Synthesis and in vitro characterization of proteolytically targeted chimeras (PROTACS) for the degradation of DNA methyltransferase 1 (DNMT1).

Abstract

Compounds that target DNMT1 for degradation (degradants) are disclosed. Pharmaceutical compositions comprising the compounds, as well as methods for treating diseases and disorders characterized by or mediated by abnormal DNMT1 activity using the compounds, are also disclosed.

Description

[Technical Field]

[0001] Related applications This application claims the benefit of priority under U.S. Provisional Patent Application No. 63 / 523,993, filed on 29 June 2023, under Section 119(e) of the U.S. Patent Act, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Deoxyribonucleic acid methyltransferase 1 (DNMT1) is an epigenetic writer protein that regulates DNA methylation during cell proliferation. DNA methylation is a well-studied epigenetic regulatory mechanism that affects the transcription of important genes, and excessive or hypomethylation of DNA has been found to be associated with many human diseases, including cancer. Therefore, abnormal DNMT1 activity plays a crucial role in the development of cancer. Existing drugs targeting DNMT1 dysregulation, such as decitabine and 5-azacitidine, are highly toxic, and cancer cells often develop drug resistance. [Overview of the Initiative]

[0003] A first aspect of this disclosure relates to a compound of formula I,

[0004] [ka] or its pharmaceutically acceptable salts or stereoisomers. [In the formula, DNMT1 targeting ligands are formula TL-1 or TL-2

[0005] [ka] [In the formula, R1 is NR3R4, R3 is H or methyl, and R4 is

[0006] [ka] And, or R3 and R4, together with the nitrogen atom to which they are bonded, form an optionally substituted 6-membered heterocycline, or R3 and R4, together with the nitrogen atoms to which they are bonded, form a 6-membered heterocycline that is optionally substituted and further bonded to the linker. R2 is NH2 or

[0007] [ka] And, R5 and R6 are independently H, optionally substituted alkyl, or

[0008] [ka] And,

[0009] [ka] This refers to a binding between the DNMT1-targeting ligand and the linker, provided that there is only one binding between the DNMT1-targeting ligand and the linker. It has, The linker represents the portion that covalently connects the degron and the targeted ligand. Degron is given by formula D1, D2, or D3

[0010] [ka] [In the formula, Q is either CH2 or C(O), X1 is O, NH, CH2, or C≡C. R7 is a C1-C3 alkyl group that is substituted with H or optionally substituted, or R7 and R8, together with the carbon atoms to which they are bonded, form a cyclopropyl group. R8 is H, methyl, or

[0011] [ka] And, R9 is C(O)CR 10 R 11 R 12 ,

[0012] [ka] And, R 10 and R 11 Both are H, or R 10 and R 11 These, together with the carbon atoms to which they are bonded, form a cyclopropyl group. R 12 is H, fluoro, cyano, or NMe2, Y is H,

[0013] [ka] And,

[0014] [ka] This is a bond between a degron and a linker, provided that there is exactly one bond between the degron and the linker. [has].

[0015] Another aspect of this 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.

[0016] Another embodiment of this disclosure provides a method for producing a compound.

[0017] Another aspect of the present disclosure relates to a method for treating a disease or disorder involving (characterized by or mediated by) abnormal DNMT1 activity, comprising the step of administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need.

[0018] While not intended to be constrained by any particular theory of action, the compounds of Formula I (also referred to herein as PROTAC or degradation agents) are thought to promote the degradation of DNMT1 via the cellular ubiquitin / proteasome system, which normally functions to identify and remove damaged proteins. Following the disruption of the DNMT1 protein molecule, the degradation agents are released and remain active. Thus, by utilizing and leveraging the body's own innate protein efflux system, the compounds of this disclosure may demonstrate potential improvements over existing small molecule inhibitors of DNMT1. Consequently, effective intracellular concentrations of the degradation agents can be significantly lower than those for small molecule DNMT1 inhibitors. [Brief explanation of the drawing]

[0019] [Figure 1] This Western blot shows that compounds 1-4 degraded DNMT1 in HL60 cells at the concentrations indicated. [Figure 2] This Western blot shows that compounds 5-8 degraded DNMT1 in HL60 cells at the concentrations indicated. [Figure 3] This Western blot shows that compounds 9-12 degraded DNMT1 in HL60 cells at the concentrations indicated. [Figure 4] This Western blot shows that compounds 13-16 degraded DNMT1 in HL60 cells at the concentrations indicated. [Figure 5] This Western blot shows that compounds 17-19 degraded DNMT1 in HL60 cells at the concentrations indicated. [Figure 6]This Western blot shows that compounds 20-23 degraded DNMT1 in HL60 cells at the concentrations indicated. [Figure 7] This Western blot shows that compound 20 degraded DNMT1 in HL60 cells at the indicated concentration. [Figure 8] This Western blot shows that compound 20 degraded DNMT1 in Jurkat cells at the indicated concentrations. [Figure 9] This Western blot shows that compound 20 degraded DNMT1 in A172 cells at the indicated concentration. [Figure 10] This Western blot shows that compound 20 (containing cereblon (CRBN)-targeted degron) degraded DNMT1 in MOLM13 ch2.2 (left). The degree of DNMT1 degradation in MOLM13 CRBN KO (right) cells indicates that the degradation is CRBN-dependent. [Figure 11] This Western blot shows that DNMT1 in HL60 cells was degraded at the point where compound 20 (3 μM) is indicated. [Figure 12] This Western blot shows that compounds 26 and 27 degraded DNMT1 in HL60 cells at the concentrations indicated. [Modes for carrying out the invention]

[0020] Unless otherwise defined, all scientific and technical terms in this specification have the same meaning as they are commonly understood by articulators in the field to which the subject matter of this specification pertains. Unless otherwise specified, the following terms have the meanings given to facilitate understanding of this disclosure, as used in this specification and the appended claims.

[0021] In this specification and the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless the context makes it clear otherwise. Thus, for example, a reference to “composition” encompasses a mixture of two or more such compositions, and a reference to “inhibitor” includes a mixture of two or more such inhibitors.

[0022] Unless otherwise stated, the term “approximately” means within 10% (e.g., within 5%, 2%, or 1%) of the specific value modified by the term “approximately.”

[0023] The transitional phrase “including,” “containing,” or “comprising,” which is synonymous with “characterizing,” is comprehensive or open-ended and does not exclude additional elements or method steps not described. When used in the context of the number of heteroatoms in a heterocyclic structure, it means that the heterocyclic group has the minimum number of heteroatoms. In contrast, the transitional phrase “consisting of” excludes any elements, steps, or components not specified in the claim. The transitional phrase “essentially consisting of” limits the scope of the claim to the specified materials or steps of this disclosure “and materials or steps that do not substantially affect the basic novel features.”

[0024] With respect to the compounds of this disclosure, the following definitions apply insofar as the following terms are used herein to further describe them.

[0025] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon radical. In some embodiments, the alkyl radical is a C1-C6 group. In some embodiments, unless otherwise disclosed for any one or more of the groups of the compounds of formula (I), the alkyl radical 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, i-propyl, 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 a methyl group.

[0026] As used herein, the term "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, having no unsaturation, and having 1 to 15 18 carbon atoms, which links the rest of the molecule to a radical group, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain can be attached to the rest of the molecule via a single bond and to the radical group via a single bond. In some embodiments, the alkylene group contains 1 to 15 15 carbon atoms (C1-C 15 alkylene). In some embodiments, the alkylene group contains 1 to 12 12 carbon atoms (C1-C 12 alkylene). In some embodiments, the alkylene group contains 1 to 10 10 carbon atoms (C1-C 10 alkylene). 15 alkylene). 12 alkylene). 10Alkylene). In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (C1 alkylene).

[0027] In this specification, the term “alkenyl” refers to a monovalent hydrocarbon radical, either linear or branched, containing at least one carbon-carbon double bond. Alkenyls include radicals having “cis” and “trans” orientations, or “E” and “Z” orientations. In some embodiments, the alkenyl radical is C2-C 18 It is a group. In some embodiments, unless otherwise disclosed, the alkenyl radical is C2-C2 of any one or more groups of the compound of formula (I). 15 , C2~C 12 , C2~C 10 These are C2-C8, C2-C6, or C2-C3 groups. Examples include ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0028] In this specification, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing at least one carbon-carbon triple bond. In some embodiments, the alkynyl radical is C2-C 18 It is a group. In some embodiments, unless otherwise disclosed, the alkynyl radical is C2-C2 of any one or more groups of the compound of formula (I). 15, C2~C 12 , C2~C 10 These are C2-C8, C2-C6, or C2-C3. Examples include ethinyl, propa-1-inyl, propa-2-inyl, buta-1-inyl, buta-2-inyl, and buta-3-inyl.

[0029] In this specification, the terms “alkoxyl” or “alkoxy” refer to the alkyl group defined above to which an oxygen radical, which is the attachment site, is attached. In some embodiments, the alkoxyl group is methoxy, ethoxy, propyloxy, or tert-butoxy. “Ether” is two hydrocarbyl groups covalently linked by an oxygen atom. Thus, the substituent of the alkyl that makes it an ether is an alkoxyl, or similar to an alkoxyl, which can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0030] In this specification, the term "halogen" (or "halo" or "halido") refers to fluorine, chlorine, bromine, or iodine.

[0031] In this specification, the term “cyclic group” is used generally, either alone or as part of a larger part, to refer to any group that includes saturated, partially saturated, or aromatic cyclic systems, such as carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl groups. A cyclic group may have one or more (e.g., condensed) cyclic systems. Thus, for example, a cyclic group may include one or more carbocyclic, heterocyclic, aryl, or heteroaryl groups.

[0032] In this specification, the term “carbocyclic” (and moreover “carbocyclyl”) refers to a group that, either alone or as part of a larger part, comprises a saturated, partially unsaturated, or aromatic ring system having 3 to 12 carbon atoms, and is used either alone or as part of a larger part (e.g., an alk carbocyclic group). The term carbocyclyl includes monocyclic, dicyclic, tricyclic, fused, bridging, and spirocyclic systems, as well as combinations thereof. In one embodiment, a carbocyclyl comprises 3 to 10 carbon atoms (C3-C 10 In one embodiment, the carbocyclyl contains 3 to 6 carbon atoms (C3 to C6). In one embodiment, the carbocyclyl contains 5 to 6 carbon atoms (C5 to C6). In some embodiments, the carbocyclyl as a biring is C6 to C 10 It includes. In another embodiment, carbocyclyl is used as the spirosystem, C5-C 11This includes... Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and phenyl. Bicyclic carbocyclyls 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 spirocarbocyclyls 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 aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocarbocyclic, dicarbocyclic, or spirocarbocyclic rings). The term carbocyclic group also includes carbocyclic rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., aryl or heterocyclic rings) where radicals or attachment sites reside on the carbocyclic ring.

[0033] Therefore, the term "carbocyclic formula" in this specification refers to formula -R c -Carbocyclyl base [in the formula, R c This also includes carbocyclylalkyl groups, which are alkylene chains. The term carbocyclic formula, as used herein, refers to the formula --O--R c -A group bonded via the oxygen atom of carbocyclyl [in the formula, R c This also includes the carbocykylalkoxy group, which is an alkylene chain.

[0034] In this specification, the term “aryl” (used alone or as part of a larger part) refers to a group comprising a monocyclic, bicyclic, or tricyclic carbocyclic system, including a fused ring, where at least one ring in the system is aromatic. In some embodiments, the aralkoxy group is a benzoxy group. The term “aryl” may be used synonymously with the term “aryl ring.” In one embodiment, the aryl includes a group having 6 to 12 carbon atoms. In another embodiment, the aryl includes a group having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, and 1,2,3,4-tetrahydronaphthalenyl, which may be substituted or independently substituted by one or more substituents described herein. A specific aryl is phenyl. In some embodiments, the aryl group is an aryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring), and includes an aryl ring where a radical or attachment site resides on the aryl ring.

