VHL derivatives and application thereof in preparation of SMARCA2 degradation agent

Abstract

The invention relates to the technical field of compounds, in particular to VHL derivatives and application thereof in preparation of SMARCA2 degradation agents. Specifically, the invention discloses a compound as shown in a chemical structural formula I, a tautomer, an enantiomer, a diastereoisomer and pharmaceutically acceptable salts, solvates or hydrates thereof. The compound or a pharmaceutical composition containing the compound can be used for preparing a PROTACS degradation agent aiming at an SMARCA2 target spot, and particularly preparing medicines for treating acute myeloid leukemia, myelodysplastic syndrome, uveal melanoma and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of compounds, in particular to VHL derivatives and uses thereof in preparing SMARCA2 degradation agents. Background Art

[0002] SMARCA2 (antibodies to the ATP-dependent helicase SMARCA2) and SMARCA4 (antibodies to the ATP-dependent helicase SMARCA4) are involved in multiple oncogenic processes, including allowing DNA to be transcribed into RNA. In certain cancers, including non-small cell lung cancer, approximately 10%-20% of patients carry SMARCA4 mutations. Because the activity of either SMARCA2 or SMARCA4 is essential for tumor cell growth, cancer cells with SMARCA4 deficiency are highly dependent on SMARCA2 for survival. Degrading SMARCA2 protein in SMARCA4-deficient cancers is thought to produce a potent "synthetic lethality" effect, leading to cancer cell death while sparing normal cells that express SMARCA4.

[0003] The development of PROTAC (Proteolysis-Targeting Chimeras) is a recent hot topic. It is a drug development technology that uses the ubiquitin-proteasome system to degrade target proteins. When PROTAC enters the cell, the target protein (POI) ligand in its structure specifically binds to the target protein, and the E3 ligase ligand at the other end binds to the E3 ligase, thereby forming a ternary complex of target protein-PROTAC-E3 ligase. The E3 ligase mediates the ubiquitin-binding enzyme E2 to ubiquitinate the target protein. After the ternary complex dissociates, the ubiquitin-tagged target protein will be transported to the proteasome for degradation, thereby selectively reducing the level of the target protein, and the PROTAC molecule can circulate multiple times in the cell to exert its effect. This is also conducive to overcoming drug resistance and prolonging the duration of action.

[0004] However, existing protein degraders have some challenges. For example, their affinity and specificity for E3 ligases and target proteins need to be improved; their structure and properties can be further optimized; their pharmacology and toxicology need to be evaluated; and rational clinical trial protocols need to be designed. Summary of the Invention

[0005] To address the above issues, the present invention provides a novel VHL derivative (Von Hippel-Lindau derivative) and its use in the preparation of SMARCA2 degraders. The compound or a pharmaceutical composition containing the compound can be used to prepare a PROTACS degrader targeting the SMARCA2 target, particularly for the preparation of a drug for the treatment of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), uveal melanoma, and the like.

[0006] In a first aspect, the present invention provides a compound as shown in chemical formula I, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, or hydrates thereof: in, R1 is selected from hydrogen, alkyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; R2 is selected from hydrogen, alkyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; L is a linker selected from any one of the structures shown in chemical formula II: in, R3, R4, R 10 、R 11 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, halogen, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocyclic ring, aromatic heterocyclic ring, substituted aromatic heterocyclic ring; R3, R4, R 10 、R 11 It can be the same or different; Group A is independently selected from the following structures: In particular, the group A is When the right side of group A is connected to the N atom of R1, a 6-membered ring is formed; In group A, R5 and R6 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, cyano, alkoxy, substituted alkoxy, trifluoromethyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; POI is a structure represented by the chemical formula III or IV: in, R7 is independently selected from hydroxy, amino, substituted amino, and hydroxymethyl; R8 is independently selected from hydrogen, trifluoromethyl, halogen, cyano, alkyl, alkoxy; R9 is independently selected from the following structures: wherein the right side of R9 is connected to the left side of group A.

[0007] Preferably, R1 is selected from hydrogen, methyl, isopropyl, saturated C 3-5 ring, cyclopropylmethyl, phenyl; R2 is selected from hydrogen or methyl; R3, R4, R 10 、R 11 are independently selected from hydrogen, methyl, isopropyl; R3, R4, R 10 、R 11 They may be the same or different; R5 and R6 are independently selected from hydrogen, fluorine, trifluoromethyl, and methoxy; R7 is hydroxy; and R8 is hydrogen.

[0008] Preferably, when there are two substitutions on the right side of group A, the right side of group A and the N atom connected to R1 form a 6-membered ring.

