Bifunctional compounds for targeting PKMYT1 and methods of use

Abstract

This invention discloses a bifunctional compound containing a targeting moiety for a conjugated protein kinase, membrane-bound tyrosine / threonine 1 (PKMYT1), a pharmaceutical composition thereof, and a method for treating PKMYT1-related disorders or diseases, such as cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This patent application claims the interests of International Application PCT / CN2023 / 114462, filed on 23 August 2023, and International Application PCT / CN2024 / 090754, filed on 30 April 2024, both of which are incorporated herein by reference.

[0002] Technical field This disclosure broadly relates to conjugated protein kinases, bifunctional compounds containing a targeting moiety for membrane-bound tyrosine / threonine 1 (PKMYT1), pharmaceutical compositions thereof, and methods for treating disorders or diseases related to PKMYT1. [Background technology]

[0003] Background of the present invention PKMYT1 (or Myt1) is a member of the Wee family and was first reported as a kinase capable of efficiently phosphorylating Cdc2 with respect to both threonine-14 and tyrosine-15 in the African clawed frog. PKMYT1 inhibits cell cycle progression by inhibiting the activity of cell cycle-related proteins such as Cyclin A, CDK1, and CDK2. PKMYT1 also promotes the progression of various tumors. Studies have revealed that immature activation of cdc2 leads to mitotic breakdown and cell death. Inhibition of Myt1 is thought to induce immature activation of cdc2, and therefore its inhibition would kill rapidly proliferating cells. In addition, Myt1 inhibition is thought to reduce resistance to conventional DNA-damaging chemotherapeutic agents because mechanisms for cell death involve blocking the G2 phase of the cell cycle and pre-mitotic DNA damage repair. This blocking is disrupted by blocking Myt1-inhibitory phosphorylation of cdc2. Thus, the cells enter mitosis while still immature. Myt1 kinase is an important cell cycle regulator, particularly during the G2 / M phase. Inhibition of Myt1 itself may have therapeutic benefits in reducing tumor growth, and it can be used in combination with conventional chemotherapy to overcome drug resistance.

[0004] In recent years, a promising alternative therapeutic approach has emerged: induced proteolysis. This approach works by creating a trimer complex between the target protein and the E3 ubiquitin ligase, and is best exemplified by proteolysis-targeting chimeras (PROTACs) that facilitate the targeting and subsequent degradation of ubiquitination.

[0005] In this field of technology, there is still a need for effective treatments for diseases and conditions related to PKMYT1 modulation or activity, such as cancer. [Overview of the project]

[0006] In one embodiment, the present disclosure relates to the following chemical structure: [ka] {In the formula, PTM is a small molecule containing a PKMYT1 protein targeting moiety; ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase; and L is the bond or chemical linkage that connects ULM and PTM. This is directed toward difunctional compounds having the characteristic, or pharmaceutically acceptable salts or stereoisomers thereof.

[0007] In another embodiment, the Disclosure is directed to pharmaceutical compositions comprising the bifunctional compounds of the Disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutically acceptable excipients.

[0008] In a further embodiment, the Disclosure relates to a method for modulating (e.g., inhibiting) PKMYT1 in a subject, comprising administering to the subject an effective amount of a difunctional compound of the Disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of the Disclosure.

[0009] In another embodiment, the present disclosure is directed to a method for inhibiting PKMYT1 and WEE1 in a subject, comprising administering to the subject an effective amount of the bifunctional compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0010] In a further embodiment, the Disclosure is directed to a method for treating a PKMYT1-related disorder or disease in a subject requiring such treatment, comprising administering to the subject an effective amount of the bifunctional compound of the Disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of the Disclosure.

[0011] In another embodiment, the Disclosure is directed toward the use of the difunctional compounds, or pharmaceutical compositions, or pharmaceutically acceptable salts or stereoisomers thereof, of the Disclosure in the manufacture of agents for treating PKMYT1-mediated disorders or diseases. [Modes for carrying out the invention]

[0012] Detailed explanation definition The following description includes certain specific details to enable a complete understanding of the various embodiments. However, those skilled in the art will understand that the invention can be carried out without these details. In other examples, well-known structures are not illustrated or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, the word “comprise” and its variations such as “comprises” and “comprising” should be interpreted in an open and inclusive sense, i.e., “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0013] Throughout this specification, any reference to “several embodiments” or “one embodiment” means that any particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment. Thus, although the phrase “in one embodiment” or “in one embodiment” appears in various places throughout this specification, not all of them necessarily refer to the same embodiment. Furthermore, any particular feature, structure, or characteristic can be combined in any preferred manner in one or more embodiments. Also, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple objects unless the context explicitly indicates otherwise. It should also be noted that the term “or” is generally used to mean “and / or” unless the context explicitly indicates otherwise.

[0014] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" also include the plural form unless the context clearly indicates otherwise. Therefore, for example, a reference to "one compound" includes multiple compounds. In this specification and the following claims, unless otherwise clearly intended, we also refer to the number of terms that will be defined to have the following meanings.

[0015] The following provides a more detailed definition of specific functional groups and chemical terms. For the purposes of this disclosure, chemical elements are identified according to the CAS Periodic Table and the 75th edition of the Handbook of Chemistry and Physics, and specific functional groups are defined generally as they are described therein. In addition, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in detail in the following works, all of which are incorporated herein by reference: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0016] Linked substituents are described in various places in this disclosure. Where a structure clearly requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if a structure requires a linking group and the definition of the Markush group for that variable lists "alkyl," then "alkyl" is understood to represent a linked alkylene group.

[0017] If a substituent is shown to cross a bond connecting two atoms in a ring, the substituent can bond to any atom in the ring. If a substituent is listed without indicating which atom it bonds to the rest of the compound in a given formula, the substituent can bond to any atom in the formula. Combinations of substituents and / or variables are permissible as long as a stable compound is produced.

[0018] Any variable (e.g., R) can be added to any component or formula of a compound. i If ) appears multiple times, the definition for each appearance is independent of the definition for each other appearance. Therefore, for example, R with 0 to 2 elements i If indicated as partially replaced, the group may optionally have up to two R i It can be replaced in parts, and each occurrence of R i R i The selection is independent of the definition. Furthermore, combinations of substituents and / or variables are permissible as long as a stable compound is produced.

[0019] As used herein, for convenience, a dash "-" is used at the beginning or end of a chemical group to indicate a substituent bond. For example, -OH is bonded via an oxygen atom. Chemical groups can be shown with or without dashes without losing their usual meaning. A wavy line drawn on a line in a structure indicates a bond of a group. Unless chemically or structurally necessary, the order of notation or naming of chemical groups does not indicate or imply direction. As used herein, a solid line extending from the center of a ring indicates that the bond of a substituent on the ring can be to any ring atom. If a substituent is listed without indicating which atom it is bonded to the rest of the compound in a given formula, the substituent can be bonded to any atom in the formula. Combinations of substituents and / or variables are permissible as long as a stable compound is produced.

[0020] The enumeration of value ranges is merely intended to serve as a shorthand notation for referring individually to each separate value within a range, unless otherwise specified herein, and each separate value is invoked herein as if it were individually enumerated herein. As used herein, ranges include two limiting values ​​unless otherwise specified. For example, the expressions "n is an integer in the range of 1 to 6" and "n is an integer between 1 and 6" both mean "n is 1, 2, 3, 4, 5, or 6."

[0021] As used herein, the terms "compounds provided herein", or "compounds disclosed herein" or "compounds of the present disclosure" refer to compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), and specific compounds disclosed herein.

[0022] As used herein, "C i -C j " refers to a range of carbon atom numbers, where i and j are integers, the range of carbon atom numbers includes the endpoints (i.e., i and j), and each integer point therebetween, where j is greater than i. For example, C 1-6 indicates a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, the term "C 1-12 " indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms. In a similar manner, the term "m-n member" ring refers to a ring containing m to n atoms, where m and n are integers and n is greater than m.

[0023] "Alkyl" means a linear or branched saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever a numerical range appears herein, such as "C1-C6 alkyl" or "C1-6 alkyl," it means that an alkyl group may consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms; however, this definition also includes the existence of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C1- 10It is alkyl. In some embodiments, the alkyl is C1-6 alkyl. In some embodiments, the alkyl is C1-5 alkyl. In some embodiments, the alkyl is C1-4 alkyl. In some embodiments, the alkyl is C1-3 alkyl. Unless otherwise specifically stated herein, the alkyl may be optionally substituted with one or more substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl. In some embodiments, the alkyl is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0024] "Alkenyl" means a linear or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group may be in a cis or trans conformation with respect to the double bond, or alternatively, in an E or Z conformation, and both isomers should be understood to be included. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, and 1,3-butadienyl. Whenever a numerical range appears herein, such as "C2-C6 alkenyl" or "C2-6 alkenyl," it means that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also includes the existence of the term "alkenyl" without a specified numerical range. Unless otherwise specifically stated herein, the alkenyl group may be optionally substituted with one or more substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, the alkenyl is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with a halogen.

[0025] "Alkynyl," whether used as part of another term or independently, means a linear or branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butazinyl. Whenever a numerical range appears herein, such as "C2-C6 alkynyl" or "C2-6 alkynyl," it means that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also includes the existence of the term "alkynyl" without a specified numerical range. Unless otherwise specifically stated herein, the alkynyl group may be optionally substituted with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, the alkynyl is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0026] "Alkylidennyl" is an alkenyl, as defined earlier, attached via a terminal divalent carbon. For example, the following compounds: [ka] In this example, the alkylidenyl group is enclosed by the box indicated by the arrow.

[0027] "alkoxy" is the formula -OR a It means radical, R ais an alkyl radical as defined. Unless otherwise specifically stated herein, the alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0028] "Amino" may be used as part of another term or independently, with the base -NR a R b This refers to R a and R b Each of these groups is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, or other suitable organic groups, and each of these groups may be optionally substituted.

[0029] "Aryl," whether used as part of another term or independently, refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals can be monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring systems, and may include condensed ring systems (where the aryl is bonded through aromatic ring atoms when condensed with a cycloalkyl or heterocycloalkyl ring), bridged, or spirocyclic systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Examples of aryl radicals derived from the hydrocarbon ring systems of anthreene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthreene, naphthylene, phenanthrene, indane, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, aryls may be optionally substituted with one or more substituents such as halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, and heteroaryls. In some embodiments, aryls are optionally substituted with one or more substituents such as halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryls are optionally substituted with one or more substituents such as halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe. In some embodiments, aryls are optionally substituted with halogens.

[0030] "Cycloalkyl," used either as part of another term or independently, refers to a partially or completely saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (where the cycloalkyl is bonded through non-aromatic ring atoms when fused with an aryl or heteroaryl ring), spirocyclic systems, or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls include those with 3 to 15 carbon atoms (C3-C3). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), 3-10 carbon atoms (C3-C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10-membered fully saturated cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6-membered fully saturated cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6-membered fully saturated cycloalkyl or a 5 to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated herein, cycloalkyls may be optionally substituted with one or more substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, cycloalkyls may be optionally substituted with one or more substituents such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl group is optionally substituted with one or more substituents such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0031] "Halo" or "halogen" means bromo, chloro, fluoro, or iodine. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0032] "Haloalkyl" means an alkyl radical as defined above, substituted with one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0033] "Hydroxyalkyl" means an alkyl radical as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0034] "Aminoalkyl" means an alkyl radical as defined above, substituted with one or more aminos. In some embodiments, the alkyl is substituted with one amino. In some embodiments, the alkyl is substituted with one, two, or three aminos. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035] "Heteroalkyl" means an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, and combinations thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, a heteroalkyl group is a C1-C6 heteroalkyl group, consisting of 1 to 6 carbon atoms and one or more non-carbon atoms, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyls are optionally substituted with halogens.

[0036] "Heterocycloalkyl," whether used as part of another term or independently, refers to a 3-24 membered partially saturated or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, heterocycloalkyl is fully saturated. In some embodiments, heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heterocycloalkyl contains 1-3 nitrogen atoms. In some embodiments, heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, heterocycloalkyl contains 1 nitrogen atom. In some embodiments, heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic or polycyclic (but not limited to bicyclic, tricyclic, or tetracyclic) ring systems, including fused ring systems (where the heterocycloalkyl is bonded through a non-aromatic ring atom when fused with an aryl or heteroaryl ring), spiro, or bridging ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized; and the nitrogen atom may optionally be quaternized. Typical heterocycloalkyls include those with 2 to 15 carbon atoms (C2-C2). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2-10 carbon atoms (C2-C 10 Fully saturated heterocycloalkyl or C2-C 10Examples of heterocycloalkyls include, but are not limited to, heterocycloalkenyls having 2 to 8 carbon atoms (C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include azilidinyl, azetidinyl, oxetanyl, dioxolanil, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, and pylori. Examples include, but are not limited to, dinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also encompasses all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbon atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it should be understood that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms constituting the heterocycloalkyl (including heteroatoms) (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated herein, heterocycloalkyls may be optionally substituted with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, as described below. In some embodiments, heterocycloalkyls are optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyls are optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyls are optionally substituted with halogens.

[0037] "Heteroaryl" means a 5-14 membered ring radical comprising 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a condensed ring system (when condensed with a cycloalkyl or heterocycloalkyl ring, the heterocycloalkyl is bonded through the aromatic ring atom), a bridged ring system, or a spiro-ring system; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized; and the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl Examples include, but are not limited to, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, heteroaryls may be optionally substituted with one or more substituents such as halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, and heteroaryls. In some embodiments, heteroaryls may be optionally substituted with one or more substituents such as halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with one or more substituents such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0038] The term "partially saturated" refers to a radical that contains at least one double or triple bond and is intended to contain a ring with multiple unsaturated sites, but not an aromatic (i.e., fully unsaturated) site.

[0039] As used herein, the term “heteroatom” means nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of nitrogen, sulfur, or phosphorus, and any quaternized form of basic nitrogen.

[0040] "Hydroxy" or "hydroxyl" refers to the -OH group, whether used as part of another term or independently.

[0041] The terms “optional” or “optionally” mean that the events or situations described thereafter may or may not occur, and that such descriptions include cases where such events or situations occur and cases where they do not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to groups containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to introduce substituents or substitution patterns that are sterically impractical and / or synthetically unrealizable. Therefore, any substituents described should generally be understood to have a maximum molecular weight of up to about 1,000 daltons, more typically up to about 500 daltons.

[0042] When referring to optional substituents, the term “one or more” means that the group in question is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the group in question is optionally substituted with one, two, three, or four substituents. In some embodiments, the group in question is optionally substituted with one, two, or three substituents. In some embodiments, the group in question is optionally substituted with one or two substituents. In some embodiments, the group in question is optionally substituted with one substituent. In some embodiments, the group in question is optionally substituted with two substituents.

[0043] As used herein, the term "oxo" refers to the group (=O) or (O).

[0044] As used herein, the term “substituted” means that one or more hydrogens of a specified part are replaced with a preferred substituent, whether or not it is preceded by the term “optionally.” “Substitution” or “substituted with” is understood to imply the implicit condition that the substitution is subject to the permissible valence of the substituted atom and that the substitution results in a stable or chemically feasible compound that does not undergo spontaneous transformations such as rearrangement, cyclization, or elimination. Unless otherwise specified, an “optionally substituted” group may have preferred substituents at each substituted position of the group, and the substituents may be the same or different at each position if multiple positions in a given structure can be substituted with substituents selected from a particular group. Substituents may include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Those skilled in the art will understand that substituents may be substituted themselves where appropriate. Unless otherwise specified as “unsubstituted”, references to chemical parts herein are understood to include substituted variants. For example, references to “aryl” groups or parts unconditionally include both substituted and unsubstituted variants.

[0045] As used herein, the term “ubiquitin ligase” refers to a family of proteins that facilitate the transport of ubiquitin to a specific substrate protein, thereby making that substrate protein a target for degradation. For example, Von Hippel-Lindau E3 ubiquitin ligase, in combination with E2 ubiquitin-conjugating enzymes or alone, is a protein that adds ubiquitin to lysine on a target protein, thereby making that specific protein substrate a target for proteasomal degradation. Thus, in complex with E2 ubiquitin-conjugating enzymes or alone, E3 ubiquitin ligases are involved in the transport of ubiquitin to the target protein. Generally, ubiquitin ligases are involved in polyubiquitination, in which a second ubiquitin is added to a first ubiquitin, and a third ubiquitin is added to a second ubiquitin. Polyubiquitination marks the protein for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which case only one ubiquitin molecule is attached to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targets for proteasome degradation, but instead may change their intracellular location and function through binding to other proteins that have domains capable of binding ubiquitin. Further complicating matters is the fact that other lysines on ubiquitin can be targeted by E3 and form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to generate polyubiquitin recognized by the proteasome. compound

[0046] In one embodiment, the following chemical structure: [ka] {In the formula, PTM is a small molecule containing a PKMYT1 protein targeting moiety; ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase; and L is the bond or chemical linkage that connects ULM and PTM. A bifunctional compound having the above characteristics, or a pharmaceutically acceptable salt or stereoisomer thereof, is provided.

[0047] In some embodiments, the bifunctional compounds of the present disclosure have the following formulas: (I''), (II''), (III''), (IV''), (V''), (VI''), (VII''), (VIII''), (X''), (XI''), or (XII''): [ka] {In the formula, Q is either N or CRQ; R Q is H, OH, or NH2; or R Q and R 3 These, together with the atoms to which they are bonded, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more R atoms; or R Q and R 6 These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted with one or more R atoms; Ring A is either absent, or is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Each R 1 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d, -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally one or more R 1a Replaced by; or Two R atoms on the same atom 1 They combine to form an oxo; Each R 1a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rs; or two Rs on the same atom 1a together form an oxo; n is an integer from 0 to 6; R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each of W is independently N or CR W ; W 1 each of is independently N or CR W ; W 2 each of is independently N or CR W ; W 3 each of is independently NR W or C(R W )2; W 4 each of is independently N or CR W ; R W each of is independently hydrogen, halogen, -CN, -OH, -OR a , -SR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; X is N or CR X and; R X These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Y is N or CR Y and; R Y These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Z is N or CR Z and; R Z These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; E is N or CR E and; R E These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; G is NR G or C(R G )2; R G Each of these is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; R 3 R is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; where each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; R 4R is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; where each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R; R 5 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; where each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; R 6 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; where each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; Each R a R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Two R's a These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms; Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Two R's bThese, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms; R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R atoms; and Each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)NH2, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 haloalkylidenyl, C3-C6 cycloalkyl, or heterocycloalkyl; or Two R atoms on the same atom form an oxo. It holds.

[0048] In some embodiments, Q is N. In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] That is the case.

[0049] In some embodiments, Q is CR Q And R Q and R 3 These, together with the atoms to which they are bonded, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more R atoms. In some embodiments, R Q and R 3 These, together with the atoms they bond to, are C, each of which is optionally replaced by one or more R atoms. 5-6 It forms a cycloalkyl, a 5-6 member heterocycloalkyl, a phenyl, or a 5-6 member heteroaryl. In some embodiments, R Q and R 3 These, together with the atoms to which they bond, form a 5-6 member heterocycloalkyl or 5-6 member heteroaryl group, each of which is optionally substituted with one or more R atoms. In some embodiments, R Q and R 3 These, together with the atoms to which they bond, form a pyrazolyl, where the pyrazolyl is optionally substituted with one or more R atoms. In some embodiments, [ka] part is, [ka] {wherein Q1 is 0, 1, 2, or 3}. In some embodiments, Q1 is 0, 1, or 2. In some embodiments, [ka] part is, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0050] In some embodiments, Q is CR Q And R Q and R 6 These, together with the atoms to which they are bonded, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more R atoms. In some embodiments, R Q and R 6 These, together with the atoms they bond to, are C, each of which is optionally replaced by one or more R atoms. 5-6 It forms a cycloalkyl, a 5-6 member heterocycloalkyl, a phenyl, or a 5-6 member heteroaryl. In some embodiments, R Q and R 6 These, together with the atoms to which they bond, form a 5-6 member heterocycloalkyl or 5-6 member heteroaryl group, each of which is optionally substituted with one or more R atoms. In some embodiments, R Q and R 6 These, together with the atoms to which they bond, form a pyrazolyl, where the pyrazolyl is optionally substituted with one or more R atoms. In some embodiments, [ka] part is, [ka] {wherein Q1 is 0, 1, 2, or 3}. In some embodiments, [ka] teeth, [ka] That is the case.

[0051] In some embodiments, Q is CR Q And R Q is OH. In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] That is the case.

[0052] In some embodiments, Q is CR Q And R Q It is NH2. In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] That is the case.

[0053] In some embodiments, the bifunctional compounds of the present disclosure have the following formulas: (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII'), (X'), (XI'), or (XII'): [ka] {In the formula, Ring A is either absent, or is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Each R 1 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally one or more R 1a Replaced by; or Two R atoms on the same atom 1 They combine to form an oxo; Each R 1a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Two R atoms on the same atom 1a They combine to form an oxo; n is an integer between 0 and 6; R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Each of W is independently N or CR W and; W 1 Each of these is independently N or CR W and; W 2 Each of these is independently N or CR W and; W 3 Each of them independently, NR W or C(R W )2; W 4 Each of these is independently N or CR W and; R W Each of these is independently hydrogen, halogen, -CN, -OH, -OR a , -SR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; X is N or CR X and; R X These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Y is N or CR Y and; R Y These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Z is N or CR Z and; R Z These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; E is N or CR E and; R E These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; G is NR G or C(R G )2; R G Each of these is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; R 3 is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 4 is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 5 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c Rd -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Each R a R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Two R's a These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms; Each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Two R's b These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms; R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R atoms; and Each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)NH2, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 haloalkylidenyl, C3-C6 cycloalkyl, or heterocycloalkyl; or Two R atoms on the same atom form an oxo. It holds.