[0035] Therefore, the term aryl is defined as in the formula disclosed above --R c -aryl [in the formula, R c This includes aralkyl groups (e.g., benzyl) that refer to the groups of alkylene chains such as methylene or ethylene. In some embodiments, the aralkyl group is a benzyl group that is optionally substituted. The term aryl is used herein in relation to the formula --OR c --Ayl[In the formula, R c This also includes aralkoxy groups, which refer to groups bonded via an oxygen atom of an alkylene chain such as methylene or ethylene.

[0036] In this specification, the term “heterocyclyl” is used alone or as part of a larger part to refer to a “carbocyclyl” including saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., 1, 2, 3, 4, or 5) carbon atoms are replaced by 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, dicyclic, tricyclic, fused, bridging, and spirocyclic systems, as well as combinations thereof. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5- to 12-membered heteroaryl ring system. The term heterocyclyl also includes C2-C8 heterocycloalkyls, which are saturated or partially unsaturated monocyclic, dicyclic, or spirocyclic systems containing 2-8 carbon atoms and one or more (e.g., 1, 2, or 3) heteroatoms.

[0037] In some embodiments, the heterocyclyl group comprises 3 to 12 ring atoms and includes monocyclic, dicyclic, tricyclic, and spirocyclic systems, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl comprises a 3 to 7-membered monocyclic ring having one or more heteroatoms selected from O, N, and S. In some embodiments, the heterocyclyl comprises a 4 to 6-membered monocyclic ring having one or more heteroatoms selected from O, N, and S. In some embodiments, the heterocyclyl comprises a 3-membered monocyclic ring. In some embodiments, the heterocyclyl comprises a 4-membered monocyclic ring. In some embodiments, the heterocyclyl comprises a 5 to 6-membered monocyclic ring. In some embodiments, the heterocyclyl group comprises 0 to 3 double bonds. In any of the above embodiments, the heterocyclyl comprises 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be optionally substituted (e.g., methyl, isopropyl) and / or quaternized (e.g., [NR4]). + Cl - [NR4] + OH -) may be done. Representative examples of heterocyclyls include oxyranil, azilidinil, thiranil, azetidinil, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, pyrrolidinil, dihydro-1H-pyrrolyl, dihydrofuranil, tetrahydropyranil, dihydrothienyl, tetrahydrothienyl, imidazolidinil, piperidinil, piperazinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholinil, dihydropyranil, tetrahydropyranil, hexahydrothiopyranil, hexahydropyrimidinil, oxadina Nyl, thiadinyl, thioxanil, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, oxazepinyl, oxazepanil, diazepanil, 1,4-diazepanil, diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranil, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinol, oxazolidinol, imidazolidinol, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[ [d]Imidazolyl, 1,6-dihydroimidazole [4,5-d]pyrrolo [2,3-b]pyridinyl, thiadinyl, thiophenyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, py Lazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1] Octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azabicyclo[4.5]decane-2-onyl (only), azaspiro[5.5] Examples include undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl. Examples of five-membered heterocyclyls containing a sulfur or oxygen atom and one to three nitrogen atoms include thiazolyl (e.g., thiazole-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl-5-yl and 1,2,4-thiadiazolyl-5-yl), oxazolyl (e.g., oxazol-2-yl), and oxadiazolyl (e.g., 1,3,4-oxadiazolyl-5-yl and 1,2,4-oxadiazolyl-5-yl). Examples of five-membered heterocyclines containing two to four nitrogen atoms include imidazolyl (e.g., imidazole-2-yl), triazollyl (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-tetrazole-5-yl). Representative examples of benzo-condensed five-membered heterocyclines include benzoxazole-2-yl, benzothiazole-2-yl, and benzimidazole-2-yl. Examples of six-membered heterocyclyls containing 1 to 3 nitrogen atoms and optionally a sulfur or oxygen atom include pyridyls (e.g., pyrido-2-yl, pyrido-3-yl, and pyrido-4-yl), pyrimidyls (e.g., pyrimido-2-yl and pyrimido-4-yl), triazinyls (e.g., 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl), pyridazinyls (e.g., pyridazin-3-yl), and pyrazinyls. In some embodiments, the heterocyclic group is a heterocyclic ring condensed to one or more (e.g., one or two) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring), and includes a heterocyclic ring where the radical or attachment site is located on the heterocyclic ring, and in some embodiments, the attachment site is a heteroatom contained within the heterocyclic ring.

[0038] Therefore, the term heterocyclic, as used herein, refers to a heterocyclyl group containing at least one nitrogen atom, and includes N-heterocyclyl groups in which the attachment site of the heterocyclyl group to the rest of the molecule is via 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 heterocyclic, as used herein, also refers to a heterocyclyl group containing at least one heteroatom, and includes C-heterocyclyl groups in which the attachment site of the heterocyclyl group to the rest of the molecule is via a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include 2- or 3-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocyclic is used as disclosed above in formula --R c -heterocycline [wherein R is R] c This also includes heterocyclylalkyl groups, which refer to the groups of an alkylene chain. The term heterocyclic is used herein to refer to the formula --O--R c -heterocycline [wherein R is R] c This also includes heterocyclylalkoxy groups, which refer to radicals bonded via the oxygen atom of an alkylene chain.

[0039] In this specification, the term “heteroaryl” (e.g., “heteroarylalkyl” (further “heteroarylalkyl”) or “heteroarylalkoxy” (further “heteroarylcoxy”), used alone or as part of a larger part, refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and the ring system contains at least one heteroatom. In one embodiment, the heteroaryl is a 5- to 6-membered monocyclic aromatic group comprising an aromatic group in which one or more ring atoms are O, N, or S. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridadinyl, triazinyl, tetradinyl, tetrazolo[1,5-b]pyridazinyl, prinyl, deazaprinyl, and benzoxazolyl. Examples include lyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazole-2-yl, 1,3,4-triazole-5-yl, 1,3-oxazole-2-yl, 1,3,4-oxadiazole-5-yl, 1,2,4-oxadiazole-5-yl, 1,3,4-thiadiazole-5-yl, 1H-tetrazole-5-yl, and 1,2,3-triazole-5-yl. The term "heteroaryl" includes groups in which the heteroaryl is condensed on one or more cyclic rings (e.g., carbocyclyl or heterocyclyl), and which have a radical or attachment site on the heteroaryl ring.Non-limiting examples include indolyl, indolidinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazoyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heteroaryl group is a heteroaryl ring fused to one or more (e.g., one or two) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring), and includes a heteroaryl ring where the radical or attachment site is located on the heteroaryl ring, and in some embodiments, the attachment site is a heteroatom contained within the heterocyclic ring.

[0040] Therefore, the term heteroaryl, as disclosed herein, refers to an N-heteroaryl group that contains at least one nitrogen atom, and includes N-heteroaryl groups in which the attachment site of the heteroaryl group to the rest of the molecule is via a nitrogen atom in the heteroaryl group. The term heteroaryl, as disclosed herein, also refers to a C-heteroaryl group that contains a carbon atom in the heteroaryl group, and also includes C-heteroaryl groups in which the attachment site of the heteroaryl group to the rest of the molecule is via a carbon atom in the heteroaryl group. The term heteroaryl, as disclosed herein, refers to a heteroaryl group of the formula --R c -heteroaryl[wherein R c This also includes heteroarylalkyl groups, which refer to the groups of the alkylene chain defined above. The term heteroaryl is used herein to refer to the formula --O--R c -heteroaryl[wherein R c This also includes heteroaralcoxy (or heteroarylalkoxy) groups, which refer to groups bonded via the oxygen atom of the alkylene group as defined above.

[0041] Unless otherwise stated, and unless further defined for any specific group in the compound of formula (I), any group described herein may be substituted or unsubstituted. Unless otherwise disclosed for any specific group, typical examples of substituents include alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkyl (e.g., substituted C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkoxy (e.g., substituted C1-C6, C1-C5, C1-C4, C1) 1-C3, C1-C2, C1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C 12 , C5~C6), substituted cyclic (e.g., substituted C3~C 12 , C5~C6), carbocyclic (e.g., C3~C 12 , C5~C6), substituted carbocyclic formulas (e.g., substituted C3~C 12 C5-C6), heterocyclic (e.g., 3-12 membered, 5-6 membered), substituted heterocyclic (e.g., substituted 3-12 membered, 5-6 membered), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or substituted phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or substituted pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C6) 12 , C6), substituted aryloxy (e.g., substituted C6~C 12 , C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., substituted C1-C6), arylthio (e.g., C6-C6) 12, C6), substituted arylthio (e.g., substituted C6~C 12 Examples of C1-C6 alkyl, halo, hydroxyl, cyano, amino, or amide groups include C1-C6 alkyl, halo, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide groups. Terminal substituents may include C1-C6 alkyl, halo, hydroxyl, cyano, amino, or amide groups.

[0042] The term “binding” as used herein, when referring to an interaction between a compound of formula (I) and a targeted protein, which in this disclosure is DNMT1, via a DNMT1-targeting ligand, typically refers to an intermolecular interaction that may be preferred (also referred to herein as “selective”) in that binding between a compound of formula (I) and other proteins present in the cell may be significantly less frequent and functionally inferior. The compounds of the present invention preferentially bind to DNMT1 and recruit DNMT1 for targeted degradation.

[0043] When the binding relates to the interaction between degron and E3 ubiquitin ligase, the term "binding" typically refers to an intermolecular interaction that exhibits or does not exhibit an affinity level equal to or greater than the affinity between the compound and DNMT1, but is nevertheless sufficient to achieve the recruitment of E3 ubiquitin ligase to DNMT1.

[0044] Generally speaking, the compounds of this disclosure are of formula (I)

[0045] [ka] [In the formula, DNMT1 targeting ligands are formula TL-1 or TL-2

[0046] [ka] [In the formula, R1 is NR3R4, R3 is H or methyl, and R4 is

[0047] [ka] And, or R3 and R4, together with the nitrogen atom to which they are bonded, form an optionally substituted 6-membered heterocycline, or R3 and R4, together with the nitrogen atoms to which they are bonded, form a 6-membered heterocycline that is optionally substituted and further bonded to the linker. R2 is NH2 or

[0048] [ka] And, Each R5 is independently H, an optionally substituted alkyl, or

[0049] [ka] And,

[0050] [ka] This refers to a binding between the DNMT1-targeting ligand and the linker, provided that there is only one binding between the DNMT1-targeting ligand and the linker. It has, The linker represents the portion that covalently connects the degron and the targeted ligand. Degron represents the portion that binds to E3 ubiquitin ligase. [has] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0051] Targeted ligand In some embodiments, the DNMT1-targeting ligand has the formula TL-1, where R2 is NH2.

[0052] In some embodiments, R1 is NR3R4[wherein R3 is H and R4 is

[0053] [ka] [is], R2 is NH2, and formula TL-1 is TL-1a

[0054] [ka] It has.

[0055] Therefore, in some embodiments, the compound is formula I-1a

[0056] [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0057] In some embodiments, R1 is NR3R4[wherein R3 is Me and R4 is

[0058] [ka] [is], R2 is NH2, and equation TL-1 is TL-1b

[0059] [ka] It has.