[0009] Preferably, group A is

[0010] Preferably, the ROI is a target protein binding ligand.

[0011] Preferably, R1 is selected from C 1-8 Alkyl, preferably C 1-5 alkyl.

[0012] Preferably, R2 is selected from C 1-8 Alkyl, preferably C 1-5 alkyl.

[0013] Preferably, the compound is selected from:

[0014] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0015] In a third aspect, the present invention provides the use of the compound, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, hydrates, or the pharmaceutical composition in the preparation of a SMARCA2 degrader.

[0016] In a fourth aspect, the present invention provides the use of the compound, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, hydrates, or pharmaceutical compositions thereof in the preparation of PROTACS degraders targeting SMARCA2.

[0017] In a fifth aspect, the present invention provides the use of the compound, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates or the pharmaceutical composition in the preparation of a drug for preventing and / or treating acute myeloid leukemia, myelodysplastic syndrome, and uveal melanoma.

[0018] Preferably, the compound, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates thereof are administered to mammals in the form of a pharmaceutical composition by parenteral, transdermal, oral, intranasal, topical, rectal or intratumoral administration. DETAILED DESCRIPTION

[0019] The present invention is further described through the following embodiments. It should be understood that the following embodiments are only used to illustrate the present invention, rather than to limit the present invention.

[0020] The present invention provides a compound as shown in chemical formula I, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, or hydrates thereof: in, R1 is selected from hydrogen, alkyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; R2 is selected from hydrogen, alkyl, C3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; L is a linker selected from any one of the structures shown in chemical formula II: in, R3, R4, R 10 、R 11 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, halogen, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocyclic ring, aromatic heterocyclic ring, substituted aromatic heterocyclic ring; R3, R4, R 10 、R 11 It can be the same or different; Group A is independently selected from the following structures: In group A, R5 and R6 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, cyano, alkoxy, substituted alkoxy, trifluoromethyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; POI is a structure represented by the chemical formula III or IV: in, R7 is independently selected from hydroxy, amino, substituted amino, and hydroxymethyl; R8 is independently selected from hydrogen, trifluoromethyl, halogen, cyano, alkyl, alkoxy; R9 is independently selected from the following structures: The left side of the group A is connected to the group POI; specifically, the left side of the group A is connected to the right side of R9 of the group POI.

[0021] As an optional embodiment, group A is independently selected from the following structures:

[0022] As an optional embodiment, R1 is selected from hydrogen, alkyl (the alkyl includes straight chain alkyl and branched chain alkyl, such as C1-C6 alkyl), C 3-8 1-membered saturated or unsaturated carbon ring (preferably C 3-5 saturated or unsaturated carbon ring), aryl (phenyl), substituted aryl, C 3-8As an optional embodiment, R1 can also be selected from cyclopropylmethyl.

[0023] As an optional embodiment, R2 is selected from hydrogen, alkyl (the alkyl includes linear alkyl and branched alkyl, such as C1-C6 alkyl, preferably methyl), C 3-8 1-membered saturated or unsaturated carbon ring (preferably C 3-5 saturated or unsaturated carbon ring), aryl (phenyl), substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle.

[0024] As an optional embodiment, R3, R4, R 10 、R 11 independently selected from hydrogen, alkyl (the alkyl includes linear alkyl and branched alkyl, such as C1-C6 alkyl, preferably methyl, ethyl, propyl, isopropyl, n-butyl, etc.), substituted alkyl, hydroxy, halogen, C 3-8 1-membered saturated or unsaturated carbon ring (preferably C 3-5 saturated or unsaturated carbon ring), aryl, substituted aryl, C 3-8 saturated or unsaturated heterocyclic ring, aromatic heterocyclic ring, substituted aromatic heterocyclic ring; R3, R4, R 10 、R 11 Can be the same or different.

[0025] As an optional embodiment, R5 and R6 of group A are independently selected from hydrogen, halogen (including fluorine, chlorine, bromine, etc., preferably fluorine), alkyl (the alkyl includes straight-chain alkyl and branched alkyl, such as C1-C6 alkyl, preferably methyl, ethyl, propyl, isopropyl, n-butyl, etc.), substituted alkyl, cyano, alkoxy (preferably methoxy), substituted alkoxy, trifluoromethyl, C 3-8 1-membered saturated or unsaturated carbon ring (preferably C 3-5 saturated or unsaturated carbon ring), aryl (phenyl), substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle.