[0054] In some embodiments, the ULM is selected from the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse double microchromosome homolog 2 (MLM), and IAP E3 ubiquitin ligase binding site (ILM).

[0055] In some embodiments, L is a bond, resulting in a bifunctional compound, where PTM is directly linked to ULM.

[0056] In some embodiments, L is a chemically linked moiety, resulting in a bifunctional compound, where PTM is indirectly linked to ULM via the chemically linked moiety.

[0057] In some embodiments, the bifunctional compounds provided herein can act as inducers of proteolysis, which offer many advantages over inhibitors of protein function and can: a) overcome resistance in certain cases; b) extend the pharmacokinetics even after the small molecule has been metabolized by disrupting proteins that require resynthesis; c) target all protein functions rather than specific catalytic activity or binding events; d) increase the number of drug targets by including all proteins that can exhibit ligands rather than proteins whose activity may be affected by small molecule inhibitors, antagonists, or agonists; and e) have increased potency compared to inhibitors due to the potential for the small molecule to act catalytically.

[0058] In some embodiments, the bifunctional compounds provided herein can induce 30% to 100% degradation or loss of a target protein. In some embodiments, the compounds provided herein can induce 50% to 100% degradation or loss of a target protein. In some embodiments, the compounds provided herein can induce 75% to 95% degradation or loss of a target protein. PTM

[0059] A PTM (or protein / polypeptide targeting moiety, protein / polypeptide targeting ligand, or ligand) is a small molecule that can or will bind to a target protein of interest.

[0060] In some embodiments, the PTM comprises a group that binds to a target protein. The target of the PTM is selected from a wide variety of intracellularly expressed proteins whose sequence is found in cells and which can bind to the PTM group. The term “protein” includes oligopeptides and polypeptide sequences of sufficient length to bind to the PTM according to this disclosure. Any protein in a eukaryotic system or a microbial system including viruses, bacteria, or fungi, as otherwise described herein, is a target of ubiquitination mediated by the compounds according to this disclosure.

[0061] In some embodiments, the PTM of the difunctional compounds provided herein is a small molecule that binds to or can bind to PKMYT1 or its mutants. In some embodiments, the small molecule that binds to or can bind to PKMYT1 or its mutants is known in the art and is suitable for use in the difunctional compounds disclosed herein. The small molecule is WO2024061343, WO2024041440, WO2024012409, WO2023249563, WO2023220831, WO2023198199, WO2023174397, WO2023177356, WO2023174329, WO2023155871, WO23 The compounds are selected from those disclosed in 155870, US20230348456A1, US20230142913A1, US20230122909A1, WO2022213204, CN117586252A, or CN117510503A (all of which are incorporated herein by reference as a whole). In some embodiments, the small molecules that bind to or can bind to PKMYT1 or its mutants are Lunresertib (RP-6306) or GSK-1520489A.

[0062] The PTMs described below exemplify some of the members of the small molecule target protein binding site. Such small molecule target protein binding sites also include their pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs. These PTMs are linked to the ULM by L, presenting the target protein near a ubiquitin ligase (to which the PTM binds) for ubiquitination and degradation.

[0063] In some embodiments, the PTM of the difunctional compounds provided herein is of the following formulas: (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (X), (XI), or (XII): [ka] {In the formula, Ring A is either absent, or is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Each R 1 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally one or more R 1a Replaced by; or Two R atoms on the same atom 1 They combine to form an oxo; Each R 1a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Two R atoms on the same atom 1a They combine to form an oxo; n is an integer between 0 and 6; R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Each of W is independently N or CR W and; W 1 Each of these is independently N or CR W and; W 2 Each of these is independently N or CR W and; W 3 Each of them independently, NR W or C(R W )2; W 4 Each of these is independently N or CR W and; R W Each of these is independently hydrogen, halogen, -CN, -OH, -OR a , -SR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; X is N or CR X and; R X These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Y is N or CR Y and; R Y These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Z is N or CR Z and; R Z These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; E is N or CR E and; R E These are hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; G is NR G or C(R G )2; R G Each of these is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; R 3 is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 4 is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 5 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c Rd -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Each R a R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Two R's a These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms; Each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Two R's b These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms; R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R atoms; and Each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)NH2, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 haloalkylidenyl, C3-C6 cycloalkyl, or heterocycloalkyl; or Two R atoms on the same atom form an oxo. It belongs to them.

[0064] In some embodiments, X is N.

[0065] In some embodiments, X is CR X That is the case.

[0066] In some embodiments, X is CR X And, R X is hydrogen, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R X is hydrogen or methyl. In some embodiments, R X It is -CN.

[0067] In some embodiments, Y is N.

[0068] In some embodiments, Y is CR Y That is the case.

[0069] In some embodiments, Y is CR Y And, R Y is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R Y is hydrogen. In some embodiments, R YIt is methyl.

[0070] In some embodiments, W is N.

[0071] In some embodiments, W is CR W That is the case.

[0072] In some embodiments, W is CR W And, R W These are hydrogen, halogen, -OH, -CN, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments, R W is hydrogen. In some embodiments, R W is a halogen. In some embodiments, R W is chloro. In some embodiments, R W It is -NH2.

[0073] In some embodiments, Z is N.

[0074] In some embodiments, Z is CR Z That is the case.

[0075] In some embodiments, Z is CR Z And, R Z is hydrogen, halogen, or C1-C6 alkyl. In some embodiments, R Z is hydrogen. In some embodiments, R Z It is methyl.

[0076] In some embodiments, E is N.

[0077] In some embodiments, E is CR E That is the case.

[0078] In some embodiments, Z is CR E And, R E is hydrogen, halogen, or C1-C6 alkyl. In some embodiments, R E is hydrogen. In some embodiments, R E It is methyl.

[0079] In some embodiments, G is NR G That is the case.

[0080] In some embodiments, G is C(R G )2.

[0081] In some embodiments, G is C(R G )2 and R G is hydrogen, halogen, or C1-C6 alkyl. In some embodiments, R G is hydrogen. In some embodiments, R G It is methyl.

[0082] In some embodiments, the PTM of the difunctional compounds provided herein is of the following formulas: (Ia), (Iaa), (IIa), (IIaa), (IIIa), (IIIaa), (IVa), (IVaa), (Va), (Vaa), (VIa), or (VIaa): [ka] {where, R 1 ~R 6 , R X , R Y , R Z , R G , R W And n have the meanings defined herein.

[0083] In some embodiments, the PTM of the difunctional compounds provided herein is of the following formulas: (Ib), (Ibb), (IIb), (IIbb), (IIIb), (IIIbb), (IVb), (IVbb), (Vb), or (Vbb): [ka] {where, R 1 ~R 6 , R X , R Y , R Z , R W , R E And n have the meanings defined herein.

[0084] In some embodiments, PTM is expressed by the following formulas: (Ic), (Icc), (IIc), (IIcc), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IVc), (IVcc), (Vc), or (Vcc): [ka] {where, R 1 ~R 6 , R X , R Y , R Z , R W , R E And n have the meanings defined herein.

[0085] In some embodiments, R 3 is a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, R 3 It is methyl.

[0086] In some embodiments, R 4is a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, R 4 It is methyl.

[0087] In some embodiments, R 5 It is hydrogen.

[0088] In some embodiments, R 6 It is hydrogen.

[0089] In some embodiments, R 2 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 These are methyl, ethyl, propyl, butyl, or pentyl compounds.

[0090] In some embodiments, R X is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 haloalkyl. In some embodiments, R X is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. In some embodiments, R X is hydrogen. In some embodiments, R X is -CN. In some embodiments, R X is a C1-C6 alkyl group. In some embodiments, R X is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, R X is methyl. In some embodiments, R X is a C1-C6 alkoxy. In some embodiments, R Xis methoxy, ethoxy, propoxy, butoxy, or pentoxy. In some embodiments, R X is methoxy. In some embodiments, R X is a C1-C6 haloalkoxy. In some embodiments, R X is fluoromethoxy, fluoroethoxy, fluoropropoxy, fluorobutoxy, or fluoropentoxy. In some embodiments, R X It is fluoromethoxy.

[0091] In some embodiments, R Y is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R Y is hydrogen. In some embodiments, R Y is a C1-C6 alkyl group. In some embodiments, R Y is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, R Y It is methyl.

[0092] In some embodiments, R Z is hydrogen, halogen, or C1-C6 alkyl. In some embodiments, R Z is hydrogen. In some embodiments, R Z is a C1-C6 alkyl group. In some embodiments, R Z is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, R Z It is methyl.

[0093] In some embodiments, R W These are hydrogen, halogens, -OH, and -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R.

[0094] In some embodiments, R W is hydrogen, halogen, -OR a , -NR c R d The elements are C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.

[0095] In some embodiments, R W is hydrogen, halogen, -OR a , -NR c R d The alkyl group is a C1-C6 alkyl group, or a heterocycloalkyl group; where each alkyl group and heterocycloalkyl group is independently and optionally substituted with one or more R groups.

[0096] In some embodiments, R W It is hydrogen.

[0097] In some embodiments, R W is a halogen. In some embodiments, R W It is chloro or fluoro.

[0098] In some embodiments, R W Each of these is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl which is optionally substituted with one or more R. In some embodiments, R W Each of these is a cycloalkyl or heterocycloalkyl that is optionally substituted with one or more R. In some embodiments, R WEach of these is a 5-membered cycloalkyl or 5-membered heterocycloalkyl that is optionally substituted with one or more R. In some embodiments, R W Each of these is a 6-membered cycloalkyl or 6-membered heterocycloalkyl that is optionally substituted with one or more R. In some embodiments, R W R is a 5-membered heterocycloalkyl that is optionally substituted with one or more R. In some embodiments, R W teeth, [ka] That is the case.

[0099] In some embodiments, R W R is an alkynyl which is optionally substituted with one or more R. In some embodiments, R W teeth, [ka] In some embodiments, R W teeth, [ka] In some embodiments, R W teeth, [ka] That is the case.

[0100] In some embodiments, R W is -OR a or -SR a In some embodiments, R W is -OR a or -SR a And, R a Each of these is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl which is optionally substituted with one or more R. In some embodiments, Ra Each of these is a five-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that is optionally substituted with one or more R. In some embodiments, R a Each of these is optionally a 5- or 6-membered cycloalkyl or heterocycloalkyl group substituted with one or more R groups. In some embodiments, R a Each of these is a 6-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that is optionally substituted with one or more R. In some embodiments, R a Each of these is a C6 aryl or 5- or 6-membered heteroaryl that is optionally substituted with one or more R. In some embodiments, R W teeth, [ka] That is the case.

[0101] In some embodiments, R W is a C1-C6 alkyl group. In some embodiments, R W It is a C1-C3 alkyl group.

[0102] In some embodiments, R W is a C1-C6 haloalkyl. In some embodiments, R W It is a C1-C3 haloalkyl group.

[0103] In some embodiments, R W -NR c R d And, R c and R d Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R W It is -NH2.

[0104] In some embodiments, R GR is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, R G is hydrogen. In some embodiments, R G is a C1-C6 alkyl group. In some embodiments, R G These are methyl, ethyl, propyl, butyl, and pentyl. In some embodiments, R G is a C1-C6 haloalkyl. In some embodiments, R G These are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, and fluoropentyl. In some embodiments, R G is fluoromethyl. In some embodiments, R G is a C3-C6 cycloalkyl group. In some embodiments, R G is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R G It is cyclopropyl.

[0105] In some embodiments, ring A is absent.

[0106] In some embodiments, ring A is a cycloalkyl or heterocycloalkyl. In some embodiments, ring A is a heterocycloalkyl. In some embodiments, ring A is a 5- or 6-membered heterocycloalkyl. In some embodiments, ring A is a 5-membered heterocycloalkyl. In some embodiments, ring A is a 6-membered heterocycloalkyl. In some embodiments, ring A is [ka] That is the case.

[0107] In some embodiments, ring A is an aryl or heteroaryl. In some embodiments, ring A is a heteroaryl. In some embodiments, ring A is a 5-12 membered heteroaryl, a 5-11 membered heteroaryl, a 5-10 membered heteroaryl, or a 5-9 membered heteroaryl. In some embodiments, ring A is a 5 membered heteroaryl. In some embodiments, ring A is a 6 membered heteroaryl. In some embodiments, ring A is a monocyclic heteroaryl. In some embodiments, ring A is a bicyclic heteroaryl. In some embodiments, ring A is a 5-6, 6-5, 5-5, or 6-6 fused bicyclic heteroaryl. In some embodiments, ring A is a fused bicyclic heteroaryl. In some embodiments, ring A is [ka] That is the case.

[0108] In some embodiments, each R 1 These are, independently, halogen, -CN, -OH, and -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally one or more R 1a It will be replaced by this.

[0109] In some embodiments, R 1 These are, independently, halogen, -OR a , -NR c Rd -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; where each alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently and optionally selected as one or more R 1a It will be replaced by this.

[0110] In some embodiments, R 1 These are, independently, halogen, -OR a , -NR c R d -C(=O)R a , C1-C6 alkyl, C1-C6 hydroxyalkyl, or heterocycloalkyl; where each alkyl, hydroxyalkyl, and heterocycloalkyl is independently and optionally selected as 1 or more R 1a It will be replaced by this.

[0111] In some embodiments, each R 1a These are, independently, halogen, -CN, -OH, and -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; where each alkyl, cycloalkyl, or heterocycloalkyl is independently and optionally selected as 1 or more R 1 It will be replaced by this.

[0112] In some embodiments, each R 1a is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl; where each alkyl is independently optionally substituted with one or more R.

[0113] In some embodiments, each R 1aThese are independently halogens, C1-C6 alkyls, or C1-C6 haloalkyls.

[0114] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0115] In some embodiments, the following: [ka] teeth, [ka] That is the case.

[0116] In some embodiments, the following: [ka] teeth, [ka] [ka] That is the case.

[0117] In some embodiments, the following: [ka] teeth, [ka] That is the case.

[0118] In some embodiments of the compounds disclosed herein, each R aR is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); each of alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a These are independently C1-C6 alkyl groups.

[0119] In some embodiments of the compounds disclosed herein, each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; each alkyl, cycloalkyl, and heterocycloalkyl is independently substituted with one or more R of any choice. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R b R is hydrogen. In some embodiments of the compounds disclosed herein, each R b These are independently C1-C6 alkyl groups.

[0120] In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); each of alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl, heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl groups is independently and optionally substituted with one or more R groups. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R dEach is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each of these is hydrogen. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently a C1-C6 alkyl group.

[0121] In some embodiments of the compounds disclosed herein, R c and R d These, together with the atoms to which they bond, form a heterocycloalkyl group that is optionally substituted with one or more R atoms.

[0122] In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; or two Rs on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, or C1-C6 alkyl; or two Rs on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -OH, or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen.

[0123] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R X , R Y , R Z , R W , R a , Rb , R c , and R d One or more of the groups contain deuterium at a higher percentage than the natural abundance of deuterium.

[0124] In some embodiments of the compounds disclosed herein, one or more 1 H is the following base R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R X , R Y , R Z , R W , R a , R b , R c , and R d In one or more of these, one or more deuterium atoms are substituted.

[0125] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R X , R Y , R Z , R W , R a , R b , R c , and R d The abundance of deuterium in each of these is, independently, at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0126] In some embodiments of the compounds disclosed herein, one or more hydrogen atoms of ring A are substituted with one or more deuterium atoms.

[0127] In some embodiments, the PTM is as follows: [ka] [ka] Selected from the group consisting of

[0128] In some embodiments, the PTM is as follows: [ka] Selected from the group consisting of

[0129] In some embodiments, the PTM is as follows: [ka] Selected from the group consisting of Linker

[0130] L (linker) is a bond or chemical linkage portion containing a hydrocarbon chain that serves to connect the ULM and PTM. In some embodiments, the hydrocarbon chain optionally contains one, two, three or more heteroatoms selected from N, O, and S. In some embodiments, the hydrocarbon chain contains only saturated chain carbon atoms and optionally contains one or more saturated chain heteroatoms. In some embodiments, the hydrocarbon chain optionally contains two or more unsaturated chain atoms, e.g., C=C or C≡C. In some embodiments, one or more chain carbon atoms in the hydrocarbon chain and optionally one or more chain heteroatoms are optionally substituted with one or more substituents, including but not limited to oxo, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, cyano, halogen, NH2, NH(alkyl), N(alkyl)2, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments, one or more carbon atoms in the hydrocarbon chain and optionally one or more heteroatoms in the chain are substituted with one or more groups, including, but not limited to, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups.

[0131] In some embodiments, L comprises at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 chain atoms selected from C, O, N, and S atoms. In some embodiments, L comprises less than 40, less than 35, less than 30, less than 25, less than 24, less than 23, less than 22, less than 21, or less than 20 chain atoms selected from C, O, N, and S atoms. In one embodiment, L contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 chain atoms selected from C, O, N, and S atoms.

[0132] In some embodiments, L is given by the following formula (L): [ka] {In the formula, A L , W L , and B L Each instance independently combines -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, and -NR. L1 -, -S(=O)NR L1 -, -NR L1 S(=O)-, -S(=O)2NR L1 -, -NR L1 S(=O)2-, -N(R L1 )C(=O)-, -C(=O)N(R L1 )-,-N(R L1 )C(=O)N(R L1 )-, -NR L1 S(=O)2NR L1 -, -N(R L1 )C(=NCN)-, -N(R L1 )C(=NCN)N(R L1Selected from -, -OC(=O)-, -C(=O)O-, -O-alkyl-, -alkyl-O-, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected as one or more R L’ Replaced by; Each R L1 R is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected as one or more R L’ Replaced by; Each R L’ These are independently halogens, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; and q is an integer between 0 and 15; In the formula, * represents a connection to ULM and ** represents a connection to PTM; or in the formula, * represents a connection to PTM and ** represents a connection to ULM. It belongs to them.

[0133] In some embodiments, q is 0, 1, 2, or 3.

[0134] In some embodiments, A L is a combination, -NR L1 -, -C(=O)-, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally one or more R L’ It will be replaced by this.

[0135] In some embodiments, A L is a combination, -NR L1 -, -C(=O)-, C2-C6 alkynyl, C3-C 12 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 12 The aryl or 5-12 membered heteroaryl is wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally one or more R L’ It is replaced by A. In some embodiments, A L is a combination, -NR L1 -, -C(=O)-, C2-C6 alkynyl, C3-C6 monocycloalkyl, C7-C 12 These are bicycloalkyls, 3-6 membered monoheterocycloalkyls, 7-12 membered bicyclic heterocycloalkyls, phenyls, 5-6 membered monoheteroaryls, and 8-12 membered bicyclic heteroaryls, where each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected as one or more R L’ It will be replaced by this.

[0136] In some embodiments, A L Each of these can be arbitrarily selected to have one or more R L’ The join is replaced by -NR L1 -, -C(=O)-, *-C≡C-CH2-, *-CH2-C≡C-, [ka] Selected from the group consisting of

[0137] In some embodiments, each W L These are independently linked, alkyl, alkynyl, -C(=O)-, and -NR L1 Selected from -, -O-alkyl-, or -alkyl-O-.

[0138] In some embodiments, each W L These are independently linked, C1-C6 alkyl, C2-C6 alkynyl, -C(=O)-, -NR L1 -, -O-(C1-C6 alkyl)-, or -(C1-C6 alkyl)-O- are selected.

[0139] In some embodiments, each W L The following are independently selected from bond, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, pentynyl, -C(=O)-, -NH-, -N(CH3)-, -OCH3-, -OCH2CH3-, -CH2O-, or -CH2CH2O-.

[0140] In some embodiments, each B L These are independently, combined, and -NR L1 -, -C(=O)-, alkynyl, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, aryl or heteroaryl are selected; where each cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally one or more R L’ It will be replaced by this.

[0141] In some embodiments, each B L These are independently, combined, and -NR L1 -, -C(=O)-, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyl-O, 3-12 member heterocycloalkyl, C6-C 12 Selected from aryl or 5-12 membered heteroaryls, where each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally one or more R L’It is replaced by B. In some embodiments, B L These are independently, combined, and -NR L1 -, -C(=O)-, C2-C6 alkynyl, C3-C6 monocycloalkyl, C7-C 12 Selected from bicycloalkyl, 3-6 member monoheterocycloalkyl, 7-12 member bicyclic heterocycloalkyl, phenyl, 5-6 member monoheteroaryl, and 8-12 member bicyclic heteroaryl, where each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected as one or more R L’ It will be replaced by this.

[0142] In some embodiments, each B L Each of them is independent, and each of them can choose one or more Rs. L’ The join is replaced by -NR L1 -, -C(=O)-, -CH=CH-, [ka] Selected from.

[0143] In some embodiments, each R L’ R is independently a halogen, oxo, or alkyl. In some embodiments, each R L’ These are independently halogen, oxo, hydroxy, or C1-C6 alkyl.

