl)-N-methylbenzamide Dissolve 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2- yl)thio)-2-phenylacetamide (5.0 mg, 0.0123 mmol), 4-(((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)methyl)benzoic acid (5.0 mg, 0.0123 mmol), and triethylamine (8.6 µL, 0.0615 mmol) in DMF (50 µL) and DCM (50 µL). Add HATU (7.0 mg, 0.0185 mmol) and stir the mixture at rt for 15 min. Purify the mixture by column chromatography (Teledyne ISCO, 4 g) eluting with a gradient of 50-100% EtOAc / hexanes to obtain the title compound (4.36 mg, 44.4%). LCMS m / z = 798.56 [M+H] + .

[0205] Example 22: Synthesis of 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)-2-phenyl Acetamide (22) 2-Bromo-2-phenylacetic acid To a mixture of 48% HBr solution (5.6 mL) and concentrated H2SO4(2.2 mL) was carefully added 2-hydroxy-2-phenylacetic acid (3.00 g, 19.7 mmol) and the mixture was refluxed at 105 °C for 3 h, then cooled to rt and poured into 25 mL of ice water. The mixture was extracted with diethyl ether (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound.

[0206] 2-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio 2-Phenylacetic acid tert-Butyl (1-(6-chloro-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)carbamate (39.0 mg, 0.100 mmol) and potassium thioacetate (13.7 mg, 0.120 mmol) were dissolved in DMF (200 µL) and the solution was stirred at rt for 30 min, then 2-bromo-2-phenylacetic acid (25.7 mg, 0.120 mmol) and triethylamine (42.1 µL, 0.300 mmol) were added. The mixture was stirred at rt for 16 h, then purified by column chromatography (Teledyne ISCO, 12 g silica gel column) eluting with a gradient of 0-100% EtOAc / hexanes to obtain the title compound (16.4 mg, 31.4%). LCMS m / z = 522.49 [M+H] + .

[0207] (1-(3,5-dicyano-6-((2-((4-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindole) (Lin-4-yl)amino)butyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin-4-yl)amino tert-butyl carbamate tert-Butyl (1-(6-chloro-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)carbamate (39.0 mg, 0.100 mmol) and potassium thioacetate (13.7 mg, 0.120 mmol) were dissolved in DMF (200 µL) and the solution was stirred at rt for 30 min, then 2-bromo-2-phenylacetic acid (25.7 mg, 0.120 mmol) and triethylamine (42.1 µL, 0.300 mmol) were added. The mixture was stirred at rt for 16 h, then purified by column chromatography (Teledyne ISCO, 12 g silica gel column) eluting with a gradient of 0-100% EtOAc / hexanes to obtain the title compound (16.4 mg, 31.4%). LCMS m / z = 522.49 [M+H] N , N ’-dicyclohexylcarbodiimide (0.9 mg, 0.00425 mmol) and hydroxybenzotriazole (0.6 mg, 0.00425 mmol) and the mixture was stirred at 0 °C for 10 min. 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.5 mg, 0.00425 mmol) and N- methylmorpholine (0.47 µL, 0.00425 mmol) and allow the mixture to warm to rt. After 16 h, the mixture is purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-5% MeOH / DCM to obtain the title compound (4.83 mg, 100%). LCMS m / z = 848.71 [M+H] + .

[0208] 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-N-(4-((2-(2, 6-Dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)-2-phenylacetamide tert-Butyl (1-(3,5-dicyano-6-((2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin-4- yl)carbamate (4.83 mg, 0.00570 mmol) and 4 M HCl in dioxane (0.1 mL) are stirred at rt for 3 h. The mixture is purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-10% MeOH / DCM to obtain the title compound (0.40 mg, 9.4%). LCMS m / z = 748.62 [M+H] + .

[0209] Example 23: Synthesis of 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio )-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)benzyl)- 2-Phenylacetamide (23) (1 -(3,5-dicyano-6-((2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxo-1 -phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin- 4-yl)amino)methyl)benzyl)-2-phenylacetamide 2-((6-(4-aminopiperidin-1 -yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-N-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2- phenylacetamide Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24) Dissolve 2-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetic acid (5.22 mg, 0.01 mmol) in DMF (50 µL) and cool to 0 °C. Add N , N ’-dicyclohexylcarbodiimide (2.1 mg, 0.01 mmol) and hydroxybenzotriazole (1.4 mg, 0.01 mmol) and stir the mixture at 0 °C for 15 min. Add 4-((4- (aminomethyl)benzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3.9 mg, 0.01 mmol) and N- methylmorpholine (1.1 µL, 0.01 mmol) and allow the mixture to warm to rt. After 3 h, the mixture is purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with DCM to obtain the title compound (2.47 mg, 27.6%). LCMS m / z = 897.66 [M+H] + .