[0026] As an optional embodiment, R1 is selected from hydrogen, methyl, isopropyl, saturated C 3-5 ring, cyclopropylmethyl, phenyl; R2 is selected from hydrogen or methyl; R3, R4, R 10 、R 11 are independently selected from hydrogen, methyl, isopropyl; R3, R4, R 10 、R 11 They may be the same or different; R5 and R6 are independently selected from hydrogen, fluorine, trifluoromethyl, and methoxy; R7 is hydroxy; and R8 is hydrogen.

[0027] As an optional embodiment, when there are two substitutions on the right side of group A, the right side of group A and the N atom connected to R1 form a 6-membered ring.

[0028] As an optional embodiment, group A is

[0029] As an optional embodiment, L is When R3, R4, R 10 、R 11 are independently selected from hydrogen, methyl, isopropyl. Preferably, R3 and R 11 More preferably, R3 and R 11 are both hydrogen, or R3 and R 11 All are methyl.

[0030] It is understandable that when R3, R4, R 10 、R 11 When all are hydrogen, it indicates that there is no substitution on the carbon chain, and the linker L consists of group A and the carbon chain. In this case, it can also be expressed as R3, R4, R 10 、R 11 Does not exist.

[0031] It is understood that when R3, R4, are all hydrogen and there is no R 10 、R 11 When , it indicates that there is no substitution on the carbon chain, and the linker L consists of the group A and the carbon chain. In this case, it can also be expressed as R3 and R4 not existing.

[0032] As an optional embodiment, when group A is When (the right side of) group A is directly connected to the nitrogen atom to which R1 is connected.

[0033] In a preferred embodiment of the present invention, the compound is selected from:

[0034] The present invention also provides a pharmaceutical composition comprising the compound, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates thereof, and pharmaceutically acceptable carriers, excipients or diluents.

[0035] The present invention also provides use of the compound, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, hydrates, or the pharmaceutical composition in the preparation of a SMARCA2 degrader.

[0036] The present invention also provides use of the compound, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, hydrates, or the pharmaceutical composition in the preparation of a PROTACS degrader targeting the SMARCA2 target.

[0037] The present invention also provides use of the compound, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, hydrates, or the pharmaceutical composition in the preparation of drugs for preventing and / or treating acute myeloid leukemia, myelodysplastic syndrome, and uveal melanoma.

[0038] In a preferred embodiment of the present invention, the compound, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates thereof are administered to a mammal in the form of a pharmaceutical composition by parenteral, transdermal, oral, intranasal, topical, rectal or intratumoral administration.

[0039] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0040] As used herein, the expression mn refers to a range from m to n and subranges consisting of individual values ​​therein and individual values. For example, the expression "C1-C20" or "C1-20" encompasses a range of 1 to 20 carbon atoms and should be understood to also encompass any subranges and individual values ​​therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C10" or "C3-10" should also be understood in a similar manner, e.g., to encompass any sub-ranges and point values ​​contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C9, etc., as well as C3, 4, 5, 6, 7, 8, 9, 10, etc. Other similar expressions herein should also be understood in a similar manner.

[0041] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

[0042] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. An "alkyl" group may have 1 to 20 carbon atoms, i.e., a "C1-C 20 Alkyl", such as C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 1-6 Alkyl, C 3-6 Alkyl. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or isomers thereof. "Subunit" refers to a group derived from a carbon atom containing a free valence electron by removing a hydrogen atom and having two attachment sites to the rest of the molecule. For example, "alkylene" or "alkyl subunit" refers to a saturated, straight-chain or branched, divalent hydrocarbon radical.

[0043] The term "alkylene", when used herein alone or in combination with other groups, refers to a straight or branched chain saturated divalent hydrocarbon group. For example, the term "C 1-20 "Alkylene" refers to an alkylene group having 1 to 20 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene or ethylpropylene. The term "cycloalkylene" refers to a cyclic, saturated, divalent hydrocarbon group. For example, the term "C 3-6 "Cycloalkylene" refers to a cycloalkylene group having 3 to 6 carbon atoms, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, etc. The term "alkoxyene" refers to "-O-alkylene" or "alkylene-O-". "C 1-8 Examples of “alkoxyene” include, but are not limited to, —O-methylene, —O-ethylene, —O-propylene, —O-butylene, methylene-O—, ethylene-O—, propylene-O—, butylene-O—, and the like.

[0044] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 2-20 "alkenyl", such as C2-4 alkenyl, C3-4 alkenyl. Non-limiting examples of alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, and the like.