[0060] Therefore, in some embodiments, the compound is formula I-1b

[0061] [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0062] In some embodiments, R1 is NR3R4 [wherein R3 and R4, together with the nitrogen atoms to which they are bonded, form a 6-membered heterocycline that is optionally substituted and further bonded to a linker], and R2 is NH2.

[0063] In some embodiments, R1 is NR3R4 [wherein R3 and R4, together with the nitrogen atom to which they are bonded, form piperidyl], and formula TL-1 is TL-1c

[0064] [ka] It has.

[0065] Therefore, in some embodiments, the compound is formula I-1c

[0066] [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0067] In some embodiments, R1 is NR3R4 [wherein R3 and R4, together with the nitrogen atom to which they are bound, form an optionally substituted six-membered heterocycline]. In some embodiments, R3 and R4, together with the nitrogen atom to which they are bound, form an optionally substituted piperidyl. In some embodiments, the piperidyl is substituted with an amino group.

[0068] In some embodiments, R1 is NR3R4 [wherein R3 and R4, together with the nitrogen atoms to which they are bonded, form a piperidyl substituted with an amino group], and R2 is

[0069] [ka] Therefore, equation TL-1 is TL-1d

[0070] [ka] It has.

[0071] Therefore, in some embodiments, the compound is formula I-1d

[0072] [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0073] In some embodiments, the DNMT1 targeting ligand has formula TL-2, and R5 is

[0074] [ka] Therefore, R6 is H.

[0075] Therefore, in some embodiments, the compound is formula I-2a

[0076] [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0077] In some embodiments, the DNMT1 targeting ligand has formula TL-2, where R5 is H or an optionally substituted alkyl, and R6 is

[0078] [ka] That is the case.

[0079] Therefore, in some embodiments, the compound is formula I-2b

[0080] [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0081] Linker The linker ("L") facilitates covalent adhesion between the targeted ligand and degron.

[0082] In some embodiments, the linker is of formula L0

[0083] [ka] or having stereoisomers thereof [in the formula, p1 is an integer selected from 0 to 6. p2 is an integer selected from 0 to 12. p3 is an integer selected from 0 to 12. W is independent of non-existence, CH2, O, S, and NR. 13 , or C(O)NR 13 And, R 13 Each of these is independently hydrogen or a C1-C6 alkyl group. W1 and W2 are independent, non-existent, (CH2) 1~3 , O, NH, or C(O)NR 13 And, Z1 and Z2 are independent of nonexistence, -O-, -S-, -N(R 13 )-, -C≡C-, -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(R13 )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 These are carbocyclenes, 3-12 member heterocyclenes, or 5-12 member heteroarylenes. The linker is next to W2.

[0084] [ka] Covalently bonded to deglon via and next to W1

[0085] [ka] The linker is covalently bound to the targeting ligand via W1, or the linker is adjacent to W1.

[0086] [ka] Covalently bonded to deglon via and next to W2

[0087] [ka] [It is covalently bound to the targeted ligand via [a specific mechanism].]

[0088] In some embodiments, p1 is an integer selected from 0 to 4. In some embodiments, p1 is an integer selected from 0 to 2. In some embodiments, p1 is an integer selected from 1 to 3.

[0089] 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.

[0090] 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.

[0091] In some embodiments, W is CH2. In some embodiments, W is O.

[0092] In some embodiments, R 10 Each of these is independently either hydrogen or methyl.

[0093] In some embodiments, W1 and W2 are independently absent, CH2, (CH2)2, (CH2)3, NH, C(O)NH, or C(O)NMe.

[0094] In some embodiments, Z1 and Z2 are independently non-existent, -O-, -N(R 13 )-, -C(O)-, -C(O)N(R 13 )-,-N(R 13 These are C(O)-, C5-C6 carbocylenes, 5-6 member heterocyclenes, or 5-6 member heteroarylenes.

[0095] In some embodiments, formula L0 is expressed as formulas L0a to L0j

[0096] [ka] It has [wherein TL represents the targeting ligand].

[0097] In some embodiments, the linker comprises an alkylene chain (e.g., having 1 to 18 alkylene units). In other embodiments, the linker may comprise an alkylene chain or a divalent alkylene chain, either of which may be -O-, -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)-, -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')-, C3~C 12It may be interrupted by and / or terminated (at either or both ends) by a carbocylene, a 3- to 12-membered heterocyclene, a 5- to 12-membered heteroarylene, or at least one of any combination thereof, and R' is H or a C1- to C6 alkyl, and the interruption and one or both terminal groups may be the same or different.

[0098] In some embodiments, the linker comprises an alkylene chain having 1 to 18 alkylene units, interleaved with and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6-carbosiclene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1 to 12 alkylene units, interleaved with and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6-carbosiclene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1 to 6 alkylene units, interleaved with and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6-carbosiclene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1 to 3 alkylene units, interleaved with and / or terminated by -C(O)-, -NH-, -C(O)NH-, -C(O)N(Me)-, C6 carbosislene, 6-membered heteroarylene, or any combination thereof. In some embodiments, the linker comprises an alkylene chain having 1 to 18 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1 to 12 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1 to 6 alkylene units. In some embodiments, the linker comprises an alkylene chain having 1 to 3 alkylene units.

[0099] "Carbocyclene" refers to a divalent carbon ring radical that has been optionally substituted.

[0100] "Heterocyclene" refers to a divalent heterocyclyl radical that may be optionally substituted.

[0101] "Heteroarylene" refers to a divalent heteroaryl radical that may be optionally substituted.

[0102] A typical example of a linker that may be suitable for use in this disclosure is an alkylene chain.

[0103] [ka] [In the formula, n is an integer from 1 to 12 ("of" means inclusive), for example, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 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], For example,

[0104] [ka] Examples include alkylene chains; Alkylene chains terminated with various functional groups (as described above), examples of which are as follows:

[0105] [ka] It has an alkylene chain; An alkylene chain interspersed with various functional groups (as described above), the following are examples:

[0106] [ka] It has an alkylene chain; An alkylene chain that is intercepted by or terminated by a heterocyclene group, for example,

[0107] [ka] [In the formula, m and n are independent integers from 0 to 10], as an example,

[0108] [ka] Examples include alkylene chains; Alkylene chains interspersed with amide, heterocyclene, and / or aryl groups, examples of which include:

[0109] [ka] Examples include alkylene chains; An alkylene chain interspersed with heterocyclenes and aryl groups, as well as heteroatoms, as an example of this,

[0110] [ka] Examples include alkylene chains; and An alkylene chain interrupted and / or terminated by heteroatoms such as N, O, or B, for example,

[0111] [ka] [In the formula, n is an integer from 1 to 10, for example, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 10, 6 to 9, 7 to 8, 8 to 10, 8 to 9, 9 to 10, and 1, 2 to 3, 4 to 5, 6 to 7, 8 to 9, and 10, and R is H or C1 to C4 alkyl]. Examples include:

[0112] [ka] It has an alkylene chain; These are some examples.

[0113] In some embodiments, the linker may contain polyethylene glycol (PEG) chains, and the polyethylene glycol chains may have -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 3~12The terminals may be at least one of carbocylene, 3-12 member heterocyclene, 5-12 member heteroarylene, or any combination thereof, where R' is H or C1-C6 alkyl, and one or both terminal groups may be the same or different.

[0114] In some embodiments, the linker comprises a polyethylene glycol chain having 1 to 10 PEG units, interleaved with 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 to 6 PEG units, interleaved with 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 to 2 PEG units, interleaved with 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 to 10 PEG units. In some embodiments, the linker comprises a polyethylene glycol chain having 1 to 6 PEG units. In some embodiments, the linker comprises a polyethylene glycol chain having one or two PEG units.

[0115] Examples of linkers containing polyethylene glycol chains include:

[0116] [ka] [In the formula, n is an integer between 2 and 10] is one example, and an example of this is:

[0117] [ka] These are some examples.

[0118] In some embodiments, linkers containing polyethylene glycol chains can be terminated with functional groups, examples of which are as follows:

[0119] [ka] There is.

[0120] In some embodiments, the linker has the following structure

[0121] [ka] It is represented by one of the following:

[0122] In some embodiments, the compounds of this disclosure have the following structure

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [Chemical formula] It can be represented by any one of, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0130] Degron The ubiquitin-proteasome pathway (UPP) is an important cellular pathway that regulates major regulatory proteins and degrades misfolded or abnormal proteins. The UPP is at the core of multiple cellular processes. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases contain more than 500 different proteins and are classified into multiple classes defined by the structural elements of their E3 functional activities.

[0131] A degron can bind to an E3 ligase that is the cereblon (CRBN) or von Hippel-Lindau (VHL) tumor suppressor.

[0132] In some embodiments, the degron that binds to cereblon is D1

[0133] [Chemical formula] represented by, or its stereoisomer [wherein, Q is CH2 or C(O), [[ID=..]]X1 is O or NH].

[0134] In some embodiments, Q is CH2.

[0135] In some embodiments, Q is C=O.

[0136] In some embodiments, X1 is O.

[0137] In some embodiments, X1 is NH.

[0138] In some embodiments, X1 is CH2.

[0139] In some embodiments, X1 is C≡C.

[0140] In some embodiments, Q is CH2 and X1 is O. In some embodiments, Q is CH2 and X1 is NH. In some embodiments, Q is CH2 and X1 is CH2. In some embodiments, Q is CH2 and X1 is C≡C.

[0141] In some embodiments, Q is C(O) and X1 is O. In some embodiments, Q is C(O) and X1 is NH. In some embodiments, Q is C(O) and X1 is CH2. In some embodiments, Q is C(O) and X1 is C≡C.

[0142] In some embodiments, formula D1 is represented by formulas D1a to D1p

[0143] [ka] It has.

[0144] Therefore, in some embodiments, the compounds of this disclosure have the following structure

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148]

change

[0149] In some embodiments, the degron can bind to an E3 ligase that is the von Hippel-Lindau (VHL) tumor suppressor, D2 or D3

[0150]

Chemical formula

[0151]

Chemical formula

[0152]

Chemical formula

[0153]

Chemical formula

[0154]

Chemical formula

[0155] In some embodiments, degron has formula D2.

[0156] In some embodiments, R7 is H, and R8 is

[0157] [ka] That is the case.

[0158] In some embodiments, R7 and R8 are both H.

[0159] In some embodiments, R7 is H and R8 is methyl.

[0160] In some embodiments, R7 is an optionally substituted C1-C3 alkyl group, and R8 is H.

[0161] In some embodiments, R7 is an optionally substituted C1-C3 alkyl group, and R8 is methyl.

[0162] In some embodiments, R7 and R8, together with the carbon atoms to which they are bonded, form a cyclopropyl group.

[0163] In some embodiments, Y is H.

[0164] In some embodiments, Y is

[0165] [ka] That is the case.

[0166] In some embodiments, R9 is

[0167] [ka] That is the case.

[0168] In some embodiments, R9 is C(O)CR 10 R 11 R 12 In some embodiments, R 10 , R 11 , and R 12 R8 is H. In some embodiments, R6 and R7, together with the carbon atoms to which they are bonded, form a cyclopropyl group, and R8 is H, fluoro, cyano, or NMe2. In some embodiments, R8 is fluoro, cyano, or NMe2.

[0169] In some embodiments, R7 is H, and R8 is

[0170] [ka] Therefore, Y is H.

[0171] In some embodiments, R7 is H, and R8 is

[0172] [ka] Y is H, and R9 is C(O)CR 10 R 11 R 12 [In the formula, R 10 and R 11 These, together with the carbon atoms to which they are bonded, form a cyclopropyl group, R 12 [It is fluoro, cyano, or NMe2.]

[0173] In some embodiments, Y is

[0174] [ka] Therefore, R7 and R8 are H.