[0144] In some embodiments, L of the bifunctional compound provided herein is: [ka] [ka] [ka] The formula is selected from the group consisting of {wherein * represents a connection to ULM and ** represents a connection to PTM, or * represents a connection to PTM and ** represents a connection to ULM}. PTM Linker

[0145] In one embodiment, the following chemical structure: [ka] {In the formula, PTM is a small molecule containing a PKMYT1 protein targeting moiety; and L is the bond or chemical linkage that connects ULM and PTM. A PTM linker portion having the same, or a pharmaceutically acceptable salt or stereoisomer thereof, is provided.

[0146] In one embodiment, the following formulas (I''), (II''), (III''), (IV''), (V''), or (VI''): [ka] {In formula, A L , W L B L , ring A, R 1 , q, n, W, X, Y, Z, E, G, R 3 , R 4 , R 5 , and R 6 A PTM linker portion having the meaning defined herein is provided.

[0147] In some embodiments, the PTM linker portion is defined by the following formulas: (Ia''), (Iaa''), (IIa''), (IIaa''), (IIIa''), (IIIaa''), (Iva''), (IVaa''), (Va''), (Vaa''), (VIa''), or (VIaa''): [ka] {In formula, A L , W L BL , ring A, R 1 q, n, R X , R Y , R G , R Z , R W , R 2 , R 3 , R 4 , R 5 , and R 6 This has the meanings defined herein.

[0148] In some embodiments, the PTM linker portion is defined by the following formulas: (Ib''), (Ibb''), (IIb''), (IIbb''), (IIIb''), (IIIbb''), (IVb''), (IVbb''), (Vb''), or (Vbb''): [ka] {In formula, A L , W L B L , ring A, R 1 q, n, R X , R Y , R Z , R W , R 2 , R 3 , R 4 , R 5 , and R 6 This has the meanings defined herein.

[0149] In some embodiments, the PTM linker portion is defined by the following formulas: (Ic''), (Icc''), (IIc''), (IIcc''), (IIIc''), (IIIcc''), (IIId''), (IIIdd''), (IIIe), (IIIee), (IVc''), (IVcc''), (Vc''), or (Vcc''): [ka] {In formula, A L , W L B L , ring A, R 1 q, n, RX , R Y , R Z , R W , R 2 , R 3 , R 4 , R 5 , and R 6 This has the meanings defined herein.

[0150] In some embodiments, the PTM linker portion is as follows: [ka] [ka] [ka] [ka] [ka] [ka] Selected from the group consisting of

[0151] In some embodiments, the PTM linker portion is as follows: [ka] Selected from the group consisting of

[0152] In some embodiments, the PTM linker portion is as follows: [ka] Selected from the group consisting of ULM

[0153] In some embodiments, the ULMs of the bifunctional compounds provided herein are LAP E3 ubiquitin ligase binding moieties (ILMs), cereblon E3 ubiquitin ligase binding moieties (CLMs), Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moieties (VLMs), and / or mouse double microchromosome 2 homologs (MDM2) E3 ubiquitin ligase binding moieties (MLMs).

[0154] The terms ULM, ILM, CLM, VLM, and MLM are used in their comprehensive sense unless otherwise indicated in the context. For example, the term ULM includes all ULMs, including those binding LAP (i.e., ILM), MDM2 (i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM). Furthermore, the term ILM includes all possible LAP E3 ubiquitin ligase binding sites, the term MLM includes all possible MDM2 E3 ubiquitin ligase binding sites, the term VLM includes all possible VHL binding sites, and the term CLM includes all cereblon binding sites.

[0155] In certain embodiments, ULM (e.g., ILM, CLM, VLM, or MLM) is an IC with a particle size of less than approximately 200 μM. 50 IC shows activity or binding to E3 ubiquitin ligases (e.g., IAP E3 ubiquitin ligase, Cereblon E3 ubiquitin ligase, VHL, or MDM2 E3 ubiquitin ligase). 50 This can be measured by any method known in the art, for example, by a fluorescence polarization assay. Compounds that bind to these ligases and can be used as ULMs are present in the published literature and are available to those skilled in the art.

[0156] In some embodiments, the ULM of the bifunctional compounds provided herein is the following formula (1) to (20): [ka] {In the formula, each J 1 , U 1 , V 1 , W 1 , X 1 , U 2 , V 2 , W 2 , and X 2 CR is independent. 21 or selected from N; Y 1 -N-, -NR 31 -O-, -C(=O)-, -CR 31 R 41 -, -N=CR 31 -, and -N=N- are selected; Z 1 It does not exist, or -C(=O)-, -NR 31 , -O-, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Selected from alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R'; R L -NR 31 , -N(R 31 )C(=O)-, -C(=O)N(R 31 )-, -OC(=O)-, -C(=O)O-, or -N(R 31 Selected from )S(=O)-; Each R 11 , R 31 , and R 41 R' is independently selected from hydrogen, alkyl, cycloalkyl or heterocycloalkyl, where each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with R' or R 31 and R 41 These, together with the atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups; Each R 21is independently selected from hydrogen, halogen, CN, NO2, OH, alkyl, cycloalkyl or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with R’; Each R 12 、R 22 、R 13 、R 23 、R 53 、R 14 、R 24 、R 34 、R 15 、R 25 、and R 35 is independently selected from hydrogen, halogen, -CN, -NO2, -OH, amino, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl or heterocycloalkyl, where each alkyl, alkenyl, alkynyl cycloalkyl, and heterocycloalkyl is independently optionally substituted with R’; R 32 and R 33 are each independently selected from hydrogen, -OH, -C(=O)R’’, -C(=O)OR’’, -C(O)N(R’’)2, -P(O)(OR’’)2; R 43 is selected from N(R’’’)2, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with R’; R 45 and R 55 are each independently selected from hydrogen, -C(=O)R’’, -C(=O)OR’’, -C(O)N(R’’)2, -S(=O)R’’, -S(=O)2R’’, -S(=O)2N(R’’)2, alkyl, alkoxyalkyl, alkylaminoalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; Each R' is independently either absent, selected from halogen, -CN, -NO2, -OH, amino, alkyl, alkoxyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl or heterocycloalkyl, or The two R' atoms, together with the atom they bond to, form a cycloalkyl or heterocycloalkyl group; Each R'' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or The two R'' atoms, together with the atom they bond to, form a cycloalkyl or heterocycloalkyl group; and Each R''' is independently selected from hydrogen, alkyl, -C(=O)R'', cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. It is one of the following.

[0157] In some embodiments, the ULM of the bifunctional compound provided herein is the compound of formula (1).

[0158] In some embodiments, R 11 It is hydrogen.

[0159] In some embodiments, Y 1 is -C (=O) or -CR 31 R 41 - is

[0160] In some embodiments, each R 31 and R 41 These are independently hydrogen or a C1-C6 alkyl group.

[0161] In some embodiments, R 31 and R 41Both are hydrogen.

[0162] In some embodiments, each U 1 , V 1 , W 1 , and X 1 CR is independent. 21 That is the case.

[0163] In some embodiments, each R 21 These are independently hydrogen or halogen.

[0164] In some embodiments, Z 1 -C(=O)-, -NR 31 These are -, -O-, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where each alkyl, alkenyl, and alkynyl is independently and optionally substituted with one or more R'.

[0165] In some embodiments, Z 1 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, Z 1 C3-C6 cycloalkyl, C6-C 12 The elements are aryl, 5-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl is independently and optionally substituted with one or more R' groups.

[0166] In some embodiments, Z 1 It does not exist.

[0167] In some embodiments, ULM is as follows: [ka] Selected from the group consisting of

[0168] In some embodiments, the ULM of the bifunctional compound provided herein is the compound of formula (2).

[0169] In some embodiments, R 11 It is hydrogen.

[0170] In some embodiments, Y 1 -NR 31 - is

[0171] In some embodiments, R 31 is alkyl. In some embodiments, R 31 is a C1-C6 alkyl group. In some embodiments, R 31 These are methyl, ethyl, propyl, butyl, or pentyl.

[0172] In some embodiments, Y 1 It is -N(CH3)-.

[0173] In some embodiments, each U 1 , V 1 , W 1 , and X 1 CR is independent. 21 That is the case.

[0174] In some embodiments, each R 21 These are independently hydrogen or halogen.

[0175] In some embodiments, Z 1 It does not exist.

[0176] In some embodiments, ULM is as follows: [ka] That is the case.

[0177] In some embodiments, the ULM of the bifunctional compound provided herein is a compound of formula (10).

[0178] In some embodiments, R 11 It is hydrogen.

[0179] In some embodiments, R 11 is alkyl. In some embodiments, R 11 is a C1-C6 alkyl group. In some embodiments, R 11 These are methyl, ethyl, propyl, butyl, or pentyl.

[0180] In some embodiments, each J 1 , U 1 , V 1 , W 1 , and X 1 CR is independent. 21 That is the case.

[0181] In some embodiments, each R 21 R is independently hydrogen or halogen. In some embodiments, each R 21 These are independently hydrogen, F, Cl, Br, or I.

[0182] In some embodiments, Z 1 It does not exist.

[0183] In some embodiments, ULM is as follows: [ka] That is the case.

[0184] In some embodiments, the ULM of the bifunctional compound provided herein is a compound of formula (11).

[0185] In some embodiments, X 1 It is N.

[0186] In some embodiments, Y 1 , NR 31It is.

[0187] In some embodiments, R 31 is hydrogen or alkyl. In some embodiments, R 31 is C1-C6 alkyl. In some embodiments, R 31 is methyl, ethyl, propyl, butyl or pentyl.

[0188] In some embodiments, Y 1 is N(CH3).

[0189] In some embodiments, each J 1 , U 1 , V 1 , and W 1 is independently CR 21 .

[0190] In some embodiments, each R 21 is independently hydrogen, halogen or alkyl. In some embodiments, each R 21 is independently hydrogen, halogen or C1-C6 alkyl. In some embodiments, each R 21 is independently hydrogen, fluoro or methyl.

[0191] In some embodiments, Z 1 is absent. <​​​​​​​​​​​​​​​​​​​​​​​​In some embodiments, the ULM of the bifunctional compound provided herein is a compound of formula (12).

[0195] In some embodiments, each J 1 , U 1 , V 1 , W 1 , and X 1 CR is independent. 21 That is the case.

[0196] In some embodiments, each R 21 Each R is independently hydrogen, halogen, or alkyl. 21 R is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments, each R 21 These are independently hydrogen, F, Cl, methyl, ethyl, propyl, butyl, or pentyl.

[0197] In some embodiments, Z 1 It does not exist.

[0198] In some embodiments, ULM is as follows: [ka] That is the case.

[0199] In some embodiments, the ULM of the bifunctional compound provided herein is a compound of formula (13).

[0200] In some embodiments, R 11 It is hydrogen.

[0201] In some embodiments, R L -NR 31 -, -N(R 31 )C(=O)-, or -C(=O)N(R 31 )-is.

[0202] In some embodiments, R 31is hydrogen or alkyl. In some embodiments, R 31 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 31 These are hydrogen, methyl, ethyl, propyl, butyl, or pentyl.

[0203] In some embodiments, each J 1 , U 1 , V 1 , W 1 , and X 1 CR is independent. 21 That is the case.

[0204] In some embodiments, J 1 , U 1 , V 1 , W 1 , or X 1 One, two, or three of them are N, and the others are independently CR 21 That is the case.

[0205] In some embodiments, each R 21 These are independently hydrogen, halogen, or alkyl.

[0206] In some embodiments, each R 21 These are independently hydrogen, methyl, or F.

[0207] In some embodiments, Z 1 It does not exist.

[0208] In some embodiments, ULM is as follows: [ka] Selected from the group consisting of

[0209] In some embodiments, the ULM of the bifunctional compound provided herein is a compound of formula (14).

[0210] In some embodiments, each R12 , R 22 and R 32 R is independently hydrogen or alkyl. In some embodiments, each R 12 , R 22 and R 32 R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R 12 , R 22 and R 32 These are independently hydrogen, methyl, ethyl, propyl, butyl, or pentyl.

[0211] In some embodiments, ULM is as follows: [ka] That is the case. ULM Linker

[0212] In one embodiment, the following chemical structure: [ka] {In the formula, ULM is a small molecule E3 ubiquitin ligase binding site that binds to E3 ubiquitin ligase; and L is the bond or chemical linkage that connects ULM and PTM. A ULM linker portion having the above, or a pharmaceutically acceptable salt or stereoisomer thereof, is provided.

[0213] In one embodiment, the following equations (1') to (20'): [ka] [ka] [ka] {In formula, B L , W L , A L , Z 1 , J 1 , U1 , V 1 , W 1 , X 1 , X 2 , U 2 , V 2 , W 2 , Y 1 , R 11 , R 12 , R 15 , R 13 , R 22 , R 23 , R 25 , R 32 , R 33 , R 43 , R 53 , R 63 , R 31 A ULM linker portion is provided having {q}, and q having the meanings defined herein.

[0214] In some embodiments, the ULM linker portion is as follows: [ka] [ka] [ka] [ka] [ka] Alternatively, selected from the group consisting of pharmaceutically acceptable salts or stereoisomers thereof. Exemplary difunctional compounds

[0215] In some embodiments, the bifunctional compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds listed in Table 1. Table 1 Exemplary difunctional compounds [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0216] In some embodiments, the bifunctional compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds listed in Table 2. Table 2 Exemplary difunctional compounds [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] Compound synthesis

[0217] The bifunctional compounds provided herein can be prepared by any known organic synthesis technique and can be synthesized according to any of a number of possible synthetic routes.

[0218] In some embodiments, methods for synthesizing the bifunctional compounds provided herein are provided, which include reacting the ULM-L moiety with the PTM moiety under conditions suitable for obtaining the compounds of the disclosed herein.

[0219] In some embodiments, methods for synthesizing the bifunctional compounds provided herein are provided, comprising reacting the ULM moiety with the PTM-L moiety under conditions suitable for obtaining the compounds of the disclosed herein.

[0220] In some embodiments, the method described above is carried out in an aqueous solution phase. In some embodiments, the method described above is carried out in a solid phase. In certain embodiments, the synthesis method is suitable for high-speed, high-volume processing techniques or techniques commonly used in combinatorial chemistry.

[0221] In some embodiments, suitable solvents can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be those that are substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out, which may range from the freezing point to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of several solvents. Those skilled in the art can select a solvent suitable for a particular reaction step, depending on that step.

[0222] The preparation of the compounds of this disclosure may involve the protection and deprotection of various chemical groups. Those skilled in the art will readily be able to determine the need for protection and deprotection, and the selection of appropriate protecting groups. For the chemistry of protecting groups, see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and Peter GM Wuts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014 (all of which are incorporated herein by reference).

[0223] The reaction can be monitored according to any suitable method known in the field. For example, nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Product formation can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometer (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Those skilled in the art can purify the compound by various methods, including high-performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883 (which is incorporated herein by reference in whole)") and normal-phase silica chromatography. Pharmaceutical composition

[0224] For administration purposes, in some embodiments, the bifunctional compounds provided herein are administered as raw chemical substances or formulated as pharmaceutical compositions.

[0225] Therefore, in a further embodiment, the Disclosure provides pharmaceutical compositions comprising compounds provided herein, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the pharmaceutical compositions of the Disclosure comprise compounds selected from formulas (I), (II), (III), (IV), (V), and (VI), or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the pharmaceutical compositions of the Disclosure comprise a first compound selected from formulas (I), (II), (III), (IV), (V), and (VI), or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more additional compounds of the same formula, wherein the first compound and the additional compounds are not the same molecule.

[0226] As used herein, the term “pharmaceutical composition” means a formulation comprising the bifunctional compound of the Disclosure in a form suitable for administration to a subject. Pharmaceutical compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, but the most preferred route in any given case depends on the specific host and the nature and severity of the medical condition to which the active ingredient is administered. Pharmaceutical compositions may conveniently be presented in unit dosage forms and may be prepared by any method well known in the art of pharmaceutics.

[0227] In some embodiments, the pharmaceutical compositions of the Disclosure comprise a therapeutically effective amount of the difunctional compound of the Disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0228] As used herein, the term “therapeutic dose” means the amount of a molecule, compound, or composition containing such molecule or compound that treats, improves, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective dose for a subject depends on the subject’s weight, size, and health, the nature and severity of the condition, the rate of administration, the therapeutic agent or combination of therapeutic agents selected for administration, and the discretion of the prescribing physician. The therapeutic dose for a given situation can be determined by routine experimentation, which is within the scope of the clinician’s skill and judgment.

[0229] In some embodiments, the pharmaceutical composition comprises a compound of the Disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0230] As used herein, the term “pharmaceutically acceptable excipient” means an excipient useful for preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary and human pharmaceutical use. “pharmaceutically acceptable excipient” includes both one and more such excipients, as used herein. The term “pharmaceutically acceptable excipient” also includes “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent.” The specific excipient used in the pharmaceutical compositions of this disclosure depends on the means and purpose to which the compounds of this disclosure are applied.

[0231] In some embodiments, the pharmaceutical compositions provided herein are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation is determined by the choice of route of administration. Outlines of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference with respect to such disclosures.

[0232] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, fragrances, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

[0233] In some embodiments, the pharmaceutical compositions of the Disclosure comprising one or more bifunctional compounds provided herein, or pharmaceutically acceptable salts or stereoisomers thereof, further comprise one or more additional therapeutic agents.

[0234] Preferred routes for administering the bifunctional compounds provided herein, or their pharmaceutically acceptable salts or stereoisomers, or the pharmaceutical compositions provided herein, include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, intraocular, nasal, and topical administration. Furthermore, as mere examples, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal injection, direct intraventricular, intraperitoneal, lymphatic, and intranasal injection. Isomers / stereoisomers

[0235] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all isomers of cis, trans, syn, anti, entgegen (E), and tuzamene (Z), as well as corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or inter-exchange are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereoisomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography. Labeled compounds

[0236] In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively 2 H(D), 3 H, 13 C, 14 C, l 5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Contains Cl. Compounds described herein, and pharmaceutically acceptable salts thereof, containing the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. Certain isotope-labeled compounds, e.g., radioactive isotopes, e.g., 3 H and 14 Those incorporating C are useful in drug and / or substrate tissue distribution assays. Tritiation, i.e. 3 H and carbon-14, that is 14 13C isotopes are particularly preferred due to their ease of preparation and detectability.

[0237] In some embodiments, the proportion of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogens and deuterium. In some embodiments, one or more substituents disclosed herein contain deuterium at a higher percentage than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced by one or more deuterium atoms in one or more substituents disclosed herein.

[0238] In some embodiments, the compounds described herein are labeled by means of other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Medicinally acceptable salts

[0239] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0240] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a number of inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free form with a suitable acid or base and then isolating the salts thus formed.

[0241] Examples of pharmaceutically acceptable salts include salts prepared by the reaction of the compounds described herein with minerals, organic acids or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfites, bromides, butyrates, butyn-1,4-geoate, camphorates, camphorsulfons, capronates, caprylates, chlorobenzoic acid, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrophosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-geoate, hydroxybenzoates, γ-hydroxybutyrates, Examples include hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methyl benzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberinate, sebacinate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0242] Furthermore, the compounds described herein include, in their free base form, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid; and acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, and 2-hydroxyethanesulfonic acid. These compounds can be prepared as pharmaceutically acceptable salts formed by reacting them with pharmaceutically acceptable inorganic or organic acids, including but not limited to organic acids such as benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octo-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, which are not pharmaceutically acceptable themselves, are used to prepare salts that are useful as intermediates in obtaining the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0243] In some embodiments, the compounds described herein containing free acid groups react with suitable bases such as pharmaceutically acceptable metal cation hydroxides, carbonates, bicarbonates, and sulfates, with ammonia, or with pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Typical salts include alkali salts or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1-4 Examples include alkyl(4) and others.

[0244] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing group they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization. Tautomers

[0245] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the movement of hydrogen atoms, involving the exchange of single bonds with adjacent double bonds. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomer forms of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Treatment method

[0246] In one embodiment, a method is provided for modulating PKMYT1 in a subject in need thereof, comprising administering a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0247] In another embodiment, a method is provided for inhibiting PKMYT1 in a subject in need thereof, comprising administering a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0248] In another embodiment, a method is provided for selectively inhibiting PKMYT1 in a subject in need, comprising administering a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0249] In another embodiment, a method is provided for selectively inhibiting PKMYT1 to WEE1 or higher in a subject in need thereof, comprising administering a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0250] In some embodiments, the compounds disclosed herein do not inhibit WEE1.

[0251] In some embodiments, the compounds disclosed herein, when measured by a WEE1 ADP-Glo ​​assay, yield at least about 100 nM, at least about 500 nM, at least about 1000 nM, or at least about 10,000 nM of IC of WEE1. 50 It has a value. For example, the IC of WEE1 50 The value can be measured according to Example B.

[0252] In one embodiment, a method is provided for the prevention or treatment of a disorder or disease that is at least partially modulated by PKMYT1 in a subject in need thereof, comprising administering a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0253] As used herein, the terms “treatment” or “to treat” refer to the management and care of a patient aimed at restoring, inhibiting, or combating a disease, condition, or impairment. As used herein, the term “prevention” refers to measures taken to maintain health and prevent the spread of a disease, condition, or impairment.

[0254] In some embodiments, the PKMYT1-mediated disorder or disease is cancer.

[0255] In some embodiments, cancer is dependent on PKMYT1 activity.