[0045] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 2-8 Alkynyl", such as C 2-4 Alkynyl, C 3-4 Alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0046] The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. The cycloalkyl group can have 3 to 10 carbon atoms, i.e., "C 3-10 Cycloalkyl", such as C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl. The term also encompasses situations where a C atom may be substituted with oxo (=O).

[0047] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group.

[0048] The term "heterocyclyl" or "heterocycloalkyl" refers to a monocyclic or bicyclic ring system (three- to ten-membered, three- to eight-membered, three- to seven-membered, four- to six-membered) having, for example, 3-10 ring atoms (suitably 3-8, more suitably 3-7, and especially 4-6), wherein at least one ring atom (e.g., 1 or 3) is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C. The ring system may be saturated (also understood as the corresponding "heterocycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds within the ring). "Heterocyclyl" or "heterocycloalkyl" is not aromatic. The term also encompasses cases where a C atom may be substituted with oxo (=O) and / or a S atom on the ring may be substituted with one or two oxo (=O) groups and / or a P atom on the ring may be substituted with one or two oxo (=O) groups.

[0049] The heterocyclic group can be, for example, a four-membered ring, such as azetidinyl, oxetanyl; or a five-membered ring, such as tetrahydrofuranyl, dioxanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithianyl; or a seven-membered ring, such as diazepine, Optionally, the heterocyclic group may be benzo-fused.

[0050] The heterocyclic group may be bicyclic, without limitation, for example, a five-membered and a five-membered ring, such as a hexahydrocyclopenta[C]pyrrol-2(1H)-yl) ring; or a five-membered and a six-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.

[0051] As mentioned above, the heterocycle may be unsaturated, i.e., it may contain one or more double bonds, without being limited thereto, for example, an unsaturated heterocycle containing a nitrogen atom may be a 1,6-dihydropyrimidine, 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-1H-pyrrole, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl ring, an unsaturated heterocycle containing an oxygen atom may be a 2H-pyran, 4H-pyran, 2,3-dihydrofuran, an unsaturated heterocycle containing a sulfur atom may be a 2H-thiopyran, 4H-thiopyran. The heterocycle may be benzo-fused, without being limited thereto, for example, a dihydroisoquinolinyl ring.

[0052] The term "hydrocarbon chain" refers to a chain group consisting of carbon atoms and hydrogen atoms, which can be straight or branched. The hydrocarbon chain can be saturated (i.e., an alkylene group) or unsaturated, i.e., can contain one or more carbon-carbon double bonds or triple bonds. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), 1,7-heptylene (-CH2CH2CH2CH2CH2CH2CH2-), etc.

[0053] The “compounds” described in the present invention include all stereoisomers, geometric isomers, tautomers and isotopes.

[0054] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all isomers include, for example, enantiomers and diastereomers. Compounds of the present invention containing asymmetric carbon atoms may be isolated in optically pure or racemic forms; optically pure forms may be resolved from racemic mixtures or synthesized using chiral starting materials or reagents.

[0055] The "compounds" described in the present invention also include geometric isomers; geometric isomers may exist as mixtures or in separated E or Z structural forms.

[0056] The “compounds” described in the present invention also include tautomeric forms; tautomeric forms are caused by the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0057] The term "compound" as used herein also includes all isotopes of atoms, whether in intermediates or final compounds; isotopes include atoms having the same number of protons but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium. Furthermore, if desired, for example, for specific therapeutic or diagnostic purposes, the compounds of the present invention may incorporate known isotopes or radioisotopes, such as 3H, 15O, 13C, or 15N.

[0058] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable salts that maintain the pharmacological activity of the parent compound while improving its physicochemical or metabolic properties. Such salts include acid addition salts or base addition salts prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, inorganic bases), or mixtures thereof. In the present invention, suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or similar acids; suitable organic acids include fumaric acid, tartaric acid, lactic acid, acetic acid, citric acid, trifluoromethanesulfonic acid, mandelic acid, salicylic acid, or their analogs.

[0059] The compounds according to the present invention may also exist in the form of solvates, such as hydrates (hemihydrate, monohydrate, dihydrate, trihydrate, etc.).

[0060] Administration and pharmaceutical compositions

[0061] In general, the compounds of the present invention can be administered in an effective amount by any acceptable mode of administration for other similar purposes. For example, the compounds of the present invention can be administered orally, parenterally, transdermally, topically, rectally, intraperitoneally or intranasally.