[0175] In some embodiments, Y is

[0176] [ka] R7 and R8 are H, and R9 is C(O)CR 10 R 11 R 12 [In the formula, R 10 and R 11 These, together with the carbon atoms to which they are bonded, form a cyclopropyl group, R 12 [It is fluoro, cyano, or NMe2.]

[0177] In some embodiments, R9 is

[0178] [ka] Therefore, Y is H, and R7 and R8 are H.

[0179] In some embodiments, R9 is

[0180] [ka] And Y is H, R7 is H, and R8 is methyl.

[0181] In some embodiments, R9 is

[0182] [ka] Y is H, R7 is an optionally substituted C1-C3 alkyl, and R8 is H.

[0183] In some embodiments, R9 is

[0184] [ka] Y is H, R7 is an optionally substituted C1-C3 alkyl, and R8 is H.

[0185] In some embodiments, R9 is

[0186] [ka] Y is H, and R7 and R8, together with the carbon atoms to which they are bonded, form a cyclopropyl group.

[0187] In some embodiments, formula D2 is represented by formulas D2a to D2o

[0188] [ka]

[0189] [ka] , or their stereoisomers It holds.

[0190] In some embodiments, degron has formula D3.

[0191] In some embodiments, the degron of formula D3 is derived from formulas D3a to D3g

[0192] [ka] , or their stereoisomers It holds.

[0193] Therefore, in some embodiments, the compounds of this disclosure have the following structure

[0194] [ka]

[0195]

change

[0196] In some embodiments, the compounds of this disclosure have the following structure

[0197] [ka]

[0198] [ka]

[0199] [ka]

[0200] [ka]

[0201] [ka]

[0202] [ka]

[0203] [ka]

[0204] [ka] They are represented by either a pharmaceutically acceptable salt or stereoisomer thereof.

[0205] The compounds of this disclosure may take the form of free acids, free bases, or pharmaceutically acceptable salts. A pharmaceutically acceptable salt of a compound of this disclosure may be formed, for example, by reacting a suitable free base of the compound with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977).

[0206] The compounds of this disclosure may have at least one chiral center, and therefore, as used herein, they may take the form of stereoisomers encompassing all isomers that differ only in the spatial orientation of their atoms. The term stereoisomer includes enantiomers (enantiomers containing the (R-) or (S-) configuration of a compound), mixtures of enantiomers of a compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and diastereomers of a compound having more than one chiral center that is not mirror image of each other. The chiral centers of a compound may undergo epimerization in vivo. Therefore, for these compounds, a dose of its (R-) form is considered equivalent to a dose of its (S-) form. Accordingly, the compounds of this disclosure may be prepared and used in the form of individual isomers substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0207] In some embodiments, the compound of formula (I) is an isotopic derivative in that it has, i.e., is enriched, at least one desired isotopic substitution of an atom in an amount exceeding the natural abundance of the isotope. In one embodiment, the compound contains deuterium or a plurality of deuterium atoms. Hereinafter, the term “compound” encompasses isotopic derivatives.

[0208] Compounds of formula (I) can also exist in the form of N-oxides, crystalline forms (which are also known as polymorphs), cocrystals, active metabolites of compounds having the same type of activity, prodrugs, tautomers, and non-solvated and solvated (e.g., hydrated) forms of the compound with pharmaceutically acceptable solvents such as water and ethanol. In this specification, the term “compound” encompasses all of these forms.

[0209] The compound of formula (I) can be prepared by crystallization under different conditions and may exist as one or a combination of polymorphs of the compound. For example, different polymorphs can be fractionated and / or prepared by carrying out crystallization at different temperatures using different solvents or mixtures of different solvents for recrystallization, or by using various modes of cooling during crystallization, ranging from fairly fast to fairly slow cooling. Polymorphs can also be obtained by heating or melting the compound and then cooling it slowly or rapidly. The presence of polymorphs can be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and / or other known techniques.

[0210] In some embodiments, the pharmaceutical composition comprises a cocrystal of the compound of formula (I). The term "cocrystal" as used herein refers to a stoichiometric multicomponent system comprising the compound of formula (I) and a cocrystal-forming agent, wherein the compound of formula (I) and the cocrystal-forming agent are linked by non-covalent interactions. The term "cocrystal-forming agent" as used herein refers to a compound that can form intermolecular interactions with the compound of formula (I) and cocrystallize with it. Typical examples of cocrystal-forming agents include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine p-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoic acid, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital.

[0211] Synthesis method In some embodiments, this disclosure relates to methods for preparing compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof. Generally, the compounds or pharmaceutically acceptable salts or stereoisomers thereof can be prepared by any process known to be applicable to the preparation of chemically related compounds. The compounds of this disclosure are described in various examples and are best understood in relation to synthetic schemes illustrating non-limiting methods by which the compounds of this disclosure can be prepared.

[0212] Pharmaceutical composition Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means, as is known in the art, a pharmaceutically acceptable material, composition, or vehicle suitable for administering the compound of this disclosure to a mammal. Suitable carriers include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases that serve to transport or deliver the compound from one organ or body part to another. The carrier is “acceptable” in the sense that it is physiologically inert and compatible with the other components of the formulation and is not harmful to the subject or patient. Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0213] In general, compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can be formulated into a given type of composition according to conventional pharmaceutical practices such as conventional mixing, dissolution, granulation, sugar-coating, polishing, emulsification, encapsulation, encapsulation, and compression processes, each of which is incorporated herein by reference in whole (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. AR Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the method of administration, which may include enteral (e.g., oral, oral, sublingual, and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection or infusion techniques, intraocular, intra-arterial, intramedullary, intrasacral, intraventricular, percutaneous, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal, bronchial, and inhalation), and topical (e.g., percutaneous).

[0214] Generally, the most appropriate route of administration depends on various factors, including, for example, the properties of the drug (e.g., its stability in the gastrointestinal environment) and / or the conditions of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral administration (e.g., intravenous) can be advantageous in that the compound can be administered relatively quickly, such as in single-dose treatments and / or acute conditions.

[0215] In some embodiments, the compound is formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0216] Therefore, 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 for dissolving the compound, suspensions for dispersing solid particles of the compound, 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 immediate, medium-duration, or sustained release.

[0217] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is a carrier such as sodium citrate or dicalcium phosphate, and a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, and d) crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethylcellulose). The solid is mixed with additional carriers or excipients such as (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and disintegrants such as sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings. They may further contain opacifying agents.

[0218] In some embodiments, the compound of formula (I) can be formulated in hard or soft gelatin capsules. Typical excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydride, microcrystalline cellulose, and sodium croscarmellose. The gelatin shell may contain gelatin, titanium dioxide, iron oxide, and colorants.

[0219] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsifies, syrups, and elixirs. Liquid dosage forms may contain, in addition to the compound, water or other solvents, solubilizers, and emulsifiers, which are commonly used in the art and may be aqueous or non-aqueous carriers (depending on the solubility of the compound), such as water or other solvents, solubilizers, and emulsifiers, etc., such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof. Oral compositions may also contain excipients such as wetting agents, suspending agents, colorants, sweeteners, flavoring agents, and fragrances.

[0220] Parenterally administered injectable formulations may include sterile aqueous solutions or oily suspensions. Injectable formulations can be formulated using suitable dispersing or wetting and suspending agents according to standard techniques. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions as solutions of non-toxic, parenterally acceptable diluents or solvents, such as 1,3-butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution (USP), and isotonic salines. In addition, sterile fixatives have conventionally been employed as solvents or suspension media. For this reason, any non-irritating fixative, including synthetic mono or diglycerides, can be employed. In addition, fatty acids such as oleic acid are used in the preparation of injectable formulations. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use. The effect of a compound can be prolonged by delaying its absorption, which can be achieved by using a liquid suspension with insufficient water solubility or by using crystalline or amorphous materials. Prolongation of absorption of a compound from parenteral formulations can also be achieved by suspending the compound in an oily vehicle.

[0221] In certain embodiments, the compound of formula (I) can be administered topically rather than systemically, for example, by direct injection of a conjugate into an organ, often as a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Injectable depot formulations are prepared by forming a microcapsule matrix of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoester), and poly(anhydride). The release rate of the compound can be controlled by changing the ratio of the compound to the polymer and the properties of the particular polymer employed. Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsifications that are compatible with body tissues. Furthermore, in other embodiments, the compound is encapsulated in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to an organ and selectively taken up by the organ.

[0222] The compositions can be formulated for oral or sublingual administration, and examples of compositions include tablets, lozenges, and gels.

[0223] The compound of formula (I) can be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists, or powders. The pharmaceutical composition can be delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve for delivering a measured amount. In some embodiments, capsules and cartridges containing gelatin, for example, capsules and cartridges for use in inhalers or injectors, can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0224] The compounds of formula (I) can be formulated for topical administration, which, as used herein, refers to intradermal administration by injection of the formulation into the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0225] Typical examples of carriers useful when formulating compounds for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, bandages, liposomes, powders, emulsions, microemulsifications, and buffer solutions (e.g., hypotonic or buffered saline). Creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitooleic acid, cetyl, or oleyl alcohol. Creams may also contain nonionic surfactants such as polyoxy-40-stearate.

[0226] In some embodiments, topical formulations may also include excipients, examples of which are penetration enhancers. These agents can deliver pharmacologically active compounds to the epidermis or dermis via the stratum corneum, preferably with little to no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in enhancing the skin penetration of drugs. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which investigates the use and testing of various skin penetration enhancers, each of which is incorporated herein by reference in whole, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Typical examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octrilphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0227] Representative examples of further excipients that may be included (to the extent possible) in topical and other types of formulations include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, 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, tocopherol, and chelating agents such as EDTA and citrate. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citrate, hydrochloric acid, and lactic acid buffers. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbate. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0228] Transdermal formulations typically require transdermal delivery devices and transdermal delivery patches, in which case the compound is dissolved and / or dispersed in a polymer or adhesive and formulated as a lipophilic emulsion or aqueous buffer solution. Patches can be constructed for continuous, pulsed, or on-demand delivery of pharmaceutical agents. Transdermal delivery of compounds may also be achieved by ionophoresis patches. Transdermal patches can result in controlled release of compounds, and the rate of absorption is reduced by using a rate-controlled membrane or by trapping the compound within a polymer matrix or gel. Absorption enhancers can be used to increase absorption, examples of which include pharmaceutically acceptable absorbable solvents that facilitate passage through the skin.

[0229] Ophthalmic preparations include eye drops.

[0230] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retained enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone and PEG. Compositions for rectal or vaginal administration may also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository wax, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectal or vaginal lumen, releasing the compound.

[0231] Dosage In this specification, the term “therapeutic dose” means the amount of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition comprising the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, that is effective in producing the desired therapeutic response in a particular patient in need thereof. Accordingly, the term “therapeutic dose” includes the amount of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, that, when administered, is sufficient to induce a positive improvement in the disease or disorder to be treated, or to prevent the onset or progression of the disease or disorder, or to some extent to alleviate one or more symptoms of the disease or disorder to be treated in the subject, or to simply kill or inhibit the growth of diseased cells (e.g., cancer, autophagy-dependent diseases (e.g., neurodegenerative disorders)), or to reduce the amount of DNMT1 in diseased cells.

[0232] The total daily dose and use of a compound can be determined, for example, by the attending physician using appropriate medical judgment, in accordance with standard medical practice. A specific therapeutically effective dose for any particular subject may depend on a variety of factors, including the disease or disorder being treated and its severity (e.g., its current condition); the subject's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the particular compound being employed; the duration of treatment; drugs used in combination with or concurrently with the compound; and similar factors well known in the medical field, which are incorporated herein by reference in whole (see, for example, 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).