[0256] In some embodiments, cancers overexpress CCNE1. Examples of cancers with a high incidence of CCNE1 overexpression in some embodiments include breast cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, gastric cancer, and uterine cancer.

[0257] In some embodiments, cancer has an inactivating mutation in the FBXW7 gene. Examples of cancers with FBXW7 defects in some embodiments include breast cancer, colorectal cancer, esophageal cancer, lung cancer, and uterine cancer.

[0258] In some embodiments, cancer is a solid tumor.

[0259] In some embodiments, the cancer is selected from the group consisting of breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer, or uterine cancer.

[0260] As used herein, the terms “cancer” and “malignant” generally refer to or describe a physiological condition in mammals characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, epithelial carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma and islet cell carcinoma), mesothelioma, Schwann cell tumor (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or malignant tumors of the lymphatic system. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, adenocarcinoma and squamous cell carcinoma of the lung), peritoneal cancer, hepatocellular carcinoma, gastric cancer (e.g., gastrointestinal cancer), pancreatic cancer, glioblastoma, neuroblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancer, liver tumors, breast cancer, colorectal cancer, rectal cancer, colorectal cancer, endometrial or uterine epithelial cancer, salivary gland epithelial cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal epithelial cancer, penile epithelial cancer, testicular cancer, esophageal cancer, biliary tract tumors, and head and neck cancers.

[0261] In some embodiments, the cancer is selected from breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer, or uterine cancer.

[0262] In some embodiments, the bifunctional compounds of the Disclosure, or their pharmaceutically acceptable salts or stereoisomers, or pharmaceutical compositions may be administered as single activators. In some embodiments, the bifunctional compounds of the Disclosure, or their pharmaceutically acceptable salts or stereoisomers, or pharmaceutical compositions may be administered in combination with one or more additional active ingredients. Those skilled in the art will recognize that various active ingredients may be combined with the bifunctional compounds of the Disclosure. In some embodiments, the additional active ingredients of a pharmaceutical combination formulation or dosage regimen have complementary activity to the compounds of the Disclosure so as not to adversely affect each other. Such components are preferably present in a combined amount effective for the intended purpose.

[0263] In some embodiments, the bifunctional compounds provided herein, or their pharmaceutically acceptable salts or stereoisomers, or the pharmaceutical compositions provided herein, can be used in combination with additional therapeutic treatments. Additional therapeutic treatments may optionally include one or more therapeutic agents, radiotherapy, surgery (e.g., tumor removal or mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or combinations thereof.

[0264] In some embodiments, the bifunctional compounds provided herein, or pharmaceutically acceptable salts or stereoisomers thereof, or (one or more) pharmaceutical compositions provided herein, may be administered simultaneously, sequentially, or separately with one or more additional therapeutic agents.

[0265] In a further embodiment, the use of the compounds provided herein or pharmaceutically acceptable salts thereof, or (one or more) pharmaceutical compositions provided herein, in the manufacture of agents for treating PKMYT1-mediated disorders or diseases is provided. [Examples]

[0266] For illustrative purposes, the following examples are included. The examples provided herein illustrate the synthesis of the compounds disclosed herein and the intermediates used in the preparation of such compounds. However, it will be understood that these examples are not intended to limit the disclosure but only to suggest ways of carrying out the disclosure. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare many other compounds of the disclosure, and that alternative methods for preparing the compounds of the disclosure are considered to be within the scope of the disclosure. For example, the synthesis of compounds not illustrated by the disclosure can be successfully carried out by modifications obvious to those skilled in the art, such as appropriately protecting interfering groups, utilizing other suitable reagents, constructing art-known blocks other than those described, and / or conventionally modifying the reaction conditions. In addition, those skilled in the art will understand that the individual steps described herein or steps within separate batches of compounds may be combined. Alternatively, it will be recognized that other reactions disclosed herein or known in the art are applicable to preparing other compounds of the disclosure. Accordingly, the following description is not intended to limit the scope of the disclosure, but rather is specified by the appended claims.

[0267] A general synthetic procedure A for substitution of arylhalides with alkylamines. To a solution (1 mmol) of the arylhalide compound in DMF (10 mL), alkylamine (1.5 mmol) and DIEA (5 mmol) were added. The mixture was stirred under N2 at 100°C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with DIEA (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the target compound.

[0268] A general synthesis procedure B for removing Boc. A solution of Boc-protecting compound (1 mmol) in DCM (10 mL) was mixed with TFA (5 mL). The mixture was stirred under N2 at room temperature for 2 hours. The reaction mixture was carefully added to ice water (50 mL) with stirring, and the pH was adjusted to ~7 with Na2CO3 (4 M in water). The mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the desired compound.

[0269] General synthetic procedure C for reductive amination. To a solution of amine compound (1 mmol) in DMF (5 mL), an aldehyde compound (1 mmol) and NaBH(OAc)3 (3 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the target compound.

[0270] General synthesis procedure D for Suzuki coupling. A mixture of boronic acid or pinacol boronic acid ester compound (1 mmol), aryl halogen compound (1.2 mmol), Pd(dtbpf)Cl2 (0.02 mmol), and K3PO4 (3 mmol) in dioxane (10 mL) and water (1 mL) was stirred under N2 at 90°C for 2 hours. The mixture was filtered and concentrated to dryness, and the residue was purified by silica gel column chromatography or preparative HPLC to obtain the coupling compound.

[0271] General synthetic procedure E for demethylation. To a solution (1 mmol) of anisole compound in DCM (10 mL), BBr3 (5 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with MeOH (10 mL) and then concentrated to dryness. The residue was purified by silica gel column chromatography to obtain the demethylated compound. Examples relating to the preparation of intermediates Example I1 [ka]

[0272] To a solution of compound INT-1-1 (5 g, 21.598 mmol) in CH3CN (150 mL), acetyl chloride (4.62 mL, 64.795 mmol) and NaI (16.2 g, 107.991 mmol) were added. The mixture was stirred at 80°C for 16 hours. After cooling to room temperature, saturated sodium bicarbonate aqueous solution (200 mL) was added. The filtration cake was recovered by filtration and washed with water. The unpurified material was resuspended in the resulting mixture of methanol (200 mL) and sodium hydroxide aqueous solution (200 mL, 1 N). The mixture was stirred at room temperature for 10 hours. The filtration cake was recovered by filtration and washed with water to obtain compound INT-1-2 (5.7 g, 82.4%). LCMS: 324.8 [M+H] + .

[0273] To a solution of compound INT-1-2 (25.85 g, 80.056 mmol) in DMF (250 mL), NaH (4.8 g, 120.084 mmol) was added while stirring at 0°C. The mixture was stirred at 0°C for 30 minutes before adding TsCl (21.4 g, 112.078 mmol). The solution was stirred at room temperature for 5 hours. The mixture was poured into water (300 mL), precipitated, and filtered. The filtered cake was washed with water (300 mL) and dried. The unpurified product was purified by silica gel column chromatography to obtain compound INT-1-3 (34.3 g, 89.7%). LCMS: 479.0 [M+H] + .

[0274] To a solution of compound INT-1-3 (23.5 g, 49.255 mmol) in DMF (235 mL), Zn(CN)2 (2.89 g, 24.627 mmol) and Pd(PPh3)4 (5.69 g, 4.925 mmol) were added. The mixture was stirred at 110°C for 16 hours. The mixture was poured into water (300 mL), precipitated, and filtered. The filtered cake was washed with water (300 mL) and dried. The unpurified product was purified by silica gel column chromatography to obtain compound INT-1-4 (13.6 g, 73.2%). LCMS: 378.1 [M+H] + .

[0275] Compound INT-1-6 was prepared from compound INT-1-4 (10 g, 26.582 mmol) and compound INT-1-5 (10.5 g, 39.872 mmol) according to general synthesis procedure D (8.3 g, 72.7%). LCMS: 432.3 [M+H] + .

[0276] To a solution of compound INT-1-6 (3 g, 6.952 mmol) in THF (50 mL), LDA (7.0 mL, 13.905 mmol) was added dropwise at -78°C. The mixture was stirred at -78°C for 30 minutes. Next, 1,2-dibromo-1,1,2,2-tetrachloroethane (4.5 g, 13.905 mmol) in THF (5 mL) was added. The mixture was stirred at -78°C for 1 hour, and then warmed to room temperature for 2 hours. The mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound INT-1-7 (1.88 g, 52.8%). LCMS: 511.7 [M+H] + .

[0277] A mixture of compound INT-1-7 (7g, 13.715 mmol) and NaOH (137 mL, 137.147 mmol) in EtOH (150 mL) and MeOH (150 mL) was heated to 60°C for 4 hours. The mixture was cooled to 0°C, the pH was adjusted to ~6 with 1N HCl, and then extracted with EA (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography and further purified by SFC to obtain compound INT-1-8 (1.5 g, 31%). LCMS: 357.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.16 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 3.83 (s, 3H), 1.88 (s, 3H), 1.79 (s, 3H).

[0278] Compound INT-1 was prepared from compound INT-1-8 (500 mg, 1.404 mmol) according to general synthesis procedure E (480 mg, 99.9%). LCMS: 344.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.16 (d, J = 4.0 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.85-6.83 (m, 2H), 1.84 (s, 3H), 1.76 (s, 3H). Example I2 [ka]

[0279] Compound INT-2-2 was prepared from compound INT-1-8 (750 mg, 2.106 mmol) and compound 2-1 (557.0 mg, 2.316 mmol) according to general synthesis procedure E (500 mg, 30.5%). LCMS: 431.2 [M+H+CH3CN] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.45 (s, 2H), 8.27 (s, 1H), 7.55 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 1.92 (s, 3H), 1.83 (s, 3H).

[0280] Compound INT-2 was prepared from compound INT-2-2 (500 mg, 1.283 mmol) according to general synthesis procedure E (480 mg, 89.0%). LCMS: 461.1 [M+CH3CN+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.38-9.36 (m, 2H), 8.26 (s, 1H), 7.55 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 1.87 (s, 3H), 1.79 (s, 3H). Example I3 [ka]

[0281] Compound INT-3-1 was prepared using similar starting materials according to the method used for the synthesis of INT-1-3. LCMS: 512.1 M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.36 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 2.39 (s, 3H), 1.86 (s, 3H), 1.77 (s, 3H).

[0282] To a solution of INT-3-1 (4124 mg, 8.08 mmol) in THF (100 mL), HOAc (485 mg, 8.08 mmol), NaOAc (663 mg, 8.08 mmol), and Pd / C (989 mg) were added. The mixture was stirred under H2 at room temperature for 16 hours. The reaction mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 0-3% MeOH in DCM) to obtain INT-3-2 (3146 mg, 90% yield) as a white solid. LCMS: 432.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 4.1 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 2.44 (s, 3H), 1.90 (s, 3H), 1.80 (s, 3H).

[0283] To a solution of INT-3-2 (2 g, 4.63 mmol) in THF (40 ml), lithium diisopropylamide (4.63 ml, 9.27 mmol) was added dropwise under N2 at -78°C. The mixture was stirred at -78°C for 0.5 hours. Next, tributylchlorostannane (3.02 g, 9.27 mmol) was added. The mixture was stirred at -78°C for 1 hour, and then warmed to room temperature for 0.5 hours. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 0-20% DCM in PE) to obtain INT-3 (1.1 g, 33% yield) as a colorless oil. LCMS: 722.2[M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 3.82 (s, 3H), 2.38 (s, 3H), 1.83 (s, 3H), 1.74 (s, 3H), 1.59 (dt, J = 15.6, 7.6 Hz, 6H), 1.35 (dd, J = 14.5, 7.2 Hz, 6H), 1.31 - 1.25 (m, 6H), 0.88 (t, J = 7.2 Hz, 9H). Examples relating to the preparation of difunctional compounds Example 1 [ka]

[0284] Compounds 1-2 were prepared from compound 1-1 (2 g, 7.241 mmol) according to general synthesis procedure A (2.1 g, 65.5%). LCMS: 387.0 [M+H- t AD] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 5.08 (dd, J = 12.8, 5.6 Hz, 1H), 3.47 (s, 8H), 2.90-2.86 (m, 1H), 2.58-2.54 (m, 2H), 2.10-1.95 (m, 1H), 1.43 (s, 9H).

[0285] Compounds 1-3 were prepared from compound 1-2 (1.6 g, 3.616 mmol) according to general synthesis procedure B (1.5 g, 92.3%). LCMS: 343.1 [M+H] +; 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.95 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 5.09 (dd, J = 12.8, 5.6 Hz, 1H), 3.74-3.61 (m, 4H), 3.24 (s, 4H), 2.91-2.87 (m, 1H), 2.59-2.55 (m, 2H), 2.07-1.96 (m, 1H).

[0286] Compounds 1-4 were prepared from compound 3 (200 mg, 0.584 mmol) and 2-methylpropan-2-yl-3-formylazetidine-1-carboxylate (108.2 mg, 0.584 mmol) according to general synthesis procedure C. LCMS: 512.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 3.88-3.84 (m, 2H), 3.63-3.34 (m, 6H), 3.19-3.15 (m, 1H), 2.95-2.80 (m, 1H), 2.73-2.69 (m, 2H), 2.58-2.54 (m, 4H), 2.49-2.45 (m, 2H), 2.13-1.95 (m, 1st hour), 1.37 (s, 9th hour).

[0287] Compounds 1-5 were prepared from compound 1-4 (210 mg, 0.410 mmol) according to general synthesis procedure B. LCMS: 412.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 5.10 (dd, J = 12.8, 5.2 Hz, 1H), 4.06-4.01 (m, 2H), 3.93-3.86 (m, 2H), 3.43-3.39 (m, 10H), 3.12-2.80 (m, 2H), 2.78-2.54 (m, 2H), 2.13-1.96 (m, 1H), 1.53 (s, 1H).

[0288] Example 1 was prepared from compounds 1-5 (45 mg, 0.109 mmol) according to general synthesis procedure A. LCMS: 751.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 11.09 (s, 1H), 9.34 (s, 1H), 9.03 (s, 2H), 8.08 (s, 1H), 7.72 (s, 1H), 7.39-7.35 (m, 2H), 7.13 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.09 (dd, J = 12.8, 5.6 Hz, 1H), 4.25-3.75 (m, 6H), 3.47-3.43 (m, 4H), 3.20-2.82 (m, 3H), 2.63-2.57 (m, 5H), 2.09-1.98 (m, 1H), 1.87 (s, 3H), 1.79 (s, 3H).

[0289] Examples 2 to 13 below were prepared using similar starting materials according to the method described in Example 1. [Table 3-1] [Table 3-2] Table 3-3 Table 3-4 Example 14

change

[0290] Compound 14-2, general synthetic formula A (380 mg, 56.5%), compound 1-1 (500 mg, 1.810 mmol) and compound 14-1 (208.5 mg, 1.810 mmol) were prepared. LCMS: 372.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J = 8.8 Hz, 1H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.05 (d, J = 13.0 Hz, 2H), 3.27 (d, J = 6.0 Hz, 2H), 3.17 (s, 1H), 2.94 (dd, J = 18.6, 7.3 Hz, 2H), 2.90-2.82 (m, 1H), 2.61 (s, 1H), 2.57-2.55 (m, 1H), 2.02-2.00 (m, 1H), 1.74 (d, J = 13.2 Hz, 2H), 1.68-1.66 (m, 1H), 1.26-1.11 (m, 2H).

[0291] To a solution of compound 14-2 (550 mg, 1.481 mmol) in DCM (5 mL), 1,1,1-triacetoxy-1,3-dihydro-1λ5-benzo[d][1,2]didoxol-3-one (1.256 g, 2.962 mmol) was added. The solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (10 mL). The organic layer was washed with Na2SO3 (20 mL aqueous solution) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by TLC for preparation to obtain compound 14-3 (170 mg, 31.1%). LCMS: 370.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.62 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.25 (dd, J = 8.4, 4.0 Hz, 1H), 5.07 (dd, J = 12.4, 4.8 Hz, 1H), 3.95-3.92 (m, 2H), 3.20-3.14 (m, 2H), 2.61-2.55 (m, 1H), 2.53-2.50 (m, 3H), 2.03-1.91 (m, 3H), 1.61-1.51 (m, 2H).

[0292] Compound 14-5 was prepared from compound 14-3 (175 mg, 0.474 mmol) and compound 14-4 (138.3 mg, 0.284 mmol) according to general synthesis procedure C (190 mg, 72.7%). LCMS: 552.3 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 8.8, 2.0 Hz, 1H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.00 (d, J = 13.2 Hz, 2H), 3.88 (s, 4H), 3.21 - 3.18 (m, 4H), 3.00 - 2.82 (m, 3H), 2.69 - 2.52 (m, 2H), 2.23 - 2.21 (m, 2H), 2.10 - 1.94 (m, ), 1.72 (d, J = 11.4 Hz, 2H), 1.52 (s, 1H), 1.36 (s, 9H), 1.13 - 1.08 (m, 2H).

[0293] Compound 14-6 was prepared from compound 14-5 (170 mg, 0.308 mmol) according to the general synthetic procedure B. LCMS: 452.5 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.10 (s, 1H), 8.80 (s, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.38 (s, 2H), 4.31 - 4.00 (m, 6H), 3.07 (s, 2H), 2.98 - 2.96 (m, 2H), 2.92 - 2.82 (m, 1H), 2.58 - 2.56 (m, 2H), 2.02 (dd, J = 8.8, 3.6 Hz, 1H), 1.86 (s, 1H), 1.71 (d, J = 11.6 Hz, 2H), 1.25 - 1.17 (m, 2H).

[0294] Compound 14-7 was prepared from compound 14-6 (200 mg, 0.443 mmol) and compound INT-2-1 (117.2 mg, 0.487 mmol) according to general synthesis procedure A. LCMS: 574.5 [M+H] + .

[0295] Example 14 was prepared from compound 14-7 (75.4 mg, 0.132 mmol) and compound INT-1 (30 mg, 0.088 mmol) according to general synthesis procedure D. LCMS: 791.7 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 11.07 (s, 1H), 9.34 (s, 1H), 9.02 (s, 2H), 8.08 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.12 (s, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.06 (dd, J = 12.6, 5.2 Hz, 1H), 4.21 (s, 4H), 4.03 (s, 2H), 3.30 (s, 8H), 2.95-2.92 (m, 2H), 2.68-2.66 (m, 1H), 2.34-2.32 (m, 1H), 2.02-2.00 (m, 1H), 1.86 (s, 3H), 1.79 (s, 3H), 1.75-1.73 (m, 2H), 1.19-1.17 (m, 2H).

[0296] Examples 15-19 below were prepared using similar starting materials according to the method described in Example 14. [Table 4-1] [Table 4-2] Example 20 [ka]

[0297] Compound 20-3 was prepared from compound 20-1 (100 mg, 0.411 mmol) and compound 20-2 (113.5 mg, 0.411 mmol) according to general synthesis procedure A (110 mg, 53.6%). LCMS: 500.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.56-7.44 (m, 1H), 7.10 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.56 (s, 1H), 4.91 (dd, J = 12.0, 5.2 Hz, 1H), 3.50-3.39 (m, 6H), 2.96-2.56 (m, 5H), 2.52-2.42 (m, 5H), 2.19-2.10 (m, 1H), 1.88-1.84 (m, 2H), 1.46 (s, 9H).

[0298] Example 20 was synthesized from compound 20-3 (110 mg, 0.220 mmol) in the same manner as the synthesis of Example 1. LCMS: 739.5 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 11.08 (s, 1H), 9.34 (s, 1H), 9.04 (s, 2H), 8.22 (s, 1H), 8.08 (s, 1H), 7.68-7.51 (m, 1H), 7.19-7.07 (m, 2H), 7.02 (dd, J = 11.2, 7.6 Hz, 2H), 6.85 (t, J = 6.8 Hz, 2H), 5.05 (dd, J = 12.8, 5.2 Hz, 1H), 3.91-3.87 (m, 4H), 3.42-3.38 (m, 4H), 2.96-2.80 (m, 2H), 2.55-2.51 (m, 2H), 2.47-2.43 (m, 2H), 2.04-2.01 (m, 1H), 1.87 (s, 3H), 1.83-1.81 (m, 2H), 1.79 (s, 3H). Example 21 [ka]

[0299] To a solution of compound 21-1 (541.0 mg, 1.605 mmol) and compound 21-2 (240 mg, 1.070 mmol) in TEA (5 mL) and DMF (5 mL), CuI (81.5 mg, 0.428 mmol) and Pd(PPh3)2Cl2 (150.2 mg, 0.214 mmol) were added. The solution was stirred under N2 at 50°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 21-3 (140 mg, 27.2%). LCMS: 418.5 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.93 (s, 1H), 7.92 (s, 2H), 5.16 (dd, J = 12.8, 5.4 Hz, 1H), 3.64 (s, 2H), 3.46 (s, 2H), 3.35 (s, 4H), 2.97-2.82 (m, 1H), 2.66-2.54 (m, 2H), 2.40-2.38 (m, 2H), 2.12-2.01 (m, 1H), 1.40 (s, 9H).