[0062] When used as a medicine, the compounds of the present invention are usually administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the field of pharmacy, and these compositions contain at least one active compound. When preparing the compositions provided by the present invention, the active ingredient is usually mixed with an excipient, diluted by the excipient, or wrapped in a capsule, pouch, paper or other form of container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid substance, which can serve as a carrier, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, sprays (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0063] Some typical excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, sterilized water, syrup and methylcellulose. In addition, lubricants (such as talc, magnesium stearate and mineral oil), wetting agents, emulsifying and suspending agents, preservatives (such as methylparaben and propylparaben), sweeteners and flavor enhancers can also be included. The pharmaceutical composition of the present invention can achieve the rapid, continuous or delayed release of the active pharmaceutical ingredient after the patient is administered by a specific excipient, which is also a method widely used in this area.

[0064] The amount of the active ingredient, ie, the compound of the present invention, in the pharmaceutical composition and unit dosage form can be varied or significantly adjusted depending on the specific application, the activity of the particular compound, and the desired concentration.

[0065] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, i.e., causing clinical symptoms of the disease not to develop; (2) inhibiting the disease, i.e., preventing the development of clinical symptoms; (3) alleviating the disease, i.e., causing the regression of clinical symptoms.

[0066] The following examples further illustrate this application, which should not be construed as further limiting. Unless otherwise indicated, the practice of the present disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the scope of those skilled in the art.

[0067] The pharmaceutical composition of the present invention comprises an effective amount of a compound represented by general formula (I) or its tautomers, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients, or diluents thereof.

[0068] An "effective amount" means an amount of a compound of the invention that: (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.

[0069] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0070] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0071] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0072] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The purity of the compounds was determined by liquid high-pressure chromatography (HPLC). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOH-d4) as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are expressed in ppm. MS measurements were performed using an Agilent 6120 mass spectrometer. HPLC measurements were performed using an Agilent 1200DAD high-pressure liquid chromatograph.

[0073] Table 1 <![CDATA[(Boc)2O]]> Di-tert-butyl dicarbonate Cbz-Cl Benzyl chloroformate DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DEA Diethyl adipate DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EA Ethyl acetate EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride FCC Flash column chromatography HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBT 1-Hydroxybenzotriazole IPA Isopropyl alcohol KOAc Potassium acetate MeCN Methyl cyanide or acetonitrile <![CDATA[NaBH(OAc)3]]> Sodium acetate borohydride NCS N-chlorosuccinimide PE Petroleum ether <![CDATA[Pd(dppf)Cl2]]> 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride <![CDATA[Pd(OAc)2]]> Palladium acetate TBAF Tetrabutylammonium fluoride TBDPSCl tert-Butyldiphenylchlorosilane TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TsCl p-Toluenesulfonyl chloride

[0074] Unless otherwise specified in the present invention, the ratio of the eluent refers to the volume ratio.

[0075] Unless otherwise specified, room temperature refers to 20-25°C.

[0076] The compounds of the present invention can be prepared according to synthetic routes known in the literature. The following embodiments provide general guidance related to the preparation of the compounds of the present invention. It will be appreciated by those skilled in the art that the compounds shown in the embodiments can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following embodiments.

[0077] Preparation of intermediates

[0078] Preparation of VHL-INT-01

[0079] Step A: 2-Fluoro-4-(4-methylthiazol-5-yl)benzonitrile

[0080] A solution of compound 1 (30.0 g, 149 mmol), 4-methylthiazole (30.0 g, 303 mmol), KOAc (30.0 g, 306 mmol) and Pd(OAc)2 (3.0 g, 13.4 mmol) in N,N'-dimethylformamide (300 mL) was stirred at 100 ° C for 18 hours. After the reaction solution was cooled to room temperature, it was diluted with H2O (500 mL) and extracted three times with EA (300 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography eluting with PE / EA (100 / 0 to 85 / 15) to give VHL-INT-01 (28 g, yield: 86%) as a yellow solid. LCMS [M+H] +m / z:219.1.

[0081] Preparation of VHL-INT-02

[0082] Step A: Methyl (2S,4R)-1-(S)-2-(tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0083] A solution of compound 1 (96 g), N,N-diisopropylethylamine (211 mL), and HBTU (153 g) in N,N'-dimethylformamide (300 mL) was stirred for 10 minutes, and SM2 (60 g) was slowly added. The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (300 mL) and extracted with EA (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using PE / EA (1 / 3) as the eluent to obtain compound 2 (72 g).

[0084] Step B: Methyl (2S,4R)-1-(S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0085] To a solution of compound 2 (72 g) in methanol (100 mL) was added HCl / MeOH (3 M, 150 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain compound 3 (69 g).