[0233] How to use In some embodiments, the disclosure relates to methods for treating a disease or disorder by reducing the level or activity of DNMT1. The method comprises the step of administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need.

[0234] Disease or disorder is characterized by, or mediated by, abnormal DNMT1 activity (e.g., elevated DNMT1 levels or otherwise functionally abnormal DNMT1, e.g., mutant DNMT1 activity associated with non-pathological conditions). “Disease” is generally considered a health condition of an object in which the object is unable to maintain homeostasis and whose health will continue to deteriorate unless the disease is improved. In contrast, “disorder” in an object is a health condition in which the object is able to maintain homeostasis, but whose health condition is less favorable than that of an object without disorder. Leaving disorder untreated does not necessarily lead to a further deterioration of the animal’s health.

[0235] The term “subject” (or “patient” as used herein includes all members of the animal kingdom who are susceptible to or suffer from the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., human or non-human mammal. The methods may also be applied to companion animals such as dogs and cats. A subject “in need of treatment” according to this disclosure is likely to have or be suspected of having a particular disease or disorder, may have been diagnosed positive, or otherwise presents a sufficient number of risk factors or a sufficient number or combination of signs or symptoms that would allow a medical professional to diagnose or suspect the subject has the disease or disorder. Thus, subjects with a particular disease or disorder and subjects suspected of having a particular disease or disorder are not necessarily two separate groups.

[0236] In some embodiments, compounds of formula (I) may be useful in treating cell proliferation disorders and impairments. Herein, the term “cell proliferation disorder or impairment” refers to conditions characterized by dysregulation or abnormal cell proliferation, or both, including noncancerous conditions such as neoplasms, precancerous conditions, benign tumors, and cancer.

[0237] In some embodiments, the methods disclosed herein include treatment of subjects having cell proliferation disorders or disorders of the blood system, liver, brain, colon, prostate, breast, and head and neck.

[0238] In this specification, “cytoproliferative disorders or disorders of the hematological system” includes lymphoma, leukemia, myeloneoplasm, mast cell neoplasm, myelodysplasia, benign monoclonal immunoglobulinemia, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, primary myelofibrosis, and essential thrombocythemia. Therefore, representative examples of hematological cancers include leukemia, multiple myeloma, and lymphoma (including T-cell lymphoma, Hodgkin lymphoma, and non-Hodgkin 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 Sézary syndrome), peripheral T-cell lymphoma (PTCL) (anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, epithelial T-cell lymphoma, and gamma-delta T-cell lymphoma). These include (including), germinal center B-cell-like diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, Burkitt lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Valdensström macroglobulinemia, refractory NHL, relapsed NHL, pediatric lymphoma, and small lymphocytic lymphoma. Examples of leukemia include childhood leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, mast cell leukemia, myeloneoplasms, and mast cell neoplasms.

[0239] In this specification, “proliferative disorders or conditions of the liver” include all forms of proliferative disorders affecting the liver. Examples of proliferative disorders of the liver include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatoblastoma), precancerous or precancerous conditions of the liver, benign tumors or lesions of the liver, and malignant tumors or lesions of the liver, as well as metastatic lesions of tissues and organs in other parts of the body. Proliferative disorders of the liver may include hepatic hyperplasia, metaplasia, and dysplasia.

[0240] In this specification, “cytoproliferative disorders or disorders of the brain” includes all forms of cytoproliferative disorders affecting the brain. Examples of cytoproliferative disorders of the brain include brain cancers (e.g., gliomas, glioblastomas, meningiomas, pituitary adenomas, vestibular schwannomas, and primitive neuroectodermal tumors (medulloblastomas)), precancerous or precancerous conditions of the brain, benign tumors or lesions of the brain, and malignant tumors or lesions of the brain, as well as metastatic lesions of tissues and organs in other parts of the body. Cytoproliferative disorders of the brain may include brain hyperplasia, metaplasia, and dysplasia.

[0241] In this specification, “cytoproliferative disorders or disorders of the colon” ​​include all forms of cytoproliferative disorders affecting colorectal cells, including colorectal cancer, precancerous or precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Colorectal cancer includes sporadic and hereditary colorectal cancer, malignant neoplasms of the colon, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colorectal cancer can be associated with hereditary syndromes such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyps, MYH-associated polyposis, Gardner syndrome, Peutz-Jeggers syndrome, Turcott syndrome, and juvenile polyposis. Cytoproliferative disorders of the colon may also be characterized by hyperplasia, metaplasia, or dysplasia of the colon.

[0242] In this specification, “proliferative disorders or conditions of the prostate” include all forms of proliferative disorders affecting the prostate. Examples of proliferative disorders of the prostate include prostate cancer, precancerous or precancerous conditions of the prostate, benign tumors or lesions of the prostate, and malignant tumors or lesions of the prostate, as well as metastatic lesions of tissues and organs in other parts of the body. Proliferative disorders of the prostate may include prostatic hyperplasia, metaplasia, and dysplasia.

[0243] In this specification, “cytoproliferative disorders or disorders of the breast” include all forms of cytoproliferative disorders affecting breast cells. Examples of cytoproliferative disorders of the breast include breast cancer, precancerous or precancerous conditions of the breast, benign tumors or lesions of the breast, and metastatic lesions of tissues and organs in other parts of the body. Cytoproliferative disorders of the breast may include breast hyperplasia, metaplasia, and dysplasia.

[0244] The above and other aspects of this disclosure are intended to illustrate certain embodiments of this disclosure, but are not intended to limit the scope defined by the claims, as can be further understood by considering the following embodiments. [Examples]

[0245] [Example 1] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(2-(2-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide (1)

[0246] [ka]

[0247] Ammonium 3,5-dicyano-4-ethyl-6-hydroxypyridine-2-oleate To a solution of 2-cyanoacetamide (28.6 g, 0.34 mol) in water (190 mL), ammonium hydroxide (25% aqueous solution, 10 mL) and propionaldehyde (10 g, 0.17 mol) were added. The mixture was stirred at room temperature (rt) for 16 hours and then filtered. The filtered cake was washed with cold methanol and dried under reduced pressure to obtain the title compound (12 g, 34.3%).

[0248] 2,6-Dichloro-4-ethylpyridine-3,5-Dicarbonitrile POCl3 (10 mL) was added to a 75 mL thick-walled reaction tube equipped with a magnetic stirring rod. Ammonium 3,5-dicyano-4-ethyl-6-hydroxypyridine-2-oleate (1.26 g, 5.82 mmol) was carefully added while stirring. The reaction tube was capped and heated at 150 °C for 30 hours. The reaction mixture was cooled to room temperature, and POCl3 was evaporated under a stream of nitrogen gas. The residue was poured into 150 mL of ice water. The resulting suspension was filtered, the filter cake was washed with water, and dried under reduced pressure to obtain the title compound as a gray solid (1.03 g, 78.2%). LCMS m / z = 206.31, 208.32, 226.38.

[0249] 2-amino-2-oxo-1-phenylethylmethanesulfonate To a solution of 2-hydroxy-2-phenylacetamide (0.90 g, 5.95 mmol) in acetonitrile (18 mL), triethylamine (1.20 g, 1.65 mL, 2 equivalents) and methanesulfonyl chloride (0.84 g, 0.52 mL, 1.23 equivalents) were added. 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, dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (1.1 g, 80%). LCMS m / z = 230.22.

[0250] tert-butyl(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate A suspension of 2,6-dichloro-4-ethylpyridine-3,5-dicarbonitride (300 mg, 1.33 mmol) in EtOH (2 mL) was cooled to -20°C. A solution of tert-butylpiperidine-4-yl carbonate (292 mg, 1.1 equivalents) 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 equivalents), triethylamine (0.46 mL), and ethanol (5 mL) were added, and the mixture was stirred at room temperature for 17 hours. 2-amino-2-oxo-1-phenylethylmethanesulfonate (608 mg, 2 equivalents) was added, and the mixture was stirred at 40°C for 3 hours, then cooled to room temperature. The mixture was filtered, and the filtered cake was washed with EtOH, water, and ether, and then dried under reduced pressure to obtain the title compound (0.283 g, 41.0%). LCMS m / z = 521.55[M+H] + .

[0251] 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide 51.96 mg, 0.1 mmol of tert-butyl 4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperazine-1-carboxylate was mixed with 0.3 mL of dioxane and 0.3 mL of 4 M HCl solution in dioxane. The mixture was stirred at room temperature for 6 hours, and the solvent was removed under reduced pressure to obtain the title compound (45.1 mg, 100%). LC-MS m / z = 422.48 [M + H] + .

[0252] N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(2-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)propenamide 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide (3.85 mg, 0.00915 mmol), 3-(2-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (4.37 mg, 1.0 equivalent), and triethylamine (4.62 mg, 5.0 equivalents) were dissolved in DMF (0.2 mL). HATU (5.22 mg, 1.5 equivalents) was added, and the solution was stirred at room temperature for 15 minutes. The reaction mixture was purified by column chromatography (Teledyne ISCO, 4g silica column) using a 0-5% MeOH / DCM gradient to obtain the title compound (3.18 mg, 39.5%). LCMS m / z = 880.78 [M+H] + .

[0253] [Example 2] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(2-(2-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanamide (2)

[0254] [ka] Compound 2 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 3-(2-(2-(2-((2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid using a procedure similar to that used in Example 1. LCMS m / z=880.82[M+H] + .

[0255] [Example 3] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)hexaneamide (3)

[0256] [ka] Compound 3 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)hexanoic acid using a procedure similar to that used in Example 1. LCMS m / z = 790.72 [M + H] + .

[0257] [Example 4] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)octanamide (4)

[0258] [ka] Compound 4 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)octanoic acid using a procedure similar to that used in Example 1. LCMS m / z = 818.77 [M + H] + .

[0259] [Example 5] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)decanamide (5)

[0260] [ka] Compound 5 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)decanoic acid using a procedure similar to that used in Example 1. LCMS m / z = 846.77 [M + H] + .

[0261] [Example 6] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-12-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)dodecanamide (6)

[0262] [ka] Compound 6 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 12-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)dodecanoic acid using a procedure similar to that used in Example 1. LCMS m / z = 874.85 [M + H] + .

[0263] [Example 7] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)cyclohexane-1-carboxamide (7)

[0264] [ka] Compound 7 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)cyclohexane-1-carboxylic acid using a procedure similar to that used in Example 1. LCMS m / z=802.77[M+H] + .

[0265] [Example 8] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzamide (8)

[0266] [ka] Compound 8 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzoic acid using a procedure similar to that used in Example 1. LCMS m / z = 810.71 [M + H] + .

[0267] [Example 9] Synthesis of N-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)-6-oxohexyl)-4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)cyclohexane-1-carboxamide (9)

[0268] [ka]

[0269] tert-butyl(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)-6-oxohexyl)carbamate 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-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 room temperature for 15 minutes. The solvent was removed under a nitrogen stream, and the residue was purified by column chromatography (Teledyne ISCO, 4 g silica column) eluting with 0 → 4% MeOH / DCM to obtain the title compound (26.7 mg, 85.6%). LCMS m / z = 634.67 [M + H] + .

[0270] 6-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide 11.9 mg, 0.0188 mmol of tert-butyl(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)-6-oxohexyl)carbamate was mixed with 4 M HCl solution in THF (0.2 mL) and dioxane (0.4 mL, 1.6 mmol). The mixture was stirred at room temperature 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] + .

[0271] N-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)-6-oxohexyl)-4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)cyclohexane-1-carboxyamide The title compound was prepared from 6-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide and 4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)cyclohexane-1-carboxylic acid using a procedure similar to that used in Example 1. LCMS m / z = 915.74 [M + H] + .