[0300] Example 21 was synthesized from compound 21-3 in the same manner as the synthesis of Example 1. LCMS: 720.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 11.13 (s, 1H), 9.33 (s, 1H), 9.06 (s, 2H), 8.08 (s, 1H), 7.95-7.92 (m, 3H), 7.13 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.16 (dd, J = 12.8, 5.2 Hz, 1H), 3.91 (s, 4H), 3.70 (s, 2H), 2.88-2.86 (dm, 1H), 2.66-2.62 (m, 4H), 2.58-2.56 (m, 2H), 2.06-2.04 (m, 1H), 1.87 (s, 3H), 1.79 (s, 3H). Example 22 [ka]

[0301] Compound 22-1 (69.5 mg, 0.584 mmol) and DIEA (226.4 mg, 1.752 mmol) were added to a solution of compound 1-3 (200 mg, 0.584 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (40 mL) and extracted with DIEA (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 22-2 (120 mg, 54.0%). LCMS: 381.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.6, 2.0 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 3.50-3.45 (m, 4H), 3.34 (d, J = 2.2 Hz, 2H), 3.19 (d, J = 2.2 Hz, 1H), 2.89-2.86 (m, 1H), 2.58-2.55 (m, 6H), 2.05-1.98 (m, 1H).

[0302] To a solution of compound 22-2 (50 mg, 0.119 mmol) in TEA (2 mL) and DMF (2 mL), compound INT-2 (67.9 mg, 0.178 mmol), CuI (9.1 mg, 0.048 mmol), and PdCl2(PPh3)2 (16.7 mg, 0.024 mmol) were added. The mixture was stirred under N2 at 50°C for 2 hours. The mixture was filtered, concentrated to dryness, and purified by preparative HPLC to obtain Example 22. LCMS: 720.4 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 11.07 (s, 1H), 9.46 (s, 2H), 9.37 (s, 1H), 8.24 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.0 Hz, 1H), 3.75 (s, 2H), 3.53 (s, 4H), 2.89-2.85 (m, 2H), 2.73 (s, 4H), 2.04-2.01 (m, 2H), 1.87 (s, 3H), 1.79 (s, 3H). Example 23 [ka]

[0303] Compound 23-1 (735.8 mg, 2.921 mmol) and K2CO3 (403.7 mg, 2.921 mmol) were added to a solution of compound 1-3 (1 g, 2.921 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (60 mL x 2), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 23-2 (1.01 g, 67.4%). LCMS: 515.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.99 (s, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 5.08-5.04 (m, 1H), 3.78 (s, 2H), 3.46-3.42 (m, 4H), 2.91-2.87 (m, 1H), 2.66-2.64 (m, 4H), 2.58-2.54 (m, 2H), 2.07-1.93 (m, 1H).

[0304] To a solution of compound 23-2 (500 mg, 0.974 mmol) in DMF (10 mL), (n-Bu)6Sn2 (678.0 mg, 1.169 mmol), LiCl (165.2 mg, 3.896 mmol), and Pd(PPh3)4 (112.5 mg, 0.097 mmol) were added. The mixture was stirred under N2 at 110°C for 16 hours. The mixture was filtered, and the filtrate was diluted with water (80 mL) and extracted with EA (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 23-3 (130 mg, 9.23%). LCMS: 725.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.82-8.63 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.24 (dd, J = 8.6, 2.0 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 3.73 (s, 2H), 3.44 (s, 4H), 2.65 (s, 4H), 1.53-1.48 (m, 4H), 1.39-0.95 (m, 18H), 0.85 (t, J = 7.2 Hz, 9H).

[0305] To a solution of compound 23-3 (110 mg, 0.152 mmol) in dioxane (6 mL), compound INT-1-8 (108.3 mg, 0.304 mmol), LiCl (12.9 mg, 0.304 mmol), and Pd(PPh3)4 (17.6 mg, 0.015 mmol) were added. The mixture was stirred under N2 at 110°C for 16 hours. The mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 23-6. LCMS: 710.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 11.07 (s, 1H), 9.47 (s, 2H), 8.24 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.6 Hz, 1H), 3.87 (s, 2H), 3.84 (s, 3H), 3.49-3.47 (m, 4H), 3.18-3.16 (m, 1H), 2.91-2.87 (m, 1H), 2.74-2.70 (m, 4H), 2.62-2.60 (m, 2H), 1.92 (s, 3H), 1.83 (s, 3H).

[0306] Example 23 was prepared from compound 23-6 (30 mg, 0.042 mmol) according to general synthesis procedure E. LCMS: 696.5 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 11.08 (s, 1H), 9.47 (s, 2H), 9.37 (s, 1H), 8.23 ​​(s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 3.87 (s, 2H), 3.48 (s, 4H), 2.72-2.67 (m, 5H), 2.33 (s, 1H), 2.04-1.97 (m, 2H), 1.88 (s, 3H), 1.80 (s, 3H). Example 24 [ka]

[0307] To a solution of compound 24-1 (1000 mg, 4.342 mmol) in DMF (10 mL), NaH (104.2 mg, 4.342 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Next, compound 24-2 (419.9 mg, 2.171 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (60 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 24-3 (330 mg, 19.6%). LCMS: 389.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 2H), 4.40 (t, J = 5.6 Hz, 2H), 3.32 (s, 2H), 3.28 (d, J = 4.8 Hz, 2H), 2.71 (t, J = 5.6 Hz, 2H), 2.44-2.33 (m, 4H), 1.39 (s, 9H).

[0308] To a solution of compound 24-3 (120 mg, 0.310 mmol) in dioxane (2 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (157.3 mg, 0.620 mmol), Pd2(dba)3 (28.4 mg, 0.031 mmol), Xphos (14.8 mg, 0.031 mmol), and AcOK (91.1 mg, 0.930 mmol) were added. The mixture was stirred under N2 at 100°C for 2 hours. The mixture was concentrated, and the unpurified compound 24-4 was used directly in the next reaction. LCMS: 353.1 [M+H] + .

[0309] Compound 24-5 was prepared from compound 24-4 (243.9 mg, 0.561 mmol) and compound INT-1-8 (100 mg, 0.281 mmol) (150 mg, 0.257 mmol) according to general synthesis procedure D. LCMS: 584.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.27 (s, 2H), 8.18 (s, 1H), 7.33 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.56-4.35 (m, 3H), 3.84 (s, 3H), 2.76-2.72 (m, 3H), 2.51-2.45 (m, 6H), 1.92 (s, 3H), 1.83 (s, 3H), 1.40 (s, 9H).

[0310] Compound 24-6 was prepared from compound 24-5 (150 mg, 0.263 mmol) according to the general synthetic procedure B. LCMS: 484.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.33 (s, 2H), 9.08 (s, 2H), 8.66 (d, J = 4.8 Hz, 1H), 8.20 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 4.75 - 4.66 (m, 2H), 4.64 - 4.54 (m, 1H), 3.84 (s, 3H), 3.54 (s, 2H), 3.37 (s, 4H), 1.92 (s, 3H), 1.83 (s, 3H).

[0311] Compound 24-7 was prepared from compound 24-6 (110 mg, 0.227 mmol) and compound 1-1 (125.6 mg, 0.455 mmol) according to the general synthetic procedure A. LCMS: 740.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 11.07 (s, 1H), 9.28 (s, 2H), 8.18 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 - 7.17 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.6 Hz, 1H), 4.57 (t, J = 5.2 Hz, 2H), 3.84 (s, 3H), 3.46 (s, 4H), 2.85 - 2.81 (m, 3H), 2.69 - 2.65 (m, 5H), 2.55 - 2.53 (m, 2H), 2.01 - 1.98 (m, 2H), 1.92 (s, 3H),1.83 (s, 3H).

[0312] Example 24 was prepared from compound 24-7 (80 mg, 0.108 mmol) according to the general synthesis procedure E. LCMS: 726.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 11.07 (s, 1H), 9.35 (s, 1H), 9.28 (s, 2H), 8.17 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.57 (t, J = 5.6 Hz, 2H), 3.46 (s, 4H), 2.91-2.77 (m, 3H), 2.67 (s, 4H), 2.59-2.55 (m, 2H), 2.08-1.95 (m, 1H), 1.87 (s, 3H), 1.80 (s, 3H). Example 25 [ka]

[0313] Compound 25-3 was prepared from compound 25-1 (216.1 mg, 0.617 mmol) and compound INT-1-8 (200 mg, 0.561 mmol) according to general synthesis procedure D (170 mg, 48.3%). LCMS: 500.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.32 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.62 (d, J = 3.6 Hz, 1H), 4.39-4.31 (m, 1H), 4.27-4.20 (m, 1H), 4.00-3.93 (m, 1H), 3.84 (s, 3H), 3.80-3.76 (m, 1H), 3.67-3.59 (m, 1H), 3.43-3.37 (m, 1H), 1.92 (s, 3H), 1.83 (s, 3H), 1.66-1.53 ​​(m, 2H), 1.48-1.38 (m, 4H).

[0314] A mixture of compound 25-3 (150 mg, 0.300 mmol) in DCM (5 mL) and MeOH (1.25 mL) and HCl / dioxane (2.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated and purified by silica gel column chromatography to obtain compound 25-3 (120 mg, 85%). LCMS: 416.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 3.76 (t, J = 6.0 Hz, 2H), 1.92 (s, 3H), 1.83 (s, 3H).

[0315] A mixture of compound 25-3 (90 mg, 0.217 mmol), MsCl (49.6 mg, 0.433 mmol), and TEA (65.8 mg, 0.650 mmol) in DCM (10 mL) was stirred at room temperature for 1 hour. The mixture was washed with saturated NH4Cl aqueous solution and brine, dried over Na2SO4, filtered, and then concentrated to obtain compound 25-4. LCMS: 494.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H), 8.47 (s, 1H), 8.34 (d, J = 1.8 Hz, 3H), 7.96 (d, J = 2.0 Hz, 1H), 7.60 (s, 1H), 7.01 (s, 1H), 3.88 (s, 2H), 3.77 (s, 3H), 3.68 (s, 2H), 3.02 (s, 3H), 1.99 (s, 3H), 1.93 (s, 3H).

[0316] A mixture of compound 25-4 (100 mg, 0.203 mmol), compound 1-3 (90.4 mg, 0.264 mmol), and DIEA (130.9 mg, 1.013 mmol) in DMF (5 mL) was stirred at 100°C for 1 hour. The mixture was diluted with water (30 mL) and extracted with phenylethylamine (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 25-5. LCMS: 740.5 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.35 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.24-7.03 (m, 4H), 6.89 (d, J = 8.4 Hz, 1H), 5.30 (s, 1H), 4.49-4.45 (m, 2H), 3.87 (s, 3H), 3.52 (s, 2H), 3.15-3.11 (m, 1H), 2.93-2.74 (m, 6H), 2.17-2.14 (m, 1H), 1.98 (s, 3H), 1.92 (s, 3H), 1.65-1.61 (m, 4H).

[0317] Example 25 was prepared using a general synthetic formula E and compound 25-5 (10 mg, 0.014 mmol). LCMS: 726.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 11.08 (s, 1H), 9.40 (s, 1H), 8.71 (s, 1H), 8.31 (s, 1H), 7.68 (d, J = 9.2 Hz, 2H), 7.57 (s, 1H), 7.35 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.30-4.29 (m, 2H), 3.43-3.39 (m, 4H), 2.93-2.84 (m, 2H), 2.81-2.78 (m, 2H), 2.64-2.61 (m, 4H), 2.03-1.98 (m, 2H), 1.87 (s, 3H), 1.79 (s, 3H). Example 26

change

[0318] Compound 26-2 was prepared (130 mg, 73.3%) from compound 26-1 (190.7 mg, 0.505 mmol) and compound INT-1-8 (120 mg, 0.337 mmol) according to general synthesis procedure D. LCMS: 527.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 4.44-4.23 (m, 3H), 3.87 (s, 3H), 2.93-2.89 (m, 2H), 2.18 (d, J = 11.8 Hz, 2H), 2.01-2.00 (m, 1H), 1.99 (s, 1H), 1.97-1.94 (m, 1H), 1.93 (s, 3H), 1.48 (s, 9H).

[0319] Compound 26-3 was prepared from compound 26-2 (100 mg, 0.190 mmol) according to general synthesis procedure B (80 mg, unpurified). LCMS: 427.3 [M+H] + .

[0320] Compound 26-5 was prepared from compound 26-3 (80 mg, 0.188 mmol) and compound 26-4 (60.0 mg, 0.281 mmol) according to general synthesis procedure C (100 mg, 85.5%). LCMS: 624.6 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 4.19-4.15 (m, 1H), 3.87 (s, 3H), 3.01-2.97 (m, 2H), 2.71 (t, J = 12.2 Hz, 2H), 2.21-2.16 (m, 8H), 1.99 (s, 3H), 1.93 (s, 3H), 1.77-1.73 (m, 2H), 1.46 (s, 9H), 1.32-1.28 (m, 2H), 1.12-1.08 (m, 2H), 0.88-0.86 (m, 1H).

[0321] Compound 26-6 was prepared from compound 26-5 (100 mg, 0.160 mmol) according to general synthesis procedure B. LCMS: 524.3 [M+H] + .

[0322] Compound 26-7 was prepared from compound 26-6 (83 mg, 0.158 mmol) and compound 1-1 (87.5 mg, 0.317 mmol) according to general synthesis procedure A. LCMS: 780.4 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 11.07 (s, 1H), 8.52 (s, 1H), 8.15 (d, J = 10.0 Hz, 1H), 8.02 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.23-4.21 (m, 1H), 4.08-4.06 (m, 1H), 3.83 (s, 3H), 3.01-2.97 (m, 4H), 2.91-2.79 (m, 1H), 2.68-2.53 (m, 5H), 2.23-2.19 (m, 2H), 2.16-2.01 (m, 6H), 1.92 (s, 3H), 1.83 (s, 3H), 1.82-1.81 (m, 2H), 1.26-1.22 (m, 2H).

[0323] In Example 26, the general synthetic formula E was used, and compound 26-7 (70 mg, 0.090 mmol) was prepared. LCMS: 766.4 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 11.07 (s, 1H), 9.31 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.88 - 6.80 (m, 2H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.24 (s, 1H), 4.07 (d, J = 13.2 Hz, 2H), 3.31 - 3.27 (m, 4H), 3.01 - 2.98 (m, 3H), 2.91 - 2.82 (m, 1H), 2.59 - 2.56 (m, 2H), 2.23 - 2.21 (m, 1H), 2.11 - 2.07 (m, 3H), 2.05 - 1.95 (m, 3H), 1.87 (s, 3H), 1.84 - 1.81 (m, 2H), 1.79 (s, 3H), 1.26 - 1.14 (m, 2H). Example 27 [Chemical formula]

[0324] Compound 27-3 was prepared from compound 27-1 (200 mg, 0.602 mmol) and compound 27-2 (157.7 mg, 0.662 mmol) according to the general synthetic procedure D (203 mg, 92.8%). LCMS: 364.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H), 5.00 (s, 1H), 4.22 (t, J = 5.2 Hz, 2H), 3.81 (s, 3H), 3.80-3.72 (m, 2H), 1.89 (s, 3H), 1.83 (s, 3H).

[0325] To a solution of compound 27-3 (180 mg, 0.495 mmol) and PPh3 (194.9 mg, 0.743 mmol) in DCM (10 mL), carbon tetrabromide (246.4 mg, 0.743 mmol) was added at 0°C. The solution was stirred under N2 at room temperature for 2 hours. The mixture was washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 27-4 (110 mg, 52.1%). LCMS: 426.2 [M+H] + .

[0326] To a solution of compound 27-4 (100 mg, 0.235 mmol) and compound 1-3 (80.3 mg, 0.235 mmol) in DMF (6 mL), TEA (0.20 mL, 1.407 mmol) was added. The mixture was stirred at 70°C for 2 hours. The mixture was concentrated, and the residue was purified by TLC for preparation to obtain compound 27-5. LCMS: 688.5 [M+H] + .

[0327] Example 27 was prepared from compound 27-5 (110 mg, 0.160 mmol) according to general synthesis procedure E. LCMS: 674.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 11.07 (s, 1H), 9.15 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.80-6.74 (m, 2H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.36 (t, J = 6.4 Hz, 2H), 3.48-3.44 (m, 4H), 2.87-2.84 (m, 3H), 2.69-2.53 (m, 7H), 1.86 (s, 3H), 1.78 (s, 3H). Example 28 [ka]

[0328] Compound 28-2 (489.1 mg, 2.548 mmol) and NaHCO3 (142.7 mg, 1.698 mmol) were added to a solution of compound 28-1 (500 mg, 1.698 mmol) in DMF (10 mL). The mixture was stirred at 60°C under N2 for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 28-3 (130 mg, 18.9%). LCMS: 306.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 6.98-6.96 (m, 1H), 6.51-6.38 (m, 2H), 6.03 (d, J = 7.8 Hz, 1H), 4.36-4.19 (m, 1H), 4.10-3.91 (m, 2H), 2.78-2.72 (m, 4H), 2.57-2.55 (m, 1H), 2.12-2.02 (m, 1H), 1.88-1.82 (m, 1H), 1.67-1.62 (m, 2H), 1.51-1.43 (m, 2H), 1.41 (s, 9H).

[0329] Example 28 was synthesized from compound 28-3 (130 mg, 0.321 mmol) in the same manner as the synthesis of Example 1. LCMS: 742.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.79 (s, 1H), 9.33 (s, 1H), 9.02 (s, 2H), 8.07 (s, 1H), 7.10 (s, 1H), 7.03-7.01 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.46-6.42 (m, 2H), 6.01 (d, J = 7.6 Hz, 1H), 4.76 (d, J = 13.2 Hz, 2H), 4.32-4.29 (m, 1H), 2.99 (t, J = 11.8 Hz, 4H), 2.75-2.59 (m, 3H), 2.54 (s, 1H), 2.21 (s, 2H), 2.07 (s, 2H), 1.86 (s, 3H), 1.83 (s, 1H), 1.79 (s, 3H), 1.68-1.66 (m, 4H), 1.32-1.29 (m, 2H), 1.10-1.08 (m, 2H).

[0330] Examples 29 to 37 below were prepared using similar starting materials according to the method described in Example 28. [Table 5-1] [Table 5-2] [Table 5-3] Example 38 [ka]

[0331] To a solution of compound 38-2 (500 mg, 2.143 mmol) in DCM (5 mL), pyridine (0.5 mL, 6.429 mmol) and Tf2O (725.5 mg, 2.572 mmol) were added at 0°C. The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain compound 38-2 (750 mg, unpurified), which was then used directly in the next step.

[0332] To a solution of compound 38-3 (250 mg, 0.816 mmol) and compound 38-2 (745.4 mg, 2.040 mmol) in THF (5 mL), DIEA (0.7 mL, 4.081 mmol) was added. The solution was stirred at 40°C for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with DIEA (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 38-4 (70 mg, 16.4%). LCMS: 522.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 6.87-6.75 (m, 1H), 6.50 (dd, J = 15.2, 2.4 Hz, 1H), 6.41 (dd, J = 8.6, 2.4 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 4.98 (t, J = 6.0 Hz, 1H), 3.86-3.60 (m, 8H), 3.43 (d, J = 6.0 Hz, 1H), 3.38 (d, J = 6.0 Hz, 1H), 2.84 (s, 4H), 2.74-2.71 (m, 1H), 2.55 (d, J = 4.4 Hz, 1H), 2.16-2.07 (m, 1H), 1.93-1.86 (m, 1H), 1.74-1.69 (m, 2H), 1.61-1.55 (m, 2H), 1.39 (s, 9H).

[0333] Example 38 was synthesized from compound 38-4 (70 mg, 0.134 mmol) in the same manner as the synthesis of Example 1. LCMS: 761.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.78 (s, 1H), 9.35 (s, 1H), 9.05 (s, 2H), 8.08 (s, 1H), 7.12 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.88-6.80 (m, 2H), 6.51 (dd, J = 15.0, 2.2 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 4.50 (d, J = 13.3 Hz, 2H), 4.32-4.15 (m, 1H), 2.86 (s, 4H), 2.78-2.67 (m, 2H), 2.64 (s, 4H), 2.59-2.54 (m, 2H), 2.13-2.06 (m, 1H), 2.04-1.94 (m, 4H), 1.87 (s, 3H), 1.86-1.85 (m, 1H), 1.79 (s, 3H), 1.78-1.74 (m, 1H), 1.68-1.65 (m, 1H). Example 39 [ka]

[0334] To a solution of compound INT-2 (40 mg, 0.095 mmol) in ACN (1 mL), NCS (12.7 mg, 0.095 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness. The residue was purified by TLC for preparation to obtain compound 39-1 (20 mg, 46.2%). LCMS: 497.1 [M+H+CH3CN] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H), 9.40 (d, J = 2.8 Hz, 1H), 9.34-9.21 (m, 2H), 8.36 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 1.87 (s, 3H), 1.79 (s, 3H).