[0210] Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24) Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24) tert-Butyl (1-(3,5-dicyano-6-((2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)benzyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin-4- yl)carbamate (2.47 mg, 0.00276 mmol) and 4 M HCl in dioxane (0.1 mL) are stirred at rt for 1 h. The mixture is purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-8% MeOH / DCM to obtain the title compound (0.57 mg, 26.0%). LCMS m / z = 796.66 [M+H] + .

[0211] Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24) (1 -(3,5-dicyano-6-((2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxo-1 -phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin- 4-yl)amino)methyl)benzyl)-2-phenylacetamide 2-((6-(4-aminopiperidin-1 -yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-N-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2- phenylacetamide tert-Butyl (1-(3,5-dicyano-6-((2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)benzyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin-4- yl)carbamate (2.47 mg, 0.00276 mmol) and 4 M HCl in dioxane (0.1 mL) are stirred at rt for 1 h. The mixture is purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-8% MeOH / DCM to obtain the title compound (0.57 mg, 26.0%). LCMS m / z = 796.66 [M+H] + .

[0212] Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24) Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24)Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24) To a solution of 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2- yl)thio)-2-phenylacetamide (2.1 mg, 0.00511 mmol), 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (2.0 mg, 0.0511 mmol) and triethylamine (3.6 µL, 0.0256 mmol) in DMF (50 µL) was added HATU (2.9 mg, 0.00767 mmol) and the mixture was stirred at rt for 15 min. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-3% MeOH / DCM to give the title compound (0.81 mg, 20.4%). LCMS m / z = 780.73 [M+H] + .

[0213] Example 24: Synthesis of N-(2-((6-((2-amino-2-oxo-1 -phenylethyl)thio)-3,5-dicyano-4- ethylpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24) ​ ​ ​ ​ ​ To a solution of 2-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetic acid (2.6 mg, 0.00500 mmol), 4-((2-(2-(2- aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.0 mg, 0.00500 mmol) and triethylamine (3.5 µL, 0.025 mmol) in DMF (50 µL) was added HATU (2.9 mg, 0.0075 mmol) and the mixture was stirred at rt for 15 min. The mixture was diluted with EtOAc (5 mL), washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (4.97 mg, 100%). LCMS m / z = 908.75 [M+H] + .

[0214] ​ ​ ​ A mixture of (1-(3,5-dicyano-6-((2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin-4-yl)carbamate tert-butyl ester (4.97 mg, 0.00547 mmol) and a dioxane solution of 4 M HCl (0.1 mL) was stirred at rt for 19 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) with a gradient elution of 0-10% MeOH / DCM to obtain the title compound (0.77 mg, 17.4%). LCMS m / z = 808.74 [M+H] + .

[0215] ​ ​ ​ (1-(3,5-dicyano-6-((2-((10-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindole) (Lin-4-yl)amino)decyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridin-2-yl)piperidin-4-yl)amino tert-butyl carbamate 2-((6-(4-(( tert-butoxycarbonyl (2.6 mg, 0.005 mmol)-((10-aminodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.2 mg, 0.005 mmol) and triethylamine (3.5 µL, 0.025 mmol) were dissolved in DMF (50 µL). HATU (2.9 mg, 0.0075 mmol) was added and the mixture was stirred at rt for 15 min. The mixture was diluted with EtOAc (5 mL), washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (4.05 mg, 86.9%).

[0216] 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-N-(10-((2- (2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)-2-phenylacetamide A mixture of tert-butyl (1-(3,5-dicyano-6-((2-((10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)amino)-2-oxo-1-phenylethyl)thio)-4- ethylpyridin-2-yl)piperidin-4-yl)carbamate (4.05 mg, 0.00434 mmol) and 4 M HCI in dioxane (0.1 mL) was stirred at rt for 19 h. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-8% MeOH / DCM to give the title compound (0.87 mg, 24.1%). LCMS m / z = 832.79 [M+H] + .