[0272] [Example 10] Synthesis of N-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)-6-oxohexyl)-4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzamide (10)

[0273] [ka] Compound 10 was prepared from 6-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide and 4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzoic acid using a procedure similar to that used in Example 1. LCMS m / z = 923.79 [M + H] + .

[0274] [Example 11] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)propanamide (11)

[0275] [ka]

[0276] Methyl 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)propanoate Methyl 3-(4-(2-aminoethyl)piperazin-1-yl)propanoate (100 mg, 0.464 mmol), 2-(2,6-dioxopiperidine-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) were added to a microwave reaction tube. The microwave reaction tube was covered and microwaved at 100°C for 1 hour. The mixture was cooled to room temperature and purified by column chromatography (Teledyne ISCO, 40 g silica column) with elution using a 0 → 5% MeOH / DCM gradient to obtain the title compound (44.16 mg, 20.1%). LCMS m / z = 472.45 [M + H] + .

[0277] 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)propanoic acid A mixture of methyl 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)propanoate (44.16 mg, 0.0937 mmol), a 4 M HCl solution in dioxane (1.6 mL), and water (0.5 mL) was heated at 100°C for 30 minutes. The solvent was removed by freeze-drying to obtain the title compound. LCMS m / z = 458.69 [M + H] + .

[0278] N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)propenamide The title compound was prepared from 6-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide and 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)propanoic acid using a procedure similar to that used in Example 1. LCMS m / z=860.64[M+H] + .

[0279] [Example 12] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)piperazine-1-yl)propanamide (12)

[0280] [ka]

[0281] Methyl 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)piperazine-1-yl)propanoate Methyl 3-(4-(2-aminoethyl)piperazin-1-yl)propanoate (91.3 mg, 0.424 mmol), 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (117.1 mg, 0.424 mmol), diisopropylethylamine (370 μL, 2.12 mmol), and N-methylpyrrolidine (2.0 mL) were added to a microwave reaction tube. The microwave reaction tube was covered and microwaved at 100°C for 1 hour. The mixture was cooled to room temperature and purified by column chromatography (Teledyne ISCO, 40 g silica column) with elution using a 0 → 15% MeOH / DCM gradient to obtain the title compound (25.0 mg, 12.5%). LCMS m / z = 473.33 [M + H] + .

[0282] 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)piperazine-1-yl)propanoic acid A mixture of methyl 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)piperazine-1-yl)propanoate (25.0 mg, 0.0531 mmol), a 4 M HCl solution in dioxane (1.0 mL), and water (0.25 mL) was heated at 100°C for 30 minutes. The solvent was removed by freeze-drying to obtain the title compound. LCMS m / z = 458.43 [M + H] + .

[0283] N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)piperazine-1-yl)propenamide The title compound was prepared from 6-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide and 3-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)piperazine-1-yl)propanoic acid using a procedure similar to that used in Example 1. LCMS m / z=860.60[M+H] + .

[0284] [Example 13] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)acetamide (13)

[0285] [ka] Compound 13 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and (2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)glycine using a procedure similar to that used in Example 1. LCMS m / z=734.49[M+H] + .

[0286] [Example 14] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)acetamide (14)

[0287] [ka] Compound 14 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)acetic acid using a procedure similar to that used in Example 1. LCMS m / z = 778.57 [M + H] + .

[0288] [Example 15] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)benzamide (15)

[0289] [ka] Compound 15 was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)benzoic acid using a procedure similar to that used in Example 1. LCMS m / z = 824.50 [M + H] + .

[0290] [Example 16] Synthesis of N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-6-((3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)propyl)amino)nicotinamide (16)

[0291] [ka]

[0292] 6-((3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)propyl)amino)nicotinic acid A mixture of 6-((3-aminopropyl)amino)nicotinic acid (2.8 mg, 0.0143 mmol), 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (4.3 mg, 0.0155 mmol), diisopropylethylamine (10.8 μL, 0.062 mmol), and N-methylpyrrolidone (0.1 mL) was stirred at 90°C for 20 hours. The mixture was cooled to room temperature and purified by column chromatography (Teledyne ISCO, 12 g silica column) with elution under a 0 → 12% MeOH / DCM gradient to obtain the title compound (1.0 mg, 14.3%). LCMS m / z = 452.34 [M + H] + .

[0293] N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)-6-((3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)propyl)amino)nicotinamide The title compound was prepared from 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetamide and 6-((3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)propyl)amino)nicotinic acid using a procedure similar to that used in Example 1. LCMS m / z = 854.57 [M + H] + .

[0294] [Example 17] Synthesis of (2S,4R)-1-((2S)-2-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexanoamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (17)

[0295] [ka]

[0296] 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 room temperature for 1.5 hours, then tert-butanol (2 mL, 34.5 mmol) was added. The solution was stirred at room temperature for 16 hours, then quenched by slowly adding saturated aqueous solution NaHCO3 (15 mL). The mixture was extracted with toluene (3 times × 20 mL), the combined organic extract was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was filtered through a silica plug and washed with 50% toluene / hexane (20 mL). The filtrate was concentrated under vacuum to obtain the title compound as a colorless oil (357.05 mg, 71.1%).

[0297] tert-butyl6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexanoate 6-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide (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 room temperature for 4 hours. A solution of tert-butyl 6-bromohexanoate (2.2 mg, 0.00893 mmol) in DMF (50 μL) was added, and the mixture was stirred at room temperature for 16 hours. An additional portion of tert-butyl 6-bromohexanoate (0.88 mg, 0.0035 mmol) was added, and the mixture was stirred for a further 6 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4g silica column) using a 0-6% MeOH / DCM gradient to obtain the title compound (2.0 mg, 28.6%). LCMS m / z = 591.54 [M+H] + .

[0298] 6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexanoic acid tert-butyl 6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)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 room temperature for 2 hours, then concentrated under vacuum to obtain the title compound. LCMS m / z = 535.45 [M + H] + .

[0299] (2S,4R)-1-((2S)-2-(6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexanoamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 6-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexanoic acid (2.0 mg, 0.00374 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-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). HATU (2.1 mg, 0.00561 mmol) was added to the solution, and the mixture was stirred at room temperature for 15 minutes. The compound was then purified by column chromatography (Teledyne ISCO, 4g silica column) using a gradient of MeOH in 0% → 20% DCM to obtain the title compound (0.62 mg, 17.2%). LCMS m / z = 961.80 [M + H] + .

[0300] [Example 18] Synthesis of (2S,4R)-1-((2S)-2-(10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)decanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (18)

[0301] [ka]

[0302] tert-butyl-10-bromodecanoate 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 room temperature for 2 hours. Tert-butanol (1 mL) was added, and the mixture was stirred for 16 hours. The reaction was slowly quenched by adding saturated aqueous solution NaHCO3 (10 mL). The mixture was extracted with toluene (3 times × 10 mL), the combined organic layers were dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (0.28 g, 92.6%).

[0303] tert-butyl10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)decanoate 6-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide (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 room temperature for 2 hours. 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 room temperature for 16 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 5% MeOH / DCM to obtain the title compound (4.51 mg, 29.3%). LCMS m / z = 647.62 [M + H] + .

[0304] 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)decanoic acid tert-butyl 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)decanoate (4.51 mg, 0.00697 mmol) and TFA (5 μL) were dissolved in DCM (50 μL), the solution was stirred at room temperature for 18 hours, and then concentrated under vacuum to obtain the title compound. LCMS m / z = 592.52 [M + H] + .

[0305] (2S,4R)-1-((2S)-2-(10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)decanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 10-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)decanoic acid (4.1 mg, 0.00697 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-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, the mixture was stirred at room temperature for 1 hour, and then purified by column chromatography (Teledyne ISCO, 4g silica column) with elution under a 0 → 15% MeOH / DCM gradient to obtain the title compound (3.73 mg, 52.6%). LCMS m / z = 10¹⁷.85 [M + H] + .

[0306] [Example 19] Synthesis of (2S,4R)-1-((2S)-2-(16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexadecanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (19)

[0307] [ka]

[0308] tert-butyl-16-bromodecanoate 16-Bromohexadecanoic acid (335.3 mg, 1 mmol) and trifluoroacetic anhydride (556 μL, 4.00 mmol) were dissolved in THF (2 mL), the solution was stirred at room temperature for 2 hours, then tert-butanol (1 mL) was added, and the mixture was stirred for 16 hours. The reaction was quenched by slowly adding saturated aqueous solution NaHCO3 (10 mL). The mixture was extracted with toluene (3 times × 10 mL), the combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (0.39 g, 100%).

[0309] tert-butyl16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexadecanoate 6-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)hexaneamide (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 room temperature for 2 hours. A solution of tert-butyl 10-bromohexadecanoate (9.3 mg, 0.0238 mmol) in DMF (50 μL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 4% MeOH / DCM to obtain the title compound (3.92 mg, 22.5%). LCMS m / z = 731.79 [M + H] + .

[0310] 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexadecanoic acid tert-butyl 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexadecanoate (3.92 mg, 0.00536 mmol) and TFA (5 μL) were dissolved in DCM (50 μL), the solution was stirred at room temperature for 18 hours, and then concentrated under vacuum to obtain the title compound. LCMS m / z = 675.67 [M + H] + .

[0311] (2S,4R)-1-((2S)-2-(16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexadecanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 16-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl)amino)hexadecanoic acid (3.6 mg, 0.00536 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-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, the solution was stirred at room temperature for 1 hour, and then purified by column chromatography (Teledyne ISCO, 4g silica column) with elution under a 0 → 15% MeOH / DCM gradient to obtain the title compound (3.89 mg, 65.9%). LCMS m / z = 1101.99 [M + H] + .

[0312] [Example 20] Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-N-methylhexanamide (20)

[0313] [ka]

[0314] tert-butyl(2-((6-chloro-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)(methyl)carbamate 2,6-Dichloro-4-ethylpyridine-3,5-dicarbonitrile (113 mg, 0.500 mmol) was dissolved in DMF (3 mL), and a solution of tert-butylmethyl (2-(methylamino)ethyl)carbamate (112 mg, 0.595 mmol) in DMF (2 mL) was added, followed by triethylamine (70.1 μL, 0.500 mmol). The mixture was stirred at room temperature for 5 minutes, then diluted with water (10 mL) and extracted with  (3 times × 10 mL). The combined organic layer was washed with water and brine, then dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (Teledyne ISCO, 12 g silica column) with elution under a 0 → 28%  / hexane gradient to obtain the title compound (152.43 mg, 80.7%). LCMS m / z = 378.31 [M + H] + .

[0315] tert-butyl(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)(methyl)carbamate A mixture of tert-butyl(2-((6-chloro-3,5-dicyano-4-ethylpyridine-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 room temperature for 30 minutes. 2-amino-2-oxo-1-phenylethylmethanesulfonate (50.7 mg, 0.221 mmol) and triethylamine (51.6 μL, 0.368 mmol) were added, and the mixture was stirred at room temperature for 15 hours. Water (2 mL) was added to the reaction mixture, the mixture was filtered, and the filtered solid was redissolved in DCM. The solution was purified by column chromatography (Teledyne ISCO, 4 g silica column) using DCM to eluate it, yielding the title compound (20.24 mg, 21.6%). LCMS m / z = 509.42[M+H] + .

[0316] 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridine-2-yl)thio)-2-phenylacetamide 20.24 mg, 0.0398 mmol of tert-butyl(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)(methyl)carbamate was added to 4M HCl solution in THF (0.1 mL) and dioxane (0.1 mL). The mixture was stirred at room temperature for 16 hours and then concentrated under vacuum to obtain the title compound. LCMS m / z = 410.39 [M + H] + .