[0086] Step C: 2S,4R-1-(S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester

[0087] Compound 3 (69 g) was added to a solution of 1-fluorocyclopropane-1-carboxylic acid (SM3, 24.4 g), N,N-diisopropylethylamine (119 mL) and HBTU (92.5 g) in N,N'-dimethylformamide (300 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (80 mL) and extracted with EA (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography using PE / EA (2 / 1) as the eluent to obtain compound 4 (50 g).

[0088] Step D: (2S,4R)-1-(S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid

[0089] To a solution of compound 4 (50 g) in tetrahydrofuran (100 mL) was added a solution of LiOH (5 g) in water (20 mL). The resulting mixed solution was stirred at room temperature for 16 hours. The solvent (tetrahydrofuran) was evaporated at room temperature, then extracted with dichloromethane, and the aqueous phase was collected. The aqueous phase was adjusted to pH 3-4 with 1.0 M HCl / H2O to produce a white solid. The white solid was collected and dried to obtain compound VHL-INT-02 (25 g). 1 H NMR (400MHz, MeOD): δ4.90(s,3H),4.57–4.42(m,2H),2.36–2.24(m,1H),2.06(m,1H),1.38–1.24(m,4H),1.05(s,9H).

[0090] Preparation of compound INT-01

[0091] Step A: 2-((3-Hydroxypropyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0092] To a DMSO (100 mL) solution of compound VHL-INT-01 (10.1 g, 46.32 mol) were added 3-aminopropan-1-ol (4.17 g, 55.59 mol) and N,N-diisopropylethylamine (14 g, 138.97 mol). The resulting mixed solution was stirred at 100 ° C overnight. After cooling to room temperature, the reaction solution was diluted with water (500 mL) and extracted 3 times with ethyl acetate. The combined organic phase was washed three times with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography using PE / DCM (100 / 0 to 50 / 50) to give a yellow oily compound 1 (5.2 g, yield: 41%). LCMS [M+H] + m / z:274.1.

[0093] Step B: 2-((3-((tert-Butyldiphenylsilyl)oxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0094] To a solution of compound 1 (3.3 g, 12.7 mmol) in dichloromethane (33 mL) were added TBDPSCl (4.24 g, 15.4 mmol) and imidazole (1.73 g, 25.4 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 3 / 1) as eluent to obtain compound 2 (1.4 g, yield: 22%). LCMS [M+H] + m / z:498.2.

[0095] Step C: 2-((3-((tert-Butyldiphenylsilyl)oxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0096] To a solution of compound 2 (18 g, 35.21 mmol) in tetrahydrofuran (200 mL) was slowly added BH3-tetrahydrofuran solution (1 M, 30 mL) at 0°C. The resulting mixture was stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction solution. Extraction was performed with tetrahydrofuran (50 mL × 3). Under nitrogen protection at 0°C, a solution of TEA (13.01 g, 128.55 mmol) and Boc2O (11.42 g, 52.32 mmol) in tetrahydrofuran (200 mL) was added to the above tetrahydrofuran extract. The resulting mixture was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction solution, extracted with EA (3 × 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain compound 3 (17.3 g, yield: 80.5%). LCMS: [M+H] + M / z=616.

[0097] Step D: tert-Butyl (2-((3-hydroxypropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0098] At 0°C under nitrogen, compound 3 (15 g, 24.35 mmol) and TBAF (12.7 g, 48.57 mmol) were dissolved in tetrahydrofuran (180 mL). The resulting mixed solution was protected with nitrogen and stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction solution. The reaction solution was extracted with EA (3×30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 4 (7 g, yield: 76.17%). LCMS: [M+H] + M / z=378.2.

[0099] Step E: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl 4-methylbenzenesulfonate

[0100] A solution of compound 4 (7 g, 18.54 mmol), TsCl (4.24 g, 22.23 mmol) and TEA (5.63 g, 55.63 mmol) in dichloromethane (100 mL) was dissolved at 0°C under nitrogen protection. The resulting mixture was stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction solution. The reaction solution was extracted with EA (3×30 mL). It was then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain the target compound INT-01 (3.47 g, yield: 35.2%). LCMS: [M+H] + M / z=532.2.