[0335] Example 39 was prepared using the general synthetic formula A, compound 39-2 (20 mg, 0.044 mmol) and compound 39-3 (21.3 mg, 0.053 mmol). LCMS: 777.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.46 (s, 1H), 8.90-8.87 (m, 2H), 8.32 (s, 1H), 8.19 (d, J = 3.6 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.86-6.82 (m, 2H), 6.51 (d, J = 15.2 Hz, 1H), 6.43 (d, J = 8.8 Hz, 1H), 5.81 (d, J = 7.6 Hz, 1H), 4.77 (d, J = 12.4 Hz, 2H), 4.27-4.25 (m, 1H), 3.05-3.01 (m, 2H), 2.87 (s, 4H), 2.79-2.66 (m, 2H), 2.62-2.54 (m, 2H), 2.22 (d, J = 6.8 Hz, 2H), 2.12-2.06 (m, 1H), 2.02-1.99 (m, 1H), 1.87 (s, 3H), 1.84 (s, 2H), 1.79 (s, 3H), 1.46 (s, 1H), 1.11-1.09 (m, 2H), 0.86-0.82 (m, 2H). Example 40

change

[0336] A mixture of compound 40-1 (1.0 g, 4.292 mmol), compound 40-2 (1.12 g, 6.009 mmol), BINAP (267.3 mg, 0.429 mmol), Pd(OAc)2 (48.2 mg, 0.215 mmol), and Cs2CO3 (1538.1 mg, 4.721 mmol) in toluene (40 mL) was stirred at 80°C for 16 hours under N2. The mixture was filtered, and the filtered liquid was concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 40-3 (1.2 g, 82.6%). LCMS: 339.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (t, J = 8.8 Hz, 1H), 6.84-6.71 (m, 2H), 3.77 (s, 3H), 3.43 (dd, J = 6.0, 2.8 Hz, 4H), 3.35 (dd, J = 6.3, 3.2 Hz, 4H), 1.42 (s, 9H).

[0337] To a solution of compound 40-3 (1.10 g, 3.251 mmol) in MeOH (33 mL), NaOH (6 M) (7.7 mL, 3.251 mmol) was added. The mixture was stirred at 55 °C for 2 hours. The reaction mixture was carefully added to ice water (50 mL) while stirring, and the pH was adjusted to ~5 with 1 N HCl. The mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to obtain compound 40-4 (1.10 g, unpurified). LCMS: 325.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.70 (t, J = 9.0 Hz, 1H), 6.79-6.70 (m, 2H), 3.48-3.39 (m, 4H), 3.33 (dd, J = 6.3, 3.8 Hz, 4H), 1.42 (s, 9H).

[0338] A mixture of compound 40-4 (1.0 g, 3.264 mmol), compound 40-5 (507.4 mg, 3.083 mmol), HATU (1.76 g, 4.624 mmol), and TEA (1.3 mL, 9.248 mmol) in DMF (30 mL) was stirred at room temperature under N2 for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EA (70 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 40-6 (800 mg, 59.7%). LCMS: 435.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.08-8.05 (m, 1H), 7.64 (t, J = 9.0 Hz, 1H), 6.88-6.71 (m, 2H), 4.77-4.67 (m, 1H), 3.49-3.38 (m, 4H), 3.32-3.27 (m, 4H), 2.82-2.67 (m, 1H), 2.58-2.51 (m, 1H), 2.18-1.96 (m, 2H), 1.42 (s, 9H).

[0339] Example 40 was synthesized from compound 40-6 (200 mg, 0.460 mmol) in the same manner as the synthesis of Example 1. LCMS: 771.7 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.84 (s, 1H), 9.34 (s, 1H), 9.02 (s, 2H), 8.07-8.01 (m, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.85-6.76 (m, 3H), 4.77-4.74 (m, 2H), 3.31 (s, 6H), 2.97-2.92 (m, 4H), 2.61-2.57 (m, 3H), 2.39-2.35 (m, 1H), 2.25-2.21 (m, 2H), 2.01-1.92 (m, 2H), 1.87 (s, 3H), 1.85-1.81 (m, 3H), 1.79 (s, 3H), 1.11-1.08 (m, 2H). Example 41 [ka]

[0340] A mixture of compound 41-1 (500 mg, 1.693 mmol) and acrylic acid (122.0 mg, 1.693 mmol) in AcOH (5 mL) was stirred at 100°C for 2 hours. The mixture was diluted with water (50 mL) and extracted with EA (20 mL x 5). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 41-2 (250 mg, 40.2%). LCMS: 368.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 6.83 (t, J = 8.8 Hz, 1H), 6.41-6.34 (m, 2H), 3.60-3.55 (m, 4H), 3.40 (s, 2H), 2.91 (s, 4H), 2.65 (t, J = 6.2 Hz, 2H), 1.48 (s, 9H).

[0341] A mixture of compound 41-2 (220 mg, 0.599 mmol) and oxomethandiamine (179.9 mg, 2.994 mmol) in AcOH (3.5 mL) and toluene (3.5 mL) was stirred overnight at 110°C. The mixture was concentrated, diluted with NaHCO3, and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 41-3 (90 mg, 38.3%). LCMS: 393.4 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.08-6.92 (m, 3H), 3.83 (t, J = 6.8 Hz, 2H), 3.63-3.55 (m, 4H), 3.08-2.98 (m, 4H), 2.83 (t, J = 6.8 Hz, 2H), 1.49 (s, 9H).

[0342] A mixture of compound 41-3 (60 mg, 0.153 mmol) in DCM (3 mL) and HCl / dioxane (1.5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to obtain compound 41-4 (60 mg, unpurified). LCMS: 293.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.18 (s, 2H), 7.24 (d, J = 14.4 Hz, 1H), 7.12-7.11 (m, 1H), 4.05 (s, 8H), 3.75 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H).

[0343] Example 41 was prepared from compound 41-5 (13 mg, 0.029 mmol) and compound 41-4 (11.0 mg, 0.038 mmol) according to general synthesis procedure C. LCMS: 729.7 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.37 (s, 1H), 9.35 (s, 1H), 9.02 (s, 2H), 8.07 (s, 1H), 7.18 (dd, J = 14.0, 2.0 Hz, 1H), 7.09 (s, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 6.93 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 4.76 (d, J = 12.8 Hz, 2H), 3.74 (t, J = 6.8 Hz, 2H), 3.06 - 2.95 (m, 7H), 2.69 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 2.24 (d, J = 6.8 Hz, 2H), 1.87 (s, 3H), 1.86 - 1.83 (m, 3H), 1.79 (s, 3H), 1.14 - 1.05 (m, 2H). Example 42 [Chemical formula]

[0344] Compound 42-2 was prepared from compound 41-4 (30 mg, 0.103 mmol) and compound 42-1 (35.0 mg, 0.154 mmol) according to the general synthetic procedure C. LCMS: 504.4 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.17 (d, J = 14.0 Hz, 1H), 7.11 - 6.96 (m, 2H), 3.90 (d, J = 12.0 Hz, 2H), 3.73 (t, J = 6.4 Hz, 2H), 3.00 (s, 4H), 2.68 (t, J = 6.4 Hz, 4H), 2.52 (s, 2H), 2.35 (s, 2H), 1.64 (d, J = 12.2 Hz, 2H), 1.39 - 1.29 (m, 4H), 1.28 (s, 9H), 1.03 - 0.95 (m, 2H).

[0345] Example 42 was synthesized from compound 42-2 (200 mg, 0.460 mmol) in the same manner as the synthesis of Example 1. LCMS: 743.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.37 (s, 1H), 9.34 (s, 1H), 9.02 (s, 2H), 8.07 (s, 1H), 7.20 (d, J = 14.8 Hz, 1H), 7.13-6.97 (m, 4H), 6.84 (d, J = 8.4 Hz, 1H), 4.75 (d, J = 12.8 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 3.03-2.97 (m, 7H), 2.69 (t, J = 6.6 Hz, 4H), 2.53 (d, J = 8.0 Hz, 2H), 1.87 (s, 3H), 1.83-1.80 (m, 2H), 1.79 (s, 3H), 1.67 (s, 1H), 1.51 (s, 2H), 1.19-1.13 (m, 3H). Example 43 [ka]

[0346] To a solution of compound 43-1 (3.0 g, 13.761 mmol) in EtOH (2 mL), methyldiazanyl sulfate (6.94 g, 48.165 mmol) and TEA (7.6 mL, 55.046 mmol) were added. The mixture was stirred overnight at 80°C. The mixture was diluted with water (50 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 43-2 (670 mg, 19.9%). LCMS: 244.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 5.6 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 5.51 (s, 2H), 3.72 (s, 3H).

[0347] To a solution of compound 43-2 (620 mg, 2.540 mmol) and acrylic acid (274.7 mg, 3.810 mmol) in HCl (2 M) (15 mL), tetrabutylammonium bromine (81.9 mg, 0.254 mmol) was added. The mixture was stirred overnight at 100 °C. The mixture was basicized to pH ~8 with a saturated solution of NaHCO3. The solution was acidified to pH ~5 with AcOH. The white solid was precipitated, filtered, washed with water, and then dried under reduced pressure to obtain compound 43-3 (600 mg, 74.7%). LCMS: 318.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 6.23 (s, 1H), 3.75 (s, 3H), 3.43 (s, 2H), 2.58 (t, J = 6.6 Hz, 2H).

[0348] To a solution of compound 43-3 (600 mg, 1.898 mmol) in AcOH (15 mL), sodium cyanate (246.8 mg, 3.796 mmol) was added. The mixture was stirred overnight at 60°C. HCl (15 mL) was added to the mixture. The mixture was stirred for a further 3 hours at 60°C. The mixture was diluted with water (100 mL), filtered, and washed with water. The cake was dried under reduced pressure to obtain compound 43-4 (450 mg, 69.5%). LCMS: 342.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 4.00 (s, 3H), 3.92 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H).

[0349] To a solution of compounds 43-4 (450 mg, 1.319 mmol) and 40-2 (737.3 mg, 3.958 mmol) in dioxane (10 mL), Pd-PEPPSI-IHeptCl (38.5 mg, 0.040 mmol) and Cs2CO3 (1.29 g, 3.958 mmol) were added. The mixture was stirred overnight at 100°C. The mixture was diluted with water (50 mL) and extracted with EA (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was ground with EA:MTBE (1:5) to obtain compound 43-5 (180 mg, 30.6%) as a gray solid. LCMS: 447.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 7.38 (d, J = 12.8 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 3.94 (s, 3H), 3.89 (t, J = 6.8 Hz, 2H), 3.52 (s, 4H), 3.06-2.98 (m, 4H), 2.74 (t, J = 6.8 Hz, 2H), 1.43 (s, 9H).

[0350] Example 43 was synthesized from compound 43-5 (80 mg, 0.179 mmol) in the same manner as the synthesis of Example 1. LCMS: 783.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.53 (s, 1H), 9.34 (s, 1H), 9.02 (s, 2H), 8.07 (s, 1H), 7.36 (d, J = 12.8 Hz, 1H), 7.14-7.06 (m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 13.8 Hz, 2H), 3.95 (s, 3H), 3.90 (t, J = 6.8 Hz, 2H), 3.10 (s, 4H), 3.01 (t, J = 11.8 Hz, 2H), 2.74 (t, J = 6.7 Hz, 2H), 2.67 (s, 1H), 2.58 (s, 4H), 2.26 (d, J = 6.6 Hz, 2H), 1.87 (s, 3H), 1.86-1.83 (m, 2H), 1.79 (s, 3H), 1.13-1.10 (m, 2H). Example 44 [ka]

[0351] To a solution of compound 44-1 (1 g, 4.031 mmol) in THF (100 mL), NaH (1.6 g, 40.306 mmol) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Next, the mixture was stirred under N2 at room temperature for 1 hour. Compound 28-2 (3.1 g, 16.123 mmol) was added. The solution was stirred at 65°C for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was ground with DCM:MeOH to obtain compound 44-2 (900 mg, 62.2%). LCMS: 358.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.20 (dd, J = 7.2, 4.8 Hz, 2H), 8.03-7.93 (m, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 5.47 (dd, J = 12.8, 5.4 Hz, 1H), 3.00-2.88 (m, 1H), 2.77-2.64 (m, 2H), 2.18-2.07 (m, 1H).

[0352] A mixture of compound 44-2 (500 mg, 1.392 mmol), compound 40-2 (331.2 mg, 1.670 mmol), Cs2CO3 (1360.5 mg, 4.176 mmol), and Pd-PEPPSI-IHeptCl (135.4 mg, 0.139 mmol) in DMF (10 mL) was stirred at 80°C for 3 hours under N2. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 44-3 (500 mg, 77.3%). LCMS: 465.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.85-7.78 (m, 1H), 7.04-6.97 (m, 2H), 5.43 (dd, J = 12.8, 5.2 Hz, 1H), 3.61 (s, 4H), 3.07-2.99 (m, 4H), 2.89 (s, 1H), 2.73 (s, 1H), 2.66 (t, J = 13.0 Hz, 1H), 2.13-2.03 (m, 1H), 1.44 (s, 9H).

[0353] Example 44 was synthesized from compound 44-3 (150 mg, 0.323 mmol) in the same manner as the synthesis of Example 1. LCMS: 801.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 11.12 (s, 1H), 9.34 (s, 1H), 9.03 (s, 2H), 8.28 (s, 1H), 8.13-8.08 (m, 2H), 7.84 (s, 1H), 7.11 (s, 1H), 7.08-6.90 (m, 3H), 6.84 (d, J = 8.2 Hz, 1H), 5.42 (s, 1H), 4.78 (d, J = 12.6 Hz, 2H), 3.13 (s, 4H), 2.96 (s, 2H), 2.76-2.72 (m, 2H), 2.67 (s, 2H), 2.64 (s, 1H), 2.54 (s, 4H), 2.33 (s, 1H), 2.09 (s, 1H), 1.88 (s, 2H), 1.87 (s, 3H), 1.79 (s, 3H), 1.23-1.20 (m, 2H). Example 45 [ka]

[0354] Example 45 was synthesized from compound 43-5 (80 mg, 0.179 mmol) in the same manner as the synthesis of Example 1. LCMS: 797.5 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.53 (s, 1H), 9.35 (s, 1H), 9.01 (s, 2H), 8.07 (s, 1H), 7.35 (d, J = 12.8 Hz, 1H), 7.11 (s, 1H), 7.09 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.75 (d, J = 12.8 Hz, 2H), 3.95 (s, 3H), 3.89 (t, J = 6.8 Hz, 2H), 3.09 (s, 4H), 2.97 (t, J = 11.6 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.58-2.51 (m, 4H), 2.43 (t, J = 6.8 Hz, 2H), 1.87 (s, 3H), 1.85-1.81 (m, 2H), 1.79 (s, 3H), 1.69-1.67 (m, 1H), 1.47-1.43 (m, 2H), 1.18-1.12 (m, 2H).

[0355] Examples 46 to 52 below were prepared using similar starting materials according to the method described in Example 1. [Table 6-1] [Table 6-2] [Table 6-3] Example 53 [ka]

[0356] Compound 53-3 was prepared from compound 21-1 (1 g, 2.966 mmol) and compound 53-2 (1.4 g, 4.449 mmol) according to general synthesis procedure D (200 mg, 15.3%). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.00-7.80 (m, 3H), 6.50 (s, 1H), 5.16 (dd, J = 12.8, 5.4 Hz, 1H), 3.57 (t, J = 5.6 Hz, 2H), 2.94-2.89 (m, 1H), 2.62-2.56 (m, 3H), 2.11-2.02 (m, 1H), 1.44 (s, 9H).

[0357] A mixture of compound 53-3 (200 mg, 0.455 mmol) in EA (4 mL) was mixed with 10% Pd / C (48.4 mg, 0.046 mmol). The mixture was stirred under H2 at room temperature for 16 hours. The mixture was filtered and then concentrated to obtain compound 53-4 (180 mg, 89.6%). 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.88-7.80 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 5.14 (dd, J = 12.8, 5.4 Hz, 1H), 4.19-4.05 (m, 2H), 2.99-2.67 (m, 4H), 2.65-2.52 (m, 2H), 2.13-2.01 (m, 1H), 1.80 (d, J = 12.4 Hz, 2H), 1.60-1.56 (m, 2H), 1.42 (s, 9H).

[0358] Example 53 was synthesized from compound 53-4 (180 mg, 0.408 mmol) in the same manner as the synthesis of Example 1. LCMS: 778.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 11.12 (s, 1H), 9.34 (s, 1H), 9.02 (s, 2H), 8.19 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.82-7.76 (m, 2H), 7.10 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.14 (dd, J = 12.8, 5.2 Hz, 1H), 4.76 (d, J = 13.2Hz, 2H), 3.02-2.93 (m, 4H), 2.91-2.70 (m, 2H), 2.70-2.52 (m, 2H), 2.22 (d, J = 6.4 Hz, 2H), 2.07-2.01 (m, 3H), 1.94-1.88 (m, 3H), 1.87 (s, 3H), 1.79 (s, 3H), 1.78-1.71 (m, 4H), 1.11-1.08 (m, 2H). Example 54 [ka]

[0359] To a solution of compound 1-3 (150 mg, 0.438 mmol) in DMSO (4 mL), compound 54-1 (298.7 mg, 1.314 mmol) and titanium isopropoxide (248.8 mg, 0.876 mmol) were added at room temperature. The mixture was stirred at 0°C for 16 hours. NaBH3CN (27.6 mg, 0.438 mmol) was added to the mixture while stirring at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (40 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 54-2 (95 mg, 39.2%). LCMS: 554.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.69 (t, J = 11.2 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 3.94 (d, J = 10.7 Hz, 2H), 3.40 (t, J = 9.6 Hz, 4H), 2.96-2.80 (m, 1H), 2.67-2.61 (m, 4H), 2.59-2.52 (m, 1H), 2.44 (d, J = 5.2 Hz, 3H), 2.36-2.19 (m, 1H), 2.00 (dd, J = 16.9, 9.9 Hz, 2H), 1.63 (d, J = 11.4 Hz, 1H), 1.53-1.49 (m, 1H), 1.39 (s, 9H), 1.03-0.89 (m, 2H), 0.88 (d, J = 6.4 Hz, 3H).

[0360] Example 54 was synthesized from compound 54-2 (95 mg, 0.172 mmol) in the same manner as the synthesis of Example 1. LCMS: 793.3 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 11.08 (s, 1H), 9.34 (s, 1H), 9.01 (s, 2H), 8.07 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.07 (dd, J = 12.4, 5.4 Hz, 1H), 4.79-4.76 (m, 2H), 3.44 (s, 5H), 3.03-2.83 (m, 3H), 2.70-2.61 (m, 5H), 2.34-2.32 (m, 1H), 2.13 (d, J = 12.3 Hz, 1H), 2.04-2.02 (m, 1H), 1.87 (s, 3H), 1.79 (s, 3H), 1.78-1.72 (m, 2H), 1.13-1.10 (m, 2H), 0.93 (d, J = 6.4 Hz, 3H). Example 55 <\ [Chemical formula]

[0361] Compound 55-2 was prepared from Compound 1-1 (500 mg, 1.81 mmol) and Compound 55-1 (179.4 mg, 1.81 mmol) according to the general synthetic procedure A (150 mg, 23.3%). LCMS: 356.2 [M+H] + ; 1 It should be noted that in the original text, there is a misspelling in the tag "<\ ", which should be " ". This has been corrected in the translation.H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 5.08 (dd, J = 12.8, 5.2 Hz, 1H), 3.86 (t, J = 6.0 Hz, 4H), 2.95-2.82 (m, 1H), 2.65-2.52 (m, 2H), 2.48 (s, 4H), 2.04-1.99 (m, 1H).

[0362] Compound 55-4 was prepared in the same manner as the synthesis of D60-2, from compound 55-2 (110 mg, 0.31 mmol) and compound 55-3 (86.2 mg, 0.402 mmol) (30 mg, 17.5%). LCMS: 554.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.07-3.82 (m, 6H), 2.98 (t, J = 11.9 Hz, 2H), 2.83-2.67 (m, 6H), 2.13 (s, 3H), 1.78-1.73 (m, 4H), 1.66-1.62 (m, 2H), 1.55-1.47 (m, 2H), 1.39 (s, 9H).

[0363] Example 55 was synthesized from compound 55-4 (30 mg, 0.054 mmol) in the same manner as the synthesis of Example 1. LCMS: 793.6 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 11.08 (s, 1H), 9.36 (s, 1H), 9.02 (s, 2H), 8.07 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.78 (d, J = 13.2 Hz, 2H), 4.08 (d, J = 12.3 Hz, 2H), 3.00 (t, J = 12.6 Hz, 4H), 2.89-2.85 (m, 2H), 2.64-2.55 (m, 2H), 2.16 (s, 2H), 2.06-1.95 (m, 2H), 1.87 (s, 3H), 1.79 (s, 6H), 1.55-1.45 (m, 4H), 1.25-1.21 (m, 2H).

[0364] Examples 56-60 below were prepared using similar starting materials according to the method described in Example 28. [Table 7-1] [Table 7-2] Example 61 [ka]

[0365] A mixture of compound INT-2 (70 mg, 0.167 mmol), Pd(PPh3)2Cl2 (13.0 mg, 0.017 mmol), compound 61-1 (60.4 mg, 0.333 mmol), CuI (3.2 mg, 0.017 mmol), and TEA (50.6 mg, 0.500 mmol) in THF (1 mL) was stirred overnight at 50°C. The mixture was filtered and then concentrated. The residue was purified by silica gel column chromatography to obtain compound 61-2 (50 mg, 57.7%) as a yellow solid. LCMS: 562.4 [M+H+CH3CN] + .

[0366] Compound 61-3 was prepared from compound 61-2 (50 mg, 0.096 mmol) according to general synthesis procedure B. LCMS: 421.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.50 (s, 1H), 9.39 (s, 1H), 8.95 (s, 1H), 8.26 (s, 1H), 7.63-7.55 (m, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.29 (s, 2H), 4.24-4.21 (m, 1H), 4.09 (s, 2H), 1.87 (s, 3H), 1.80 (s, 3H), 1.73-1.57 (m, 1H).