[0217] Example 28: Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- Ethylpyridin-2-yl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- (28)-( ... Dissolve 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2- yl)thio)-2-phenylacetamide (6.0 mg, 0.0161 mmol), 6-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)hexanoic acid (6.6 mg, 0.0161 mmol), and triethylamine (11.3 µL, 0.0805 mmol) in DMF (80 µL). Add HATU (9.2 mg, 0.0242 mmol) and stir the mixture at rt for 15 min. Purify the mixture by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-15% MeOH / EtOAc. Collect the product fractions and concentrate under vacuum, then purify again by preparative HPLC to give the title compound (0.34 mg, 2.8%). LCMS m / z = 764.70 [M+H] + .

[0218] Example 29: Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- Ethylpyridin-2-yl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindole) lin-4-yl)oxy)-N-methylhexanoamide (29) Dissolve 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2- yl)thio)-2-phenylacetamide (3.9 mg, 0.0100 mmol), 6-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)hexanoic acid (4.1 mg, 0.0100 mmol), and triethylamine (7.0 μί, 0.0500 mmol) in DMF (50 μί). Add HATU (5.7 mg, 0.0150 mmol) and stir the mixture at rt for 4 h. Purify the mixture by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-5% MeOH / DCM to obtain the title compound (0.32 mg, 4.1%). LCMS m / z = 779.67 [M+H] + .

[0219] Example 30: Synthesis of 2-((7-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- (amino)hexanoyl)-2-(4-hydroxypiperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)thio)- 2-Phenylacetamide (30) 4-((2-amino-2-oxo-1-phenylethyl)thio)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-tert-butyl formate Dissolve 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-tert-butyl carboxylate (30.4 mg, 0.100 mmol) and potassium thioacetate (13.7 mg, 0.120 mmol) in DMF (300 μί) and stir the mixture at rt for 2 h. Add 2-amino-2-oxo-l-phenylethyl methanesulfonate (27.5 mg, 0.120 mmol), triethylamine (28.0 μί), and DMF (300 μί) and stir the mixture at rt for 15 h. Purify the mixture by column chromatography (Teledyne ISCO, 12 g silica gel column) eluting with a gradient of 20-50% EtOAc / hexanes to obtain the title compound (27.6 mg, 63.5%). LCMS m / z = 435.35 [M+H] + .

[0220] 4-((2-amino-2-oxo-1-phenylethyl)thio)-2-(4-hydroxypiperidin-1-yl)-5,8-dihydropyridine [3,4-d]pyrimidin-7(6H)-tert-butyl formate Tert-butyl 4-((2-amino-2-oxo-l-phenylethyl)thio)-2-chloro-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (9.3 mg, 0.0214 mmol), piperidin-4-ol (6.5 mg, 0.0642 mmol), and diisopropylethylamine (18.7 µL, 0.107 mmol) were dissolved in 2-butanol (200 µL) and 2-propanol (50 µL). The mixture was heated at 130 °C in a sealed reaction tube for 3 hours. The mixture was cooled to rt, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (6.35 mg, 59.4%).

[0221] 2-((2-(4-hydroxypiperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)thio)-2-benzene Acetamide Tert-butyl 4-((2-amino-2-oxo-l-phenylethyl)thio)-2-chloro-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (9.3 mg, 0.0214 mmol), piperidin-4-ol (6.5 mg, 0.0642 mmol), and diisopropylethylamine (18.7 µL, 0.107 mmol) were dissolved in 2-butanol (200 µL) and 2-propanol (50 µL). The mixture was heated at 130 °C in a sealed reaction tube for 3 hours. The mixture was cooled to rt, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (6.35 mg, 59.4%). + .

[0222] 2-((7-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexanoyl (2-(4-hydroxypiperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)thio)-2-phenylacetamide Tert-butyl 4-((2-amino-2-oxo-l-phenylethyl)thio)-2-chloro-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (9.3 mg, 0.0214 mmol), piperidin-4-ol (6.5 mg, 0.0642 mmol), and diisopropylethylamine (18.7 µL, 0.107 mmol) were dissolved in 2-butanol (200 µL) and 2-propanol (50 µL). The mixture was heated at 130 °C in a sealed reaction tube for 3 hours. The mixture was cooled to rt, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (6.35 mg, 59.4%). + .