[0101] Preparation of INT-02

[0102] Step A: 2-((2-Hydroxyethyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0103] To a solution of compound 1 (10.0 g, 45.82 mol) in DMSO (100 mL) were added SM2 (3.36 g, 54.98 mol) and TEA (9.25 g, 91.64 mol). The resulting mixture was stirred at 100 ° C overnight. LCMS showed that most of compound 1 was consumed. After the reaction solution was cooled to room temperature, it was diluted with water (500 mL) and extracted 3 times with ethyl acetate. The combined organic phase was washed three times with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 50 / 50) to give a yellow oily compound 2 (5.2 g, yield: 44%). LCMS [M+H] + m / z:260.0.

[0104] Step B: 2-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0105] To a solution of compound 2 (3.3 g, 12.7 mmol) in dichloromethane (33 mL) were added TBDPSCl (4.2 g, 15.2 mmol) and imidazole (1.73 g, 25.4 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 3 / 1) to obtain compound 3 (1.4 g, yield: 22%). LCMS [M+H] + m / z: 498.4.

[0106] Step C: 2-(Aminomethyl)-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(4-methylthiazol-5-yl)aniline

[0107] At 0 ° C, to a solution of compound 3 (5 g, 10 mmol) in tetrahydrofuran (50 mL) was slowly added BH3-tetrahydrofuran solution (1 M, 100 mL). The resulting mixed solution was protected with N2 and stirred at 25 ° C for 18 hours. LCMS showed that the reaction was successful. The reaction solution was diluted with water (500 mL) and extracted 3 times with ethyl acetate. The combined organic phase was washed 3 times with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4 (5.1 g), which was used directly in the next reaction.

[0108] Step D: tert-Butyl (2-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0109] At 0°C under a nitrogen atmosphere, compound 4 (5.1 g, 10.1 mmol), TEA (2.57 g, 25.2 mmol) and Boc2O (3.33 g, 15.1 mmol) were dissolved in tetrahydrofuran (50 mL). The resulting mixture was stirred at 25°C for 4 hours. LCMS showed that the reaction was successful. The reaction was quenched with saturated NH4Cl solution (20 mL). The reaction solution was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (PE / EA=3 / 1) to obtain compound 5 (3.32 g, yield: 54%). LCMS[M+H] + m / z:602.4.

[0110] Step E: tert-Butyl (2-((2-hydroxyethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0111] Compound 5 (3.32 g, 5.51 mmol) and TBAF (2.88 g, 11.02 mmol) were dissolved in tetrahydrofuran (50 mL) at 0 ° C under nitrogen. The resulting mixture was stirred at 25 ° C for 4 hours. LCMS showed that the reaction was successful. The reaction was quenched with saturated NH4Cl solution (20 mL). The reaction solution was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 6 (0.5 g, yield: 25%). LCMS[M+H] + m / z:364.2.

[0112] Step F: 2-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)amino)ethyl 4-methylbenzenesulfonate

[0113] To a solution of compound 6 (7 g, 18.54 mmol) in dichloromethane (100 mL) was slowly added TsCl (4.24 g, 22.23 mmol) and TEA (5.63 g, 55.63 mmol) at 0°C. The resulting mixture was protected with nitrogen and stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with EA (3×80 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain the target compound INT-02 (3.47 g, yield: 35.2%). LCMS: [M+H] + M / z=518.2.

[0114] Preparation of WH-INT-01-MOM

[0115] Step A: Benzyl 4-(3-amino-6-chloropyridin-4-yl)piperazine-1-carboxylate

[0116] To a solution of compound 1 (40 g) in DMSO (100 mL) was added benzyl piperazine-1-carboxylate (42 g) and N,N-diisopropylethylamine (25 mL). The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using EA / PE (50 / 50-100 / 0) as the eluent to obtain compound 2 (50 g).

[0117] Step B: Benzyl 4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazine-1-carboxylate

[0118] To a solution of compound 2 (50 g) in dioxane / water (5:1, 600 mL) were added (2-(methoxymethoxy)phenyl)boronic acid (31.46 g), Pd(dppf)Cl2 (5.19 g), and potassium carbonate (59.6 g). The atmosphere was replaced with nitrogen three times. The resulting mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EA (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with MeOH / DCM (0 / 100-10 / 90) to obtain compound 3 (50 g).

[0119] Step C: 6-(2-(methoxymethoxy)phenyl)-4-(piperazin-1-yl)pyridazin-3-amine

[0120] To a solution of compound 3 (50 g) in ethanol (500 mL) were added Pd / C (10%, 5 g) and Pd(OH)2 (5 g). The mixture was replaced twice under a hydrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through a pad of Celite and washed with ethanol (2 x 50 mL). The filtrate was concentrated to obtain the target compound WH-INT-01-MOM (25.3 g). 1 H NMR (400MHz, MeOD): δ7.54(dd,J=7.6,1.7Hz,1H),7.40–7.34(m,1H),7.26(s,2H),7.13–7.05(m,1H),5.20(s,2H),3.39(s,3H),3.04(d,J=3.6Hz,8H).