[0367] Example 61 was prepared from compound 61-3 (50 mg, 0.119 mmol) and compound 61-4 (39.6 mg, 0.119 mmol) according to general synthesis procedure C. LCMS: 738.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 10.77 (s, 1H), 9.45-9.41 (m, 3H), 8.24 (s, 1H), 7.55 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 16.8, 8.8 Hz, 2H), 6.50 (dd, J = 15.0, 2.4 Hz, 1H), 6.45-6.36 (m, 1H), 5.78 (d, J = 7.6 Hz, 1H), 4.33-4.17 (m, 1H), 3.65-3.51 (m, 4H), 3.13-3.08 (m, 4H), 2.75-2.70 (m, 1H), 2.61-2.53 (m, 2H), 2.34 (d, J = 6.2 Hz, 2H), 2.12-2.05 (m, 1H), 1.88 (s, 3H), 1.87-1.82 (m, 1H), 1.80 (s, 3H), 1.75-1.71 (m, 2H), 1.30-1.24 (m, 3H). Example 62 [ka]

[0368] Compound 62-1 was synthesized from the corresponding starting materials according to the procedure described in Example 1.

[0369] To a solution of compound 62-1 (505.9 mg, 2.874 mmol) and compound 62-2 (120 mg, 0.287 mmol) in DMF (1 mL), DIEA (0.1 mL, 0.862 mmol) was added. The solution was stirred at 100°C for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain compound 62-3 (70 mg, 42.5%). LCMS: 575.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 9.2, 2.4 Hz, 1H), 6.84-6.79 (m, 2H), 6.50 (dd, J = 15.2, 2.4 Hz, 1H), 6.43-6.37 (m, 1H), 5.79 (d, J = 7.6 Hz, 1H), 4.28-4.20 (m, 2H), 2.85-2.74 (m, 6H), 2.72-2.64 (m, 1H), 2.59-2.54 (m, 2H), 2.48-2.43 (m, 2H), 2.37-2.33 (m, 2H), 2.12-2.04 (m, 1H), 1.86-1.82 (m, 1H), 1.72 (d, J = 12.0 Hz, 2H), 1.57-1.55 (m, 1H), 1.40-1.38 (m, 2H), 1.23-1.09 (m, 2H).

[0370] To a solution of compound 62-3 (50 mg, 0.087 mmol) and B2pin2 (44.3 mg, 0.174 mmol) in dioxane (2 mL), AcOK (25.6 mg, 0.262 mmol) and Pd(dppf)Cl2 (6.4 mg, 0.009 mmol) were added. The solution was stirred at 90°C for 3 hours. The reaction mixture was filtered and concentrated to dryness. The residue was purified by preparative HPLC to obtain compound 62-4. LCMS: 539.2 [M+H] + .

[0371] Example 62 was prepared from compound 62-4 (59.0 mg, 0.11 mmol) and compound INT-1 (25 mg, 0.073 mmol) according to general synthesis procedure D. LCMS: 756.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.77 (s, 1H), 9.36 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 8.21-8.09 (m, 1H), 8.03 (s, 1H), 7.02-6.97 (m, 3H), 6.82 (t, J = 8.0 Hz, 2H), 6.54-6.47 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.80 (d, J = 7.8 Hz, 1H), 4.42 (d, J = 12.8 Hz, 2H), 4.26-4.23 (m, 1H), 2.94-2.84 (m, 6H), 2.78-2.65 (m, 2H), 2.58 (d, J = 4.0 Hz, 4H), 2.38 (t, J = 7.2 Hz, 2H), 2.11-2.08 (m, 1H), 1.87 (s, 3H), 1.80 (s, 2H), 1.79 (s, 3H), 1.77-1.75 (m, 1H), 1.63-1.61 (m, 1H), 1.43-1.41 (m, 2H), 1.18-1.12 (m, 2H). Example 63 [ka]

[0372] To a solution of INT-3 (500 mg, 0.694 mmol) in toluene (10 mL), 63-M1 (167 mg, 0.694 mmol), Pd(PPh3)4 (80 mg, 0.069 mmol), and copper(I) iodide (26.4 mg, 0.139 mmol) were added. The mixture was stirred under N2 at 120°C for 3 hours. The mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (elution with ELISA from 0 to 20% in petroleum ether) to obtain 63-1 (150 mg, 40% yield) as a yellow solid. LCMS: 544.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H), 2.40 (s, 3H), 1.87 (s, 3H), 1.78 (s, 3H).

[0373] Compound 63-2 was prepared using similar starting materials according to the method for the synthesis of INT-1. LCMS: 417.2 [M+CH3CN+H] + .

[0374] Compound 63-2 (23 mg, 0.061 mmol) and DIPEA (39.5 mg, 0.306 mmol) were added to a solution of 63M2 (40.9 mg, 0.092 mmol) in DMSO (0.5 mL). The mixture was stirred under N2 at 100°C for 16 hours. The mixture was filtered and purified by preparative HPLC to obtain Example 63 (1.84 mg, 4% yield). LCMS: 785.6[M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 10.78 (s, 1H), 9.35 (s, 1H), 8.18 (d, J = 9.6 Hz, 1H), 8.13 (s, 1H), 7.46 (d, J = 9.7 Hz, 1H), 7.31 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 6.54 - 6.41 (m, 2H), 5.78 (d, J = 19.5 Hz, 1H), 4.26 (s, 1H), 3.99 (s, 2H), 3.64 (s, 2H), 3.26 - 3.23 (m, 2H), 2.94 (s, 2H), 2.86 (s, 4H), 2.67 (s, 2H), 2.55 (s, 4H), 2.33 (s, 1H), 2.07 (s, 2H), 1.88 (s, 3H), 1.80 (s, 3H), 1.74 (s, 2H), 1.69 - 1.63 (m, 2H).

[0375] Examples 64 to 128 below were prepared using similar starting materials according to the method described above. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13] [Table 8-14] [Table 8-15] [Table 8-16] [Table 8-17] [Table 8-18] Examples 135, 136, 137, and 138 [ka]

[0376] Compound 56-2 (6.37 g, 33.2 mmol) and sodium bicarbonate (4.18 g, 49.8 mmol) were added to a solution of compound 56-1 (4.9 g, 16.59 mmol) in DMF (30 mL). The mixture was stirred under N2 at 65°C for 16 hours. The reaction mixture was diluted with water (40 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (elution with MeOH from 0 to 8% in DCM) to obtain the product (5.3 g, 79% yield) as a white solid. The products were separated by SFC (column: Daicel CHIRALCEL AD, 250*30mm*10μm; conditions: 50% MeOH with 50% CO2 (+0.1% 7.0 mol / L ammonia in MeOH); wavelength: 214 nm; flow rate: 140 mL / min; column temperature: 35°C; back pressure: 100 bar) to obtain compound 56-3-M1 (short retention time) and compound 56-3-M2 (long retention time).

[0377] 56-3-M1: LCMS: 407.2 [M+H] + ; 1 H NMR: (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.89 (s, 1H), 6.47 - 6.38 (m, 2H), 4.01 (dd, J = 12.5, 4.8 Hz, 1H), 3.60 (s, 4H), 3.00 - 2.84 (m, 5H), 2.79 - 2.65 (m, 1H), 2.57 - 2.43 (m, 1H), 1.97 - 1.84 (m, 1H), 1.48 (s, 9H).

[0378] 56-3-M2: LCMS: 407.2 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 6.90 - 6.79 (m, 1H), 6.52(dd, J = 16.0, 4.0 Hz, 1H), 6.42 (dd, J = 8.0, 4.0 Hz, 1H), 5.85 (d, J = 7.4 Hz, 1H), 4.25 (s, 1H), 3.43 (s, 4H), 2.82 - 2.75 (m, 4H), 2.79 - 2.66 (m, 1H), 2.62 - 2.55 (m, 1H), 2.12 - 2.03 (m, 1H), 1.92 - 1.78 (m, 1H), 1.41 (s, 9H).

[0379] To a solution of compound 56-3-M1 (65 mg, 0.160 mmol) in DCM (1 mL), HCl / dioxane (4.0 M, 1 mL) was added. The mixture was stirred for 1 hour. The mixture was concentrated to obtain compound 56-4-M1 (42.9 mg, 87% yield) as a gray solid. LCMS: 307.1 [M+H] + ; 1 H NMR: (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.50 (s, 2H), 7.01 - 6.91 (m, 1H), 6.68 - 6.50 (m, 1H), 4.34 (dd, J = 11.5, 4.8 Hz, 1H), 3.20 - 3.01 (m, 8H), 2.84 - 2.72 (m, 1H), 2.64 - 2.54 (m, 1H), 2.12 - 2.03 (m, 1H), 1.93 - 1.82 (m, 1H).

[0380] To a solution of compound 56-4-M1 (500 mg, 1.632 mmol) and compound 56-5 (833 mg, 3.26 mmol) in DMF (5 mL), sodium triacetoxyborohydride (1038 mg, 4.90 mmol) was added. The mixture was stirred for 2 hours. The reaction mixture was diluted with water (40 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (elution with MeOH from 0 to 8% in DCM) to obtain the product. The products were separated by SFC (column: Daicel CHIRALCEL OD, 250*25mm*10μm; conditions: 55% MeOH with 45% CO2 (+0.1% 7.0 mol / L ammonia in MeOH); wavelength: 214 nm; flow rate: 140 mL / min; column temperature: 35°C; back pressure: 100 bar) to obtain compound 56-6-M1P1 (short retention time) and compound 56-6-M1P2 (long retention time) as gray solids.

[0381] 56-6-M1P1:LCMS: 546.4 [M+H] + .

[0382] 56-6-M1P2:LCMS: 546.5 [M+H] + .

[0383] Compound 56-4-M2 was used with a similar protocol and chiral SFC (column: Daicel CHIRALCEL OD, 250*25mm*10μm; conditions: 55% MeOH with 45% CO2 (+0.1% 7.0 mol / L ammonia in MeOH); wavelength: 214 nm; flow rate: 140 mL / min; column temperature: 35°C; back pressure: 100 bar) to obtain compound 56-6-M2P1 (short retention time) and compound 56-6-M2P2 (long retention time).

[0384] 56-6-M2P1: LCMS: 546.4 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 6.84 - 6.78 (m, 1H), 6.50 (dd, J = 15.0, 2.5 Hz, 1H), 6.41 (dd, J = 8.7, 2.4 Hz, 1H), 5.80 (d, J = 7.7 Hz, 1H), 4.28 - 4.22 (m, 1H), 3.92 (dd, J = 8.3, 6.8 Hz, 1H), 3.57 - 3.54 (m, 1H), 3.43 - 3.40 (m, 2H), 3.23 (s, 2H), 2.98 - 2.90 (m, 1H), 2.84 (s, 4H), 2.77 - 2.67 (m, 1H), 2.60 - 2.53 (m, 2H), 2.43 (s, 2H), 2.12 - 2.05 (m, 1H), 2.02 - 1.96 (m, 1H), 1.86 - 1.82 (m, 1H), 1.58 - 1.53 (m, 4H), 1.43 (s, 2H), 1.38 (s, 9H)。

[0385] 56-6-M2P2: LCMS: 546.4 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 6.84 - 6.78 (m, 1H), 6.50 (dd, J = 15.0, 2.5 Hz, 1H), 6.41 (dd, J = 8.6, 2.4 Hz, 1H), 5.80 (d, J = 7.7 Hz, 1H), 4.29 - 4.21 (m, 1H), 3.92 (dd, J = 8.3, 6.7 Hz, 1H), 3.56 (dd, J = 14.0, 5.9 Hz, 1H), 3.43 (d, J = 13.1 Hz, 2H), 3.22 (s, 2H), 2.99 - 2.90 (m, 1H), 2.84 (s, 4H), 2.77 - 2.67 (m, 1H), 2.60 - 2.53 (m, 2H), 2.43 (s, 2H), 2.12 - 2.04 (m, 1H), 1.99 (dd, J = 12.3, 7.8 Hz, 1H), 1.89 - 1.80 (m, 1H), 1.55 (dd, J = 10.0, 4.5 Hz, 3H), 1.52 - 1.48 (m, 1H), 1.47 - 1.40 (m, 2H), 1.39 (s, 9H).

[0386] A solution of compound 56-6-M1P1 (220 mg, 0.403 mmol) in DCM (3 mL) and TFA (3 mL) was stirred for 1 hour. The mixture was concentrated to obtain compound 56-7-M1P1. LCMS: 446.3 [M+H] + .

[0387] A mixture of compound 56-7-M1P1 (100 mg, 0.238 mmol) and compound INT-2 (170 mg, 0.381 mmol) in DMSO (1.5 mL) was added to DIPEA (0.208 mL, 1.190 mmol). The mixture was stirred at 100°C for 1 hour. The mixture was filtered and purified by preparative HPLC to obtain Example 135. LCMS: 785.7 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.77 (s, 1H), 9.33 (s, 1H), 9.02 (s, 2H), 8.07 (s, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.82 (t, J = 9.2 Hz, 2H), 6.57 - 6.39 (m, 2H), 5.81 (d, J = 7.6 Hz, 1H), 4.26 (t, J = 12.0 Hz, 1H), 4.12 (d, J = 13.1 Hz, 2H), 4.04 - 3.95 (m, 1H), 3.69 - 3.58 (m, 3H), 3.07 - 3.00 (m, 1H), 2.89 - 2.73 (m, 4H), 2.79 - 2.66 (m, 2H), 2.58 (d, J = 4.3 Hz, 2H), 2.54 (s, 2H), 2.13 - 2.03 (m, 2H), 1.99 - 1.82 (m, 5H), 1.79 (s, 3H), 1.70 (s, 2H), 1.66 - 1.59 (m, 2H).

[0388] Examples 136-138 were prepared from the corresponding chiral intermediates.

[0389] 136 (prepared from 56-7-M1P2): LCMS: 785.7 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.79 (s, 1H), 9.34 (s, 1H), 9.03 (s, 2H), 8.08 (s, 1H), 7.12 (s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.53 - 6.43 (m, 2H), 5.92 - 5.85 (m, 1H), 4.28 (s, 1H), 4.19 - 4.11 (m, 4H), 3.66 (d, J = 8.3 Hz, 2H), 3.49 (s, 1H), 2.97 - 2.91 (m, 4H), 2.78 - 2.52 (m, 4H), 2.33 (s, 2H), 2.12 - 1.97 (m, 2H), 1.89 - 1.82 (m, 5H), 1.79 (s, 3H), 1.69 - 1.61 (m, 4H).

[0390] 137(56-7-M2P1からmodulationした): LCMS: 785.7 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.77 (s, 1H), 9.33 (s, 1H), 9.02 (s, 2H), 8.17 (s, 1H), 8.07 (s, 1H), 7.10 (d, J = 1.4 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.87 - 6.77 (m, 2H), 6.53 - 6.46 (m, 1H), 6.42 (d, J = 8.3 Hz, 1H), 5.81 (d, J = 7.4 Hz, 1H), 4.29 - 4.21 (m, 1H), 4.12 (d, J = 13.1 Hz, 2H), 4.02 - 3.95 (m, 1H), 3.71 - 3.60 (m, 3H), 3.06 - 2.96 (m, 1H), 2.86 (s, 4H), 2.78 - 2.67 (m, 1H), 2.61 - 2.53 (m, 3H), 2.48 - 2.41 (m, 2H), 2.12 - 2.02 (m, 2H), 1.87 (s, 3H), 1.83 (d, J = 4.4 Hz, 1H), 1.79 (s, 3H), 1.68 - 1.62 (m, 5H).

[0391] 138(56-7-M2P2からmodulationした): LCMS: 785.4 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.78 (s, 1H), 9.33 (s, 1H), 9.03 (s, 2H), 8.07 (s, 1H), 7.10 (d, J = 1.9 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.83 (t, J = 8.3 Hz, 2H), 6.51 - 6.42 (m, 2H), 5.82 (d, J = 6.9 Hz, 1H), 4.29 - 4.21 (m, 1H), 4.12 (d, J = 13.3 Hz, 2H), 4.00 (s, 1H), 3.73 - 3.60 (m, 3H), 3.02 (s, 1H), 2.87 (s, 4H), 2.77 - 2.67 (m, 1H), 2.61 - 2.51 (m, 5H), 2.14 - 2.01 (m, 2H), 1.90 - 1.82 (m, 4H), 1.79 (s, 3H), 1.68 - 1.60 (m, 5H). Examples 139 and 140 [ka]

[0392] A mixture of compound 56-4-M1 (2 g, 6.53 mmol) and tert-butylmethyl (3-oxocyclobutyl) carbamate (1.95 g, 9.79 mmol) in DMF (20 mL) was added to sodium triacetoxyborohydride (4.15 g, 19.59 mmol). The mixture was stirred for 2 hours, diluted with water (30 mL), and adjusted to pH ~8 with saturated NaHCO3 solution. The solution was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with MeOH from 0 to 10% in DCM) to obtain compound 131-1-M1 as a green solid. LCMS: 490.4 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 6.87 - 6.77 (m, 1H), 6.46 (ddd, J = 11.9, 11.0, 2.4 Hz, 2H), 5.80 (d, J = 7.7 Hz, 1H), 4.32 - 3.84 (m, 2H), 3.50 - 3.37 (m, 1H), 2.84 (s, 4H), 2.78 - 2.68 (m, 4H), 2.57 (dt, J = 17.5, 4.1 Hz, 1H), 2.47 - 2.14 (m, 7H), 2.13 - 2.02 (m, 1H), 1.92 - 1.77 (m, 3H), 1.37 (s, 9H).

[0393] To a solution of compound 131-1-M1 (1.5 g, 3.06 mmol) in DCM (20 mL), HCl / dioxane (4.0 M, 20 mL) was added. The mixture was stirred for 1 hour. The mixture was concentrated to obtain compound 131-2-M1 as a green solid. LCMS: 390.3 [M+H] + ; 1 H NMR: (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.81 (s, 1H), 9.59 (s, 2H), 6.94 - 6.88 (m, 2H), 6.61 (dd, J = 14.8, 2.4 Hz, 1H), 6.52 (dd, J = 8.7, 2.2 Hz, 1H), 4.32 (dd, J = 11.5, 4.8 Hz, 1H), 3.74 - 3.61 (m, 1H), 3.56 - 3.43 (m, 3H), 3.29 (d, J = 11.3 Hz, 2H), 3.22 - 2.98 (m, 4H), 2.81 - 2.70 (m, 3H), 2.65 - 2.54 (m, 3H), 2.51 (s, 1H), 2.49 (d, J = 5.4 Hz, 2H), 2.14 - 2.01 (m, 1H), 1.89 (dt, J = 12.3, 3.9 Hz, 1H).

[0394] A mixture of compound 131-2-M1 (500 mg, 1.190 mmol) and compound INT-2 (602 mg, 1.547 mmol) in DMSO (10 mL) was added to DIPEA (2.078 mL, 11.90 mmol). The mixture was stirred at 100°C for 1 hour. The mixture was diluted with water (50 mL) and extracted with dimethyl phosphate (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with MeOH from 0 to 10% in DCM) to obtain the product. The products were separated by chiral chromatography (column: Daicel CHIRALPAK IE, 250*25mm*10m; conditions: 50% EtOH (+0.1% 7.0 mol / L ammonia in MeOH) with 50% ACN; wavelength: 254 nm; flow rate: 50 mL / min; column temperature: 35°C) to obtain Example 139 (short retention time) and Example 140 (long retention time).

[0395] 139: LCMS: 729.2 [M+H] + ; 1 H NMR: (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.78 (s, 1H), 9.34 (s, 1H), 9.04 (s, 2H), 8.08 (s, 1H), 7.11 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.89 - 6.80 (m, 2H), 6.52 (d, J = 16.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.81 (d, J = 7.6 Hz, 1H), 5.02 - 4.89 (m, 1H), 4.27 (t, J = 4.0 Hz, 1H), 3.15 (s, 3H), 2.88 (s, 4H), 2.79 - 2.71 (m, 1H), 2.62 - 2.53 (m, 3H), 2.47 - 2.35 (m, 5H), 2.12 - 2.00 (m, 3H), 1.91 - 1.83 (m, 4H), 1.80 (s, 3H).