[0223] Example 31: Synthesis of 2-((7-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- 4-yl)amino)decanoyl)-2-(4-hydroxypiperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)thio (31)-2-phenylacetamide Dissolve 2-((2-(4-hydroxypiperidin-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)thio)-2-phenylacetamide (2.5 mg, 0.00635 mmol), 10-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)decanoic acid (2.8 mg, 0.00635 mmol), and triethylamine (4.5 μL, 0.0318 mmol) in DMF (90 μL). Add HATU (3.6 mg, 0.00953 mmol) and stir the mixture at rt for 30 min, then purify by column chromatography (Teledyne ISCO, 4 g silica gel column) eluting with a gradient of 0-7% MeOH / DCM to obtain the title compound (2.88 mg, 55.0%). LCMS m / z = 825.72 [M+H] + .

[0224] Example 32: Synthesis of 2-((3,5-dicyano-6-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)octyl)amino)-4-ethylpyridin-2-yl)thio)-2- phenylacetamide (32) 2-((3,5-dicyano-6-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide 2-((3,5-dicyano-6-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide 2-((3,5-dicyano-6-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide Dissolve 2,6-dichloro-4-ethylpyridine-3,5-dicarbonitrile (11.3 mg, 0.050 mmol), 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (24.0 mg, 0.060 mmol), and triethylamine (7.0 μL, 0.050 mmol) in DMF (300 μL) and stir the mixture at rt for 3 h. Then add triethylamine (21 μL, 0.150 mmol) and stir the mixture at rt for 24 h. Dilute the mixture with water (10 mL) and extract with EtOAc (3 x 10 mL). Dry the combined organic layers over sodium sulfate, filter, and concentrate in vacuo to obtain the title compound (26.2 mg, 88.8%). LCMS m / z = 590.51 [M+H] + .

[0225] Example 33: Degradation activity - Western Blot Figures 1-12 Dissolve 2-chloro-6-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octyl)amino)-4-ethylpyridine-3,5-dicarbonitrile (11.8 mg, 0.020 mmol) and potassium thioacetate (2.7 mg, 0.024 mmol) in DMF (100 µL) and stir the mixture at rt for 1 hour. Add 2-amino-2-oxo-1-phenylethyl methanesulfonate (5.5 mg, 0.024 mmol), triethylamine (5.6 µL, 0.040 mmol) and DMF (50 µL) and stir the mixture at rt for 16 hours. Purify the mixture by column chromatography (Teledyne ISCO, 12 g silica gel column) eluting with a gradient of 20-100% EtOAc / hexanes to obtain the title compound (3.35 mg, 23.2%). LCMS m / z = 721.76 [M+H] + .

[0226] ​ Suspend HL60 cells at 1*10 6 cells / well in a 6-well plate and treat with compound at the indicated concentration and time. Extract total protein from cells using RIPA buffer (Abeam) supplemented with Halt protease inhibitor cocktail (Sigma). Load samples into Invitrogen Bolt™ Bis-Tris Plus gels (ThermoFisher® Scientific) and transfer to Invitrolon™ PVDF membranes (ThermoFisher® Scientific) using Invitrogen Bolt™ wet gel transfer device. Perform immunodetection with standard techniques. Use the following primary and secondary antibodies at the concentrations recommended by the manufacturer: anti-DNMT1, CRBN and b-actin (Cell Signaling Technology®) and IRDye secondary antibodies.

[0227] Compounds show downregulation of DNMT1 ​ .

[0228] All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All such publications are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference.

[0229] While the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is therefore to be understood that numerous modifications can be made to the illustrative embodiments and that other arrangements can be devised without departing from the spirit and scope of the present disclosure as defined by the appended claims.

Claims

1. A compound of Formula (I): wherein: (I), or a pharmaceutically acceptable salt or stereoisomer thereof, the DNMT1 -targeting ligand is of Formula TL-1 or TL-2: wherein: (TL-1) or (TL-2), R1is NR3R4; R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl, or R3 is H or methyl, and R4 is , or R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl, which is further bound to the linker; the linker represents a moiety covalently linking the degrader and the targeting ligand; and R2 is NH2 or ; R5and R6are independently H, optionally substituted alkyl or ; wherein is a bond between the DNMT1 -targeting ligand and the linker, provided that there is only one bond between the DNMT1 -targeting ligand and the linker; the degrader is of Formula D1, D2, or D3: wherein: Q is CH2or C(O); and X1is O, NH, CH2, or CºC, R7is H or optionally substituted C1-C3alkyl, or R7and R8together with the carbon atom to which they are attached form cyclopropyl; 2. The compound of claim 1, wherein R2is NH2. R8is H, methyl or ; R9is C(O)CR 10 R 11 R 12 、 ; R 10 and R 11 are both H, or R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl group; R 12 is H, fluoro, cyano or NMe2; and Y is H, , , or ; wherein is a bond between the degron and the linker, provided that there is only one bond between the degron and the linker.