[0317] N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-N-methylhexaneamide 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridine-2-yl)thio)-2-phenylacetamide (5.0 mg, 0.0123 mmol), 6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)hexanoic acid (4.7 mg, 0.0123 mmol), and TEA (8.6 μL, 0.0615 mmol) were dissolved in DMF (50 μL) and DCM (50 μL). HATU (7.0 mg, 0.0185 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was then purified by column chromatography (Teledyne ISCO, 4 g silica column) with elution at 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] + .

[0318] [Example 21] Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)-4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)-N-methylbenzamide (21)

[0319] [ka] 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridine-2-yl)thio)-2-phenylacetamide (5.0 mg, 0.0123 mmol), 4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzoic acid (5.0 mg, 0.0123 mmol), and triethylamine (8.6 μL, 0.0615 mmol) were dissolved in DMF (50 μL) and DCM (50 μL). HATU (7.0 mg, 0.0185 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was purified by column chromatography (Teledyne ISCO, 4 g) with an elution gradient of 50 → 100% ethylacetamide / hexane to obtain the title compound (4.36 mg, 44.4%). LCMS m / z = 798.56[M+H] + .

[0320] [Example 22] Synthesis of 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)butyl)-2-phenylacetamide (22)

[0321] [ka]

[0322] 2-Bromo-2-phenylacetic acid 2-hydroxy-2-phenylacetic acid (3.00 g, 19.7 mmol) was carefully added to a mixture of 48% HBr solution (5.6 mL) and concentrated H2SO4 (2.2 mL). The mixture was refluxed at 105°C for 3 hours, then cooled to room temperature and poured into 25 mL of ice water. This mixture was extracted with ether (2 times × 50 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the title compound.

[0323] 2-((6-(4-((tert-butoxycarbonyl)amino)piperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetic acid 39.0 mg, 0.100 mmol of tert-butyl(1-(6-chloro-3,5-dicyano-4-ethylpyridine-2-yl)piperidine-4-yl) carbamate and 13.7 mg, 0.120 mmol of potassium thioacetate were dissolved in 200 μL of DMF. The solution was stirred at room temperature for 30 minutes, and 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 room temperature for 16 hours, and then purified by column chromatography (Teledyne ISCO, 12 g silica column) with elution under a 0 → 100% siRNA / hexane gradient to obtain the title compound (16.4 mg, 31.4%). LCMS m / z = 522.49 [M + H] + .

[0324] tert-butyl(1-(3,5-dicyano-6-((2-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)butyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate 2-((6-(4-((tert-butoxycarbonyl)amino)piperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetic acid (2.2 mg, 0.00425 mmol) was dissolved in DMF (100 μL) and cooled to 0°C. N,N'-dicyclohexylcarbodiimide (0.9 mg, 0.00425 mmol) and hydroxybenzotriazole (0.6 mg, 0.00425 mmol) were added, and the mixture was stirred at 0°C for 10 minutes. 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (1.5 mg, 0.00425 mmol) and N-methylmorpholine (0.47 μL, 0.00425 mmol) were added, and the mixture was warmed to room temperature. After 16 hours, the mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) using a 0 → 5% MeOH / DCM gradient to obtain the title compound (4.83 mg, 100%). LCMS m / z = 848.71 [M + H] + .

[0325] 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)butyl)-2-phenylacetamide A solution of tert-butyl(1-(3,5-dicyano-6-((2-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)butyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate (4.83 mg, 0.00570 mmol) and dioxane (0.1 mL) in 4 M HCl was stirred at room temperature for 3 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 10% MeOH / DCM to obtain the title compound (0.40 mg, 9.4%). LCMS m / z = 748.62 [M + H] + .

[0326] [Example 23] Synthesis of 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzyl)-2-phenylacetamide (23)

[0327] [ka]

[0328] tert-butyl(1-(3,5-dicyano-6-((2-((4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate 2-((6-(4-((tert-butoxycarbonyl)amino)piperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetic acid (5.22 mg, 0.01 mmol) was dissolved in DMF (50 μL) and cooled to 0°C. N,N'-dicyclohexylcarbodiimide (2.1 mg, 0.01 mmol) and hydroxybenzotriazole (1.4 mg, 0.01 mmol) were added, and the mixture was stirred at 0°C for 15 minutes. 4-((4-(aminomethyl)benzyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (3.9 mg, 0.01 mmol) and N-methylmorpholine (1.1 μL, 0.01 mmol) were added, and the mixture was warmed to room temperature. After 3 hours, the mixture was purified by column chromatography using DCM (Teledyne ISCO, 4g silica column) to obtain the title compound (2.47 mg, 27.6%). LCMS m / z = 897.66 [M + H] + .

[0329] 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzyl)-2-phenylacetamide A solution of tert-butyl(1-(3,5-dicyano-6-((2-((4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)benzyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate) (2.47 mg, 0.00276 mmol) and dioxane (0.1 mL) in 4 M HCl was stirred at room temperature for 1 hour. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 8% MeOH / DCM to obtain the title compound (0.57 mg, 26.0%). LCMS m / z = 796.66 [M + H] + .

[0330] [Example 24] Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)-N-methylpropanamide (24)

[0331] [ka] 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridine-2-yl)thio)-2-phenylacetamide (2.1 mg, 0.0511 mmol), 3-(2-(2-((2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (2.4 mg, 0.00511 mmol), and triethylamine (3.6 μL, 0.0256 mmol) were dissolved in DMF (50 μL). HATU (2.9 mg, 0.00767 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was purified by column chromatography (Teledyne ISCO, 4g silica column) using a 0-15% MeOH / DCM gradient to obtain the title compound (1.97 mg, 44.5%). LCMS m / z = 868.82 [M+H] + .

[0332] [Example 25] Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)-3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)-N-methylpropanamide (25)

[0333] [ka] 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridine-2-yl)thio)-2-phenylacetamide (2.1 mg, 0.00511 mmol), 3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)propanoic acid (2.0 mg, 0.0511 mmol), and triethylamine (3.6 μL, 0.0256 mmol) were dissolved in DMF (50 μL). HATU (2.9 mg, 0.00767 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 3% MeOH / DCM to obtain the title compound (0.81 mg, 20.4%). LCMS m / z = 780.73[M+H] + .

[0334] [Example 26] Synthesis of 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(2-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-phenylacetamide (26)

[0335] [ka]

[0336] tert-butyl(1-(3,5-dicyano-6-((2-((2-((2-((2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate 2-((6-(4-((tert-butoxycarbonyl)amino)piperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetic acid (2.6 mg, 0.00500 mmol), 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (2.0 mg, 0.00500 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 room temperature for 15 minutes. The mixture was diluted with toluene (5 mL), washed with water, dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (4.97 mg, 100%). LC-MS m / z = 908.75 [M + H] + .

[0337] 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(2-(2-(2-((2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-phenylacetamide A mixture of tert-butyl(1-(3,5-dicyano-6-((2-((2-(2-((2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate (4.97 mg, 0.00547 mmol) and a 4 M HCl solution in dioxane (0.1 mL) was stirred at room temperature for 19 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 10% MeOH / DCM to obtain the title compound (0.77 mg, 17.4%). LCMS m / z = 808.74 [M + H] + .

[0338] [Example 27] Synthesis of 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)decyl)-2-phenylacetamide (27)

[0339] [ka]

[0340] tert-butyl(1-(3,5-dicyano-6-((2-((10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)decyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate 2-((6-(4-((tert-butoxycarbonyl)amino)piperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-2-phenylacetic acid (2.6 mg, 0.005 mmol), 4-((10-aminodecyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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 room temperature for 15 minutes. The mixture was diluted with  (5 mL), washed with water, dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (4.05 mg, 86.9%).

[0341] 2-((6-(4-aminopiperidine-1-yl)-3,5-dicyano-4-ethylpyridine-2-yl)thio)-N-(10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)decyl)-2-phenylacetamide A mixture of tert-butyl(1-(3,5-dicyano-6-((2-((10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)decyl)amino)-2-oxo-1-phenylethyl)thio)-4-ethylpyridine-2-yl)piperidine-4-yl)carbamate (4.05 mg, 0.00434 mmol) and a 4 M HCl solution in dioxane (0.1 mL) was stirred at room temperature for 19 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 8% MeOH / DCM to obtain the title compound (0.87 mg, 24.1%). LCMS m / z = 832.79 [M + H] + .

[0342] [Example 28] Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)amino)-N-methylhexanamide (28)

[0343] [ka] 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridine-2-yl)thio)-2-phenylacetamide (6.0 mg, 0.0161 mmol), 6-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)amino)hexanoic acid (6.6 mg, 0.0161 mmol), and triethylamine (11.3 μL, 0.0805 mmol) were dissolved in DMF (80 μL). HATU (9.2 mg, 0.0242 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with elution under a 0 → 15% MeOH / siRNA gradient. The product fraction was collected, concentrated under vacuum, and then re-purified by preparative HPLC to obtain the title compound (0.34 mg, 2.8%). LC-MS m / z = 764.70 [M + H] + .

[0344] [Example 29] Synthesis of N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridine-2-yl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)-N-methylhexanamide (29)

[0345] [ka] 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridine-2-yl)thio)-2-phenylacetamide (3.9 mg, 0.0100 mmol), 6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)hexanoic acid (4.1 mg, 0.0100 mmol), and triethylamine (7.0 μL, 0.0500 mmol) were dissolved in DMF (50 μL). HATU (5.7 mg, 0.0150 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was purified by column chromatography (Teledyne ISCO, 4 g silica column) with an elution gradient from 0 to 5% MeOH / DCM to obtain the title compound (0.32 mg, 4.1%). LCMS m / z = 779.67[M+H] + .

[0346] [Example 30] Synthesis of 2-((7-(6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)hexanoyl)-2-(4-hydroxypiperidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)thio)-2-phenylacetamide (30)

[0347] [ka]

[0348] tert-butyl4-((2-amino-2-oxo-1-phenylethyl)thio)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 30.4 mg, 0.100 mmol of tert-butyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate and 13.7 mg, 0.120 mmol of potassium ethanethioate were dissolved in 300 μL of DMF, and the mixture was stirred at room temperature for 2 hours. 27.5 mg, 0.120 mmol of 2-amino-2-oxo-1-phenylethylmethanesulfonate, 28.0 μL of triethylamine, and 300 μL of DMF were added, and the mixture was stirred at room temperature for 15 hours. The mixture was purified by column chromatography (Teledyne ISCO, 12 g silica column) with elution under a 20 → 50% siRNA / hexane gradient to obtain the title compound (27.6 mg, 63.5%). LCMS m / z = 435.35 [M + H] + .

[0349] tert-butyl4-((2-amino-2-oxo-1-phenylethyl)thio)-2-(4-hydroxypiperidine-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate Tert-butyl 4-((2-amino-2-oxo-1-phenylethyl)thio)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (9.3 mg, 0.0214 mmol), piperidine-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 in a sealed reaction tube at 130 °C for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (6.35 mg, 59.4%).

[0350] 2-((2-(4-hydroxypiperidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)thio)-2-phenylacetamide tert-butyl 4-((2-amino-2-oxo-1-phenylethyl)thio)-2-(4-hydroxypiperidine-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (6.4 mg, 0.0127 mmol) was dissolved in 4 M HCl solution in dioxane (0.1 mL) and THF (0.1 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to obtain the title compound (5.1 mg, 100%). LCMS m / z = 400.39 [M + H] + .