[0396] 140: LCMS: 729.4 [M+H] + ; 1 H NMR: (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.78 (s, 1H), 9.34 (s, 1H), 9.04 (s, 2H), 8.08 (s, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.90 - 6.81 (m, 2H), 6.53 (d, J = 15.1 Hz, 1H), 6.45 (d, J = 8.7 Hz, 1H), 5.84 (d, J = 7.4 Hz, 1H), 5.49 - 5.33 (m, 1H), 4.32 - 4.22 (m, 1H), 3.21 (s, 3H), 3.01 - 2.90 (m, 5H), 2.80 - 2.53 (m, 6H), 2.33 (s, 4H), 2.13 - 2.06 (m, 1H), 1.90 - 1.83 (m, 4H), 1.79 (s, 3H). Biological assays Assay A: PKMYT1 HTRF assay

[0397] Serial dilutions of the compound were performed using Echo, and the final concentration varied from 10 μM to 0.5 nM. This was then packed into assay plates containing the compound by adding 5 μL / well of the enzyme solution. The plates were centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 15 minutes. Next, 5 μL / well of the tracer solution (tracer 178) was added to initiate the reaction, and the plates were incubated at 25°C for 60 minutes. Then, 5 μL of GST-Tb was added to the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 15 minutes. The assay plates were read using Envision. Assay B: WEE1 ADP-Glo ​​Assay

[0398] Serial dilutions of the compound were performed by Echo, with final concentrations ranging from 10 μM to 0.5 nM. These were then packed into assay plates containing the compound by adding 5 μL / well of enzyme solution. The plates were centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 15 minutes. Next, 5 μL / well of substrate solution was added to initiate the reaction, and the plates were incubated at 25°C for 60 minutes. Then, 10 μL of kinase detection reagent was added to the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. The assay plates were read by Envision for US LUM as RLU. Assay C: MYT1 degradation in HCC1569 cells

[0399] HCC1569 cells were seeded in 6-well microplates and cultured overnight at 37°C in a cell incubator. The compound was added to the cell plate at the indicated concentration and cultured for 24 hours. Next, the cells were collected and lysed with cell lysis buffer (Thermo, FNN0011). The protein concentration of the lysate was measured by BCA assay (Beyotime, P0012) and then subjected to a Western blot assay. The primary antibodies were PKMYT1 (CST, 4282S) and Phospho-CDK1 (Thr14) (Abcam, ab58509), and the internal standard was GAPDH (Merck, MAB374) or Vinculin (CST, 13901). The grayscale values ​​of the WB bands were quantified using analytical software included in the imaging system. The residual % for each group was calculated using the mean value of the DMSO group as 100%. Activation % = Average of sample / DMSO * 100. Assay D: In-cell Western assay for pCDK1 in HCC1569 cells

[0400] HCC1569 cells were seeded at 6000 cells / well in a 384-well plate and incubated overnight at 37°C in 5% CO2. The following day, 40 nL of serially diluted compound (ultimately 0.1% DMSO) was added to the plate using an Echo 655 and incubated in an incubator for 6 hours. Next, the cells were fixed with 40 μL of 8% fixative at room temperature for 20 minutes. After two washes with PBS, the cells were permeabilized with 40 μL of methanol at room temperature for 10 minutes. 20 μL of Li-Cor blocking buffer was added to each well and incubated at room temperature for 1 hour. Next, blocking buffer containing the primary antibody, anti-CDK1 phospho T14 (ab58509), and anti-GAPDH (CST# 97166) was added to the plate and incubated overnight at 4°C. The following day, the plate was washed three times with PBST. Next, blocking buffer containing secondary antibodies, IRDye 800CW goat anti-rabbit IgG (H+L) and RDye 680RD goat anti-mouse IgG (H+L), was added to the wells, and the plates were incubated in the dark at room temperature for 1 hour. After washing three times with PBST, the plates were scanned with an Odyssey CLx. Assay E: HCC1569 Growth Assay

[0401] HCC1569 cells were seeded at 2000 cells / well in a 96-well plate and incubated overnight at 37°C and 5% CO2. The following day, 1 μL of serially diluted compound (ultimately 0.3% DMSO) was added to the plate using an Echo655 and incubated in an incubator for 7 days. On day 7, the plate was removed from the incubator and allowed to return to room temperature. 60 μL of CellCounting-lite reagent was added to each well and incubated in the dark at room temperature for 30 minutes. The luminescence signal was read using a BMG plate reader. In vivo efficacy study in assay F:CDX model

[0402] All animal experiment procedures were carried out in accordance with AAALAC guidelines and IACUC rules. Female BAlb / c nude mice were acclimatized for approximately one week prior to use. Human cancer cell lines, such as HCC1569, Ovcar3, HCC1599, HUCCT1, SW1573, MDA-MB-157, Ovcar8, HCC1806, MKN7, MKN1, and SW837, were transplanted subcutaneously into the right flank of the animals at a rate of 1 to 10 million cells (n=5-6 per group). The average tumor size was 100-200 mm. 3 Treatment was initiated when the tumor volume reached a certain level. Mice were assigned to groups so that the average tumor volume was equal for each treatment group and time point. The compound was weighed and dissolved in the formulation so that it was a clear solution before use. Tumor size was measured twice a week using calipers, and tumor volume (mm²) was measured. 3 ) is given by the formula: TV = a × b 2 The TGI was estimated using the formula: / 2{where a and b are the long and short diameters of the tumor}. TV was limited to the duration of medication, formula: TGI(%)=[1-(T n -T0) / (C n This was used to calculate the tumor growth inhibition (TGI) value using -C0) × 100% (from day 0 to day n of medication).

[0403] Table 3 shows the data for the exemplary compounds provided herein in assays A, B, C, and D. Table 3 [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] MYT1 HTRF IC 50(nM):0 <A≦10;10<B≦50;50<C≦500;500<D≦5000;5000<E; WEE1 ADP-Glo ​​IC 50 (nM):0 <A≦10;10<B≦50;50<C≦500;500<D≦5000;5000<E; MYT1 DC 50 (nM): A≦1;1 <B≦10;10<C≦50;50<D≦500;500<E≦1000;1000<F; pCDK1 Internal 50 (nM):0 <A≦10;10<B≦50;50<C≦500;500<D≦1000;1000<E; NT: Not tested.

[0404] The above description is intended solely to illustrate the principles of this disclosure. Furthermore, since numerous modifications and variations are readily apparent to those skilled in the art, it is undesirable to limit the present invention to the specific configurations and processes described above. Accordingly, all suitable modifications and equivalents can be considered to fall within the scope of the present invention as defined by the following claims.

Claims

1. The following chemical structure: 【Chemistry 1】 {During the ceremony, PTM is a small molecule containing a PKMYT1 protein targeting moiety; ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase; and L is the bond or chemical linkage that connects ULM and PTM. A bifunctional compound having, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The aforementioned bifunctional compound is one of the following formulas: (I''), (II''), (III''), (IV''), (V''), (VI''), (VII''), (VIII''), (X''), (XI''), or (XII''): 【Chemistry 2】 {During the ceremony, Q is either N or CRQ; R Ｑ is H, OH, or NH ２ is; or R Ｑ and R ３ These, together with the atoms to which they are bonded, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more R atoms; or R Ｑ and R ６ These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted with one or more R atoms; Ring A is either absent, or is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Each R １ is, independently, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O)[[ID=ID=19]] ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ , -NR ｃ C(=O)NR ｄ R ｂ , -NR ａ C(=O)R ｂ , -NR ｂ C(=O)OR ｂ , -NR ２ S(=O) ａ R ａ , -C(=O)R ｂ , -C(=O)OR ｃ , -C(=O)NR ｄ R １ , C ６ -C １ -C ６ haloalkyl, C １ , -C ６ hydroxyalkyl, C １ , -C ６ aminoalkyl, C １ , -C ６ , -C ２ , -C ６ alkenyl, C ２ , -C ６ )]]alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is, independently, optionally, substituted with one or more R １ａ )]]; or Two R atoms on the same atom １ They combine to form an oxo; Each R １ａ is independently halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ , -NR<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ Two Rs on the same atom １ａ combine to form an oxo; n is an integer between 0 and 6; R2 is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ It is heteroalkyl, cycloalkyl, or heterocycloalkyl; Each of W is independently N or CR Ｗ And; W １ Each of these independently is N or CR Ｗ And; W ２ Each of these independently is N or CR Ｗ And; W ３ Each of these is independent of NR Ｗ or C(R Ｗ ) ２ And; W ４ Each of these independently is N or CR Ｗ And; R Ｗ Each of these independently consists of hydrogen, halogen, -CN, -OH, and -OR. ａ ,-SR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; X is N or CR Ｘ And; R Ｘ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Y is N or CR Ｙ And; R Ｙ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Z is N or CR Ｚ And; R Ｚ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; E is N or CR Ｅ And; R Ｅ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; G is NR Ｇ or C(R Ｇ ) ２ And; R Ｇ Each of these independently consists of hydrogen, halogen, -CN, -OH, and -OR. ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; R ３ is hydrogen, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ It is a heteroalkyl, cycloalkyl, or heterocycloalkyl; where each C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more R groups; R ４ is hydrogen, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ It is a heteroalkyl, cycloalkyl, or heterocycloalkyl; where each C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more R groups; R ５ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, or heterocycloalkyl; where each C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, cycloalkyl, or heterocycloalkyl groups are optionally substituted with one or more R groups; R ６ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, or heterocycloalkyl; where each C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, cycloalkyl, or heterocycloalkyl groups are optionally substituted with one or more R groups; Each R ａ These are, independently, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Alkyl (heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Two R's ａ These, together with the atoms to which they are bonded, form a heterocycloalkyl group that is optionally substituted with one or more R atoms; Each R ｂ These are, independently, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Alkyl (heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Two R's ｂ These, together with the atoms to which they are bonded, form a heterocycloalkyl group that is optionally substituted with one or more R atoms; R ｃ and R ｄ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Alkyl (heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or R ｃ and R ｄ These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R atoms; and Each R is independently halogen, -CN, -OH, and -S(=O)CH ３ , -S (=O) ２ CH ３ , -S (=O) ２ NH ２ , -S (=O) ２ NHCH ３ , -S (=O) ２ N(CH ３ ) ２ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)NH ２ , -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Haloalkylidenyl, C ３ -C ６ It is cycloalkyl or heterocycloalkyl; or Two R atoms on the same atom form an oxo. A bifunctional compound as described in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The PTM is defined by the following formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (X), (XI), or (XII): 【Transformation 3】 {During the ceremony, Ring A is either absent, or is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Each R １ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally one or more R １ａ It is replaced by; or Two R atoms on the same atom １ They combine to form an oxo; Each R １ａ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Two R atoms on the same atom １ａ They combine to form an oxo; n is an integer between 0 and 6; R2 is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ It is heteroalkyl, cycloalkyl, or heterocycloalkyl; Each of W is independently N or CR Ｗ And; W １ Each of these independently is N or CR Ｗ And; W ２ Each of these independently is N or CR Ｗ And; W ３ Each of these is independent of NR Ｗ or C(R Ｗ ) ２ And; W ４ Each of these independently is N or CR Ｗ And; R Ｗ Each of these independently consists of hydrogen, halogen, -CN, -OH, and -OR. ａ ,-SR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; X is N or CR Ｘ And; R Ｘ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Y is N or CR Ｙ And; R Ｙ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Z is N or CR Ｚ And; R Ｚ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; E is N or CR Ｅ And; R Ｅ These are hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; G is NR Ｇ or C(R Ｇ ) ２ And; R Ｇ Each of these independently consists of hydrogen, halogen, -CN, -OH, and -OR. ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ The elements are alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; R ３ is halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl, cycloalkyl, or heterocycloalkyl; R ４ is halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl, cycloalkyl, or heterocycloalkyl; R ５ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ It is an alkynyl, cycloalkyl, or heterocycloalkyl; R ６ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ It is an alkynyl, cycloalkyl, or heterocycloalkyl; Each R ａ These are, independently, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Alkyl (heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Two R's ａ These, together with the atoms to which they are bonded, form a heterocycloalkyl group that is optionally substituted with one or more R atoms; Each R ｂ These are, independently, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Alkyl (heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Two R's ｂ These, together with the atoms to which they are bonded, form a heterocycloalkyl group that is optionally substituted with one or more R atoms; R ｃ and R ｄ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Alkyl (heteroaryl); where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or R ｃ and R ｄ These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R atoms; and Each R is independently halogen, -CN, -OH, -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N(CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)NH ２ , -C(=O)OCH ３ , C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ３ -C ６ cycloalkyl, or heterocycloalkyl; or Two R atoms on the same atom form an oxo. A bifunctional compound as described in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The PTM is the following formula (Ia), (Iaa), (IIa), (IIaa), (IIIa), (IIIaa), (IVa), (IVaa), (Va), (Vaa), (VIa), or (VIaa): 【Chemistry 4】 The difunctional compound described in claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The PTM is defined by the following formulas: (Ib), (Ibb), (IIb), (IIbb), (IIIb), (IIIbb), (IVb), (IVbb), (Vb), or (Vbb): 【Transformation 5】 The difunctional compound described in claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The PTM is defined by the following formulas: (Ic), (Icc), (IIc), (IIcc), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IVc), (IVcc), (Vc), or (Vcc): 【Transformation 6】 The difunctional compound described in claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. Said R ３ is halogen, C １ -C ６ alkyl, or C １ -C ６ haloalkyl, the bifunctional compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The aforementioned R ４ However, halogen, C １ -C ６ Alkyl, or C １ -C ６ A difunctional compound according to any one of claims 2 to 7, which is a haloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The aforementioned R ５ The difunctional compound according to any one of claims 2 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is hydrogen.

10. The aforementioned R ６ The difunctional compound according to any one of claims 2 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is hydrogen.

11. The aforementioned R ２ However, hydrogen or C １ -C ６ A difunctional compound according to any one of claims 2 to 10, which is alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

12. The aforementioned R Ｘ However, hydrogen, halogen, -CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy or C １ -C ６ A difunctional compound according to any one of claims 2 to 11, which is a haloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

13. The aforementioned R Ｙ However, hydrogen, halogen, C １ -C ６ Alkyl, or C １ -C ６ A difunctional compound according to any one of claims 2 to 12, which is a haloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. The aforementioned R Ｚ However, hydrogen, halogen, or C １ -C ６ A difunctional compound according to any one of claims 2 to 13, which is alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The aforementioned R Ｗ However, hydrogen, halogen, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ A difunctional compound according to any one of claims 2 to 14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R.

16. The aforementioned R Ｇ However, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C ３ -C ６ A cycloalkyl, difunctional compound according to any one of claims 2 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof.

17. A bifunctional compound according to any one of claims 2 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the aforementioned ring A is absent.

18. A difunctional compound according to any one of claims 2 to 16, wherein ring A is a 5- or 6-membered heterocycloalkyl group, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. The aforementioned ring A is 【Transformation 7】 A bifunctional compound according to any one of claims 2 to 16 or 18, or a pharmaceutically acceptable salt or stereoisomer thereof.

20. A difunctional compound according to any one of claims 2 to 16, wherein ring A is a 5- or 12-membered heteroaryl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

21. The aforementioned ring A is 【Transformation 8】 A bifunctional compound according to any one of claims 2 to 16 or 20, or a pharmaceutically acceptable salt or stereoisomer thereof.

22. Each of the foregoing Rs １ is, independently, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is, independently, optionally, substituted with one or more Rs １ａ ; a bifunctional compound according to any one of claims 2 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof.

23. Each of the aforementioned R １ａ However, independently, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ The elements are haloalkyl, cycloalkyl, or heterocycloalkyl; where each alkyl, cycloalkyl, or heterocycloalkyl is independently and optionally selected to have one or more R １ A bifunctional compound according to any one of claims 2 to 22, or a pharmaceutically acceptable salt or stereoisomer thereof, substituted with.

24. A bifunctional compound according to any one of claims 2 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0, 1, or 2.

25. The aforementioned PTM is as follows: 【Chemistry 9-1】 【Chemistry 9-2】 A bifunctional compound according to any one of claims 2 to 24, selected from the group consisting of the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

26. A bifunctional compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the ULM is selected from the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse double microchromosome homolog 2 (MLM), and IAP E3 ubiquitin ligase binding moiety (ILM).

27. The aforementioned ULM is given by the following equations (1) to (20): 【Chemistry 10】 {During the ceremony, Each J １ , U １ , V １ , W １ , X １ , U ２ , V ２ , W ２ , X １ and X ２ CR is independent ２１ or selected from N; Y １ -N-, -NR ３１ , -O-, -C(=O)-, -CR ３１ R ４１ -, -N = CR ３１ - and -N=N- are selected; Z １ It does not exist, or -C(=O)-, -NR ３１ , -O-, C １ -C １０ Alkyl, C ２ -C １０ Alkenil, C ２ -C １０ Selected from alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R'; R Ｌ -NR ３１ , -N(R ３１ )C(=O)-, -C(=O)N(R ３１ )-, -OC(=O)-, -C(=O)O-, or -N(R ３１ ) Selected from S (=O); Each R １１ , R ３１ , and R ４１ R' is independently selected from hydrogen, alkyl, cycloalkyl or heterocycloalkyl, where each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with R' or R ３１ and R ４１ These, together with the atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups; Each R ２１ These are independently hydrogen, halogen, CN, NO ２ Selected from OH, alkyl, cycloalkyl or heterocycloalkyl, where each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with R'; Each R １２ , R ２２ , R １３ , R ２３ , R ５３ , R １４ , R ２４ , R ３４ , R １５ , R ２５ , and R ３５ These are independently hydrogen, halogen, -CN, and -NO ２ Selected from -OH, amino, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, alkenyl, alkynylcycloalkyl, and heterocycloalkyl is independently and optionally substituted with R'; R ３２ and R ３３ These are hydrogen, -OH, -C(=O)R'', -C(=O)OR'', and -C(O)N(R''), respectively. ２ , -P(O)(OR'') ２ Selected from; R ４３ is N(R''') ２ Selected from alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with R'; R ４５ and R ５５ These are, independently, hydrogen, -C(=O)R'', -C(=O)OR'', and -C(O)N(R''). ２ , -S(=O)R'', -S(=O) ２ R'', -S (=O) ２ N(R'') ２ Selected from alkyl, alkoxyalkyl, alkylaminoalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; Each R' is either absent, halogen, -CN, or -NO. ２ Selected from -OH, amino, alkyl, alkoxyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl or heterocycloalkyl, or The two R' atoms, together with the atom they bond to, form a cycloalkyl or heterocycloalkyl group; Each R'' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or The two R'' atoms, together with the atom to which they are bonded, form a cycloalkyl or heterocycloalkyl group; and Each R''' is independently selected from hydrogen, alkyl, -C(=O)R'', cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. A bifunctional compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or stereoisomer thereof.

28. The aforementioned ULM is as follows: 【Chemistry 11】 A bifunctional compound according to any one of claims 1 to 27, selected from the group consisting of the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

29. The aforementioned ULM is as follows: 【Chemistry 12】 A bifunctional compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof.

30. The aforementioned ULM is as follows: 【Chemistry 13】 A bifunctional compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof.

31. The aforementioned ULM is as follows: 【Chemistry 14】 A bifunctional compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof.

32. The aforementioned ULM is as follows: 【Chemistry 15】 A bifunctional compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof.

33. The aforementioned ULM is as follows: 【Chemistry 16】 A bifunctional compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof.

34. The aforementioned ULM is as follows: 【Chemistry 17】 A bifunctional compound according to any one of claims 1 to 27, selected from the group consisting of the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

35. The aforementioned ULM is as follows: [Chemistry 18] A bifunctional compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof.

36. The above L is given by the following formula (L): 【Chemistry 19】 {During the ceremony, A Ｌ , W Ｌ , and B Ｌ Each instance is independent, combined, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ２ -, -NR Ｌ１ -, -S(=O)NR Ｌ１ -, -NR Ｌ１ S(=O)-, -S(=O) ２ NR Ｌ１ -, -NR Ｌ１ S (=O) ２ -, -N(R Ｌ１ )C(=O)-, -C(=O)N(R Ｌ１ )-,-N(R Ｌ１ ) C(=O)N(R Ｌ１ ) -, -NR Ｌ１ S (=O) ２ NR Ｌ１ -, -N(R Ｌ１ )C(=NCN)-,-N(R Ｌ１ )C(=NCN)N(R Ｌ１ Selected from )-, -OC(=O)-, -C(=O)O-, -O-alkyl-, -alkyl-O-, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected as one or more R Ｌ’ Replaced by; Each R Ｌ１ These are, independently, hydrogen, halogen, and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Selected from alkyl (heteroaryl), where each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected as one or more R Ｌ’ Replaced by; Each R Ｌ’ These are independently halogen, oxo, -CN, -OH, and -S(=O)CH ３ , -S (=O) ２ CH ３ , -S (=O) ２ NH ２ , -S (=O) ２ NHCH ３ , -S (=O) ２ N(CH ３ ) ２ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, or C ３ -C ６ It is cycloalkyl; and q is an integer between 0 and 15; In the formula, * represents a connection to ULM, and ** represents a connection to PTM. A bifunctional compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt or stereoisomer thereof.

37. The difunctional compound according to claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein q is 0, 1, 2, or 3.

38. A Ｌ However, each of them can be arbitrarily selected, with one or more Rs. Ｌ’ The bond that is replaced by -NR Ｌ１ -, -C(=O)-, *-C≡C-CH ２ -, *-CH ２ -C≡C-, 【Chemistry 20】 A bifunctional compound according to any one of claims 36 to 37, selected from the group consisting of the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

39. Each of the above W Ｌ However, independently, the bonds are methyl, ethyl, propyl, ethinyl, propynyl, butynyl, pentynyl, -C(=O)-, -NH-, -N(CH ３ ) -, -OCH ３ -, -OCH ２ CH ３ -ien-CH ２ O-, or -CH ２ CH ２ A bifunctional compound according to any one of claims 36 to 38, selected from O-, or a pharmaceutically acceptable salt or stereoisomer thereof.

40. Each of the above B Ｌ However, independently, each of them can choose one or more Rs. Ｌ’ The bond that is replaced by -NR Ｌ１ -, -C(=O)-, -CH=CH-, 【Chemistry 21】 A bifunctional compound according to any one of claims 36 to 39, selected from the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

41. The above L is as follows: 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 A bifunctional compound according to any one of claims 1 to 40, selected from the group consisting of {wherein * represents linkage to ULM and ** represents linkage to PTM, or * represents linkage to PTM and ** represents linkage to ULM}, or a pharmaceutically acceptable salt or stereoisomer thereof.

42. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the compounds found in Table 1 or Table 2.

43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

44. A method for treating cancer in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 43.

45. A method for modulating or inhibiting PKMYT1 in a subject, comprising administering to the subject a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 43.

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