5. The compound of claim 1 or 2, wherein R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl, which is further bound to the linker.

3. The compound of claim 1 or 2, wherein R3 is H and R4 is and Formula TL-1 has TL-1a: (TL-1a).

4. The compound according to claim 1 or 2, wherein R3 is Me and R4 is and formula TL-1 has TL-1b: (TL-1b).

7. The compound of claim 1, wherein R3and R4together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl.

6. The compound of claim 5, wherein R3 and R4 together with the nitrogen atom to which they are attached form piperidinyl, Formula TL-1 has TL-1c: (TL-1c).

8. The compound of claim 7, wherein R3and R4together with the nitrogen atom to which they are attached form an optionally substituted piperidinyl.

9. The compound of claim 8, wherein piperidinyl is substituted with amino.

12. The compound of any one of claims 1-11, wherein the degrader is of Formula D1.

10. The compound according to any one of claims 7-9, wherein R2 is and formula TL-1 has TL-1d: (TL-1d).

11. The compound of claim 1, wherein the DNMT1 -targeting ligand is of Formula TL-2, and R5 is and R6 is H, or R5 is H or optionally substituted alkyl and R6 is .

13. The compound of claim 12, wherein Formula D1 is of Formula D1a-D1p:

14. The compound of any one of claims 1-11, wherein the degrader is of Formula D2 or D3. 。 15. The compound of claim 14, wherein the degrader is of Formula D2a-D2o or D3a-D3g:

16. The compound of any one of claims 1-15, wherein the linker is of Formula L0: or stereoisomers thereof. or a stereoisomer thereof, wherein (L0)， p1is an integer selected from 0 to 6; p2is an integer selected from 0 to 12; p3is an integer selected from 0 to 12; 17. The compound of claim 16, wherein Formula L0is of Formula L0a-L0j: each W is independently absent, CH2, O, S, NR 13 or C(O)NH; each R is independently hydrogen or C1-C6alkyl; 13 independently hydrogen or C1-C6alkyl; W1and W2are independently absent, (CH2) 1-3 , O, NH, or C(O)NR 13 ; and Z1and Z2are independently absent, -O-, -S-, -N(R 13 )- 13 )- 13 )- 13 )C(O)- 13 )C(O)N(R 13 )- 13 )C(O)- 13 )C(O)N(R 13 )- 13 )C(O)O- 13 )- 13 )- 13 )C(NR 13 )- 13 )N(R 13 )- 13 )C(NR 13 )N(R 13 )- 13 )S(O)2- 13 )- 13 )S(O)- 13 )- 13 )S(O)2N(R 13 )- 13 )S(O)N(R 13 )- 12 C3-C12carbocyclyl or 3- to 12-membered heterocyclyl; wherein the linker is covalently bonded to the targeting ligand through W2 covalently bonded to a degrader and through W1 covalently bonded to a targeting ligand, or the linker is covalently bonded to the targeting ligand through W1 covalently bonded to a degrader and through W2 covalently bonded to a targeting ligand.

20. The compound of any one of claims 1-15, wherein the linker is represented by any one of the following structures: wherein TL represents a targeting ligand.

18. The compound according to any one of claims 1-15, wherein the linker is a bond or comprises an alkylene chain or divalent alkylene chain, either of which can be interrupted and / or terminated at either or both ends with at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, C3-C12carbocycloalkylene, 3- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein R' is H or C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different. 12 C3-C12carbocycloalkylene, 3- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein R' is H or C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different.

19. The compound of any one of claims 1-15, wherein the linker is a polyethylene glycol (PEG) chain, which can be interrupted and / or terminated at either or both ends with at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, C3-C12 carbocycloalkylene, 3- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein R' is H or C1-C6 alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different. 12 C3-C12 carbocycloalkylene, 3- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene, or any combination thereof, wherein R' is H or C1-C6 alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different.

21. The compound of claim 1, which is: 。 or a pharmaceutically acceptable salt or stereoisomer thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

23. A method of treating a disease or disorder characterized by or mediated by aberrant DNMT1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt or stereoisomer thereof.

24. The method of claim 23, wherein the disease or disorder is cancer. ​ 25. The method of claim 24, wherein the cancer is breast cancer, colon cancer, or prostate cancer.

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