[0351] 2-((7-(6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)hexanoyl)-2-(4-hydroxypiperidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)thio)-2-phenylacetamide 2-((2-(4-hydroxypiperidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)thio)-2-phenylacetamide (2.5 mg, 0.00635 mmol), 6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)hexanoic acid (2.5 mg, 0.000635 mmol), and triethylamine (4.5 μL, 0.0318 mmol) were dissolved in DMF (90 μL). HATU (3.6 mg, 0.00953 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then purified by column chromatography (Teledyne ISCO, 4 g silica column) with elution under a 0 → 7% MeOH / DCM gradient to obtain the title compound (3.35 mg, 68.6%). LCMS m / z = 769.64[M+H] + .

[0352] [Example 31] Synthesis of 2-((7-(10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)decanoyl)-2-(4-hydroxypiperidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)thio)-2-phenylacetamide (31)

[0353] [ka] 2-((2-(4-hydroxypiperidine-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)thio)-2-phenylacetamide (2.5 mg, 0.00635 mmol), 10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)decanoic acid (2.8 mg, 0.00635 mmol), and triethylamine (4.5 μL, 0.0318 mmol) were dissolved in DMF (90 μL). HATU (3.6 mg, 0.00953 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was then purified by column chromatography (Teledyne ISCO, 4 g silica column) with elution under a 0 → 7% MeOH / DCM gradient to obtain the title compound (2.88 mg, 55.0%). LCMS m / z = 825.72[M+H] + .

[0354] [Example 32] Synthesis of 2-((3,5-dicyano-6-((8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)octyl)amino)-4-ethylpyridine-2-yl)thio)-2-phenylacetamide (32)

[0355] [ka]

[0356] 2-Chloro-6-((8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)octyl)amino)-4-ethylpyridine-3,5-dicarbonitrine 2,6-Dichloro-4-ethylpyridine-3,5-dicarbonitride (11.3 mg, 0.050 mmol), 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (24.0 mg, 0.060 mmol), and triethylamine (7.0 μL, 0.050 mmol) were dissolved in DMF (300 μL), and the mixture was stirred at room temperature for 3 hours. Then, triethylamine (21 μL, 0.150 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The mixture was diluted with water (10 mL) and extracted with RINKAN (3 times × 10 mL). The combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (26.2 mg, 88.8%). LCMS m / z = 590.51 [M + H] + .

[0357] 2-((3,5-dicyano-6-((8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)octyl)amino)-4-ethylpyridine-2-yl)thio)-2-phenylacetamide 2-chloro-6-((8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)octyl)amino)-4-ethylpyridine-3,5-dicarbonitride (11.8 mg, 0.020 mmol) and potassium ethanethioate (2.7 mg, 0.024 mmol) were dissolved in DMF (100 μL), and the mixture was stirred at room temperature for 1 hour. 2-amino-2-oxo-1-phenylethylmethanesulfonate (5.5 mg, 0.024 mmol), triethylamine (5.6 μL, 0.040 mmol), and DMF (50 μL) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was purified by column chromatography (Teledyne ISCO, 12g silica column) using a 20-100% siRNA / hexane gradient to obtain the title compound (3.35 mg, 23.2%). LCMS m / z = 721.76 [M+H] + .

[0358] [Example 33] Degradation activity - Western blot HL60 cells were placed in a 6-well plate at a rate of 1 × 10⁶ 6 Cells were seeded in wells and treated with the compound at the indicated concentrations and times. Total protein was extracted from cells using RIPA buffer (Abcam) supplemented with Halt Protease Inhibitor Cocktail (Millipore®-Sigma). Samples were loaded onto Invitrogen Bolt® Bis-Tris Plus gels (ThermoFisher® Scientific) and transferred to Invitrolon® PVDF membranes (ThermoFisher® Scientific) using an Invitrogen Bolt® wet gel transfer device. Immunodetection was performed using standard techniques. The following primary and secondary antibodies were used: anti-DNMT1, CRBN, and β-actin (Cell Signaling Technology®), as well as IRDye secondary antibody at concentrations recommended by the manufacturer.

[0359] The compounds showed downregulation of DNMT1 (Figures 1-12).

[0360] All patent and non-patent publications suggest the level of skill of a person skilled in the art to which this disclosure pertains. All such publications are incorporated herein by reference to the same extent as each individual publication is specifically and individually indicated as being incorporated by reference.

[0361] While the present disclosure has been described with reference to specific embodiments, these embodiments should be understood to be merely illustrative of the principles and applications of the present disclosure. Therefore, numerous modifications can be made to the exemplary embodiments, and other configurations can be conceived without departing from the spirit and scope of the present disclosure as defined in the appended claims.

Claims

1. Compound of formula (I) 【Chemistry 1】 or its pharmaceutically acceptable salt or stereoisomer [In the formula, DNMT1-targeting ligands are formula TL-1 or TL-2 【Chemistry 2】 [In the formula, R １ NR ３ R ４ And, R ３ is H or methyl, and R ４ teeth, 【Transformation 3】 And, or R ３ and R ４ These, together with the nitrogen atom to which they are bonded, form a optionally substituted six-membered heterocycline, or R ３ and R ４ together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclyl further attached to the linker R ２ NH ２ or 【Chemistry 4】 And, R ５ and R ６ H, optionally substituted alkyl, or 【Transformation 5】 And, 【Transformation 6】 This refers to a binding between the DNMT1-targeting ligand and the linker, provided that there is only one binding between the DNMT1-targeting ligand and the linker. It has, The linker represents a portion that covalently connects the degron and the targeted ligand, The degron is defined by formulas D1, D2, or D3 【Transformation 7】 [In the formula, Q is CH ２ or C(O), X １ O, NH, CH ２ , or C ≡ C, R ７ C is replaced by H or of any choice. １ ~C ３ It is alkyl, or R ７ and R ８ These, together with the carbon atoms to which they are bonded, form a cyclopropyl group. R ８ is H, methyl, or 【Transformation 8】 And, R ９ は、C(O)CR １０ R １１ R １２ 、 【Chemistry 9】 And, R １０ and R １１ Both are H, or R １０ and R １１ These, together with the carbon atoms to which they are bonded, form a cyclopropyl group. R １２ is H, fluoro, cyano, or NME ２ And, Y is H, 【Chemistry 10】 And, 【Chemistry 11】 This is a bond between the degron and the linker, provided that there is only one bond between the degron and the linker. [Has]

2. R ２ However, NH ２ The compound according to claim 1.

3. R ３ However, H is R ４ but 【Chemistry 12】 Therefore, formula TL-1 is TL-1a 【Chemistry 13】 A compound according to claim 1 or 2, having the following characteristics.

4. R ３ However, it is Me, and R ４ but 【Chemistry 14】 Therefore, equation TL-1 is equal to TL-1b 【Chemistry 15】 A compound according to claim 1 or 2, having the following characteristics.

5. R ３ and R ４ The compound according to claim 1 or 2, wherein they, together with the nitrogen atoms to which they are bonded, form a six-membered heterocycline that is optionally substituted and further bonded to the linker.

6. R ３ and R ４ However, together with the nitrogen atoms to which they are bonded, they form piperidyl, and the formula TL-1 becomes TL-1c 【Chemistry 16】 The compound according to claim 5, having the following characteristics.

7. R ３ and R ４ The compound according to claim 1, wherein they combine with the nitrogen atoms to which they are bonded to form an optionally substituted six-membered heterocycline.

8. R ３ and R ４ The compound according to claim 7, wherein they combine with the nitrogen atoms to which they are bound to form optionally substituted piperidyls.

9. The compound according to claim 8, wherein piperidyl is substituted with an amino group.

10. R ２ but, 【Chemistry 17】 Therefore, equation TL-1 is TL-1d [Chemistry 18] A compound according to any one of claims 7 to 9, having the following characteristics.

11. The DNMT1-targeting ligand has formula TL-2, and R ５ but, 【Chemistry 19】 And R ６ is H, or R ５ R is an alkyl group that is substituted with H or optionally substituted, ６ but 【Chemistry 20】 The compound according to claim 1.

12. The compound according to any one of claims 1 to 11, wherein the degron has formula D1.

13. Equation D1 is, Equations D1a to D1p 【Chemistry 21-1】 【Chemistry 21-2】 The compound according to claim 12, having the following characteristics.

14. The compound according to any one of claims 1 to 11, wherein the degron has formula D2 or D3.

15. The aforementioned degron is a formula D2a to D2o or D3a to D3g 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 【Chemistry 22-4】 The compound according to claim 14, or having stereoisomers thereof.

16. The linker is, formula L0 【Chemistry 23】 or its stereoisomer [In the formula, p1 is an integer selected from 0 to 6. p2 is an integer selected from 0 to 12. p3 is an integer selected from 0 to 12. Each W is independent, non-existent, CH ２ O, S, NR １３ , or C(O)NH, R １３ Each of them independently represents hydrogen or C １ ~C ６ It is alkyl, W １ and W ２ Independently, non-existent, (CH ２ ) １～３ , O, NH, or C(O)NR １３ And, Z １ and Z ２ is independently non - existent, - O -, - S -, - N(R １３ ), - C≡C -, - 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 ２ O -, - N(R １３ ),S(O ２ )-, - S(O ２ ),N(R １３ ), - N(R １３ ),S(O)-, - S(O)N(R １３ ), - N(R １３ ),S(O ２ ),N(R １３ ), - N(R １３ ),S(O)N(R １３ ), - C ３ ~C １２ is carbocyclic or 3 - to 12 - member heterocyclic, The linker is W ２ Next to 【Chemistry 24】 Covalently bonded to deglon via W １ Next to 【Chemistry 25】 The linker is covalently bound to the targeted ligand via W １ Next to 【Chemistry 26】 Covalently bonded to deglon via W ２ Next to 【Chemistry 27】 [Covalently bound to the targeted ligand via [a certain mechanism]] A compound according to any one of claims 1 to 15, having the following characteristics.

17. Equation L0 corresponds to equations L0a to L0j 【Chemistry 28】 The compound according to claim 16, wherein TL represents a targeted ligand.

18. The linker is a bond, or includes an alkylene chain or a divalent alkylene chain, and either the alkylene chain or the divalent alkylene chain may be -O-, -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)-, -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) ２ O-, -N(R')S(O) ２ -, -S(O) ２ N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O) ２ N(R')-, -N(R')S(O)N(R')-, C ３ ~C １２ It may be interrupted by at least one of carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or any combination thereof, and / or terminated by either or both ends thereof, and R' is H or C １ ~C ６ The compound according to any one of claims 1 to 15, wherein the interceptor and one or both terminal groups are the same or different.

19. The linker is a polyethylene glycol (PEG) chain, and the polyethylene glycol chain has -O-, -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)-, -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) ２ O-, -N(R')S(O) ２ -, -S(O) ２ N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O) ２ N(R')-, -N(R')S(O)N(R')-, C ３ ~C １２ It may be interrupted by at least one of carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or any combination thereof, and / or terminated with either or both ends thereof, and R' is H or C １ ~C ６ The compound according to any one of claims 1 to 15, wherein the interceptor and one or both terminal groups are the same or different.

20. The linker has a structure 【Chemistry 29】 A compound according to any one of claims 1 to 15, represented by any one of the following: 【Request Item 21】 【Chemistry 30-1】 【Chemistry 30-2】 【Transformation 30-3】 【Transformation 30-4】 【Transformation 30-5】 【Transformation 30-6】 【Transformation 30-7】 【Transformation 30-8】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

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

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

24. The method according to claim 23, wherein the disease or disorder is cancer.

25. The method according to claim 24, wherein the cancer is breast, colorectal, or prostate cancer.

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