[0121] Preparation of WH-INT-02

[0122] Step A: 3-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenol

[0123] A solution of WH-INT-01-MOM (1 g, 3.175 mmol) and 4-hydroxybenzaldehyde (465 mg, 3.810 mmol) in dichloroethane (30 mL) was stirred at room temperature for 30 minutes. Sodium acetate borohydride (2.02 g, 9.252 mmol) was slowly added to the mixture. The mixture was stirred at room temperature for 18 hours. The reaction solution was filtered through a celite pad. The filtrate was concentrated to obtain a residue. The residue was purified by silica gel chromatography and eluted with dichloromethane / methanol (100 / 1 to 9 / 1) to obtain the target compound WH-INT-02 (450 mg). LCMS: m / z = 422.1 [M+H] + .

[0124] Preparation of compound A1

[0125] Step A: (2-((2-((4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)ethyl)amino)tert-butyl)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0126] To a solution of compound 1 (250 mg, 0.5 mmol) in N,N'-dimethylformamide (3 mL) were added WH-INT-02 (760 mg, 0.5 mmol) and potassium carbonate (140 mg, 1.0 mmol). The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 hours. The reaction solution was extracted with ethyl acetate, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with PE / EA (100 / 0 to 1 / 2) to obtain a yellow solid compound 2 (300 mg, yield: 80%). LCMS [M+H] + m / z:767.4.

[0127] Step B: 2-(6-amino-5-(4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)ethoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0128] To a solution of compound 2 (150 mg, 0.2 mmol) in methanol (5 mL) was added HCl / Diox (4 M, 2.5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to afford the crude product, compound 3 (90 mg, yield: 74%), which was used in the next step without further purification. LCMS [M+H] + m / z:623.3.

[0129] Step C: (2S,4R)-N-(2-((2-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)ethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0130] To a solution of compound 3 (90 mg, 0.14 mmol), VHL-INT-02 (71 mg, 0.21 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) in N,N'-dimethylformamide (2 mL) was added HATU (80 mg, 0.21 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 20 / 80) to obtain the target compound A1 (18 mg, yield: 15%) as a white solid. LCMS [M+H] + m / z:935.4. 1 H NMR (400MHz, MeOD): δ8.84(s,1H),8.48(s,1H),7.78-7.76(d,J=7.3Hz,1H),7.51(s ,1H),7.29-7.22(m,4H),6.95-6.90(m,4H),6.76(s,1H),6.73(d,J=1.6Hz,1H),4.69 (s,1H),4.58(m,1H),4.39-4.34(m,3H),4.22-4.21(m,2H),3.77(m,1H),3.61-3.53( m,6H),3.20(m,4H),2.74(m,4H),2.30-2.01(m,2H),1.33-1.24(m,6H),1.01(s,9H).

[0131] Preparation of compound A2

[0132] Step A: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0133] A solution of INT-01 (220 mg, 0.414 mmol), WH-INT-02 (232 mg, 0.497 mmol) and potassium carbonate (172 mg, 1.242 mmol) in N,N'-dimethylformamide (2 mL) was stirred at 100 ° C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted 3 times with EA (50 mL). The combined organic phase was washed three times with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 85 / 15) to give a yellow solid compound 2 (230 mg, yield: 87%). LCMS [M+H] + m / z:781.3.

[0134] Step B: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0135] To a solution of compound 2 (230 mg, 0.294 mmol) in EA (2 mL) was added HCl / dioxane (4 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford the crude product, compound 3, which was used in the next step without further purification.

[0136] Step C: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0137] To a solution of compound 3 (0.295 mmol), VHL-INT-02 (97 mg, 0.354 mmol), and N,N-diisopropylethylamine (76 mg, 0.59 mmol) in N,N'-dimethylformamide (500 mL) at 0°C was added HATU (134 mg, 0.354 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, resulting in a yellow solid precipitate. The filter cake was filtered and washed with water. The filter cake was purified by silica gel column chromatography, eluting with PE / EA (100 / 0 to 0 / 100) and then with dichloromethane / methanol (90 / 10) to obtain a crude yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A2 (10 mg, yield: 0.3%) as a light yellow solid. LCMS [M+H] + m / z:949.4. 1 H NMR (400MHz, MeOD) δ8.82 (s, 1H), 7.77 (d, J=7.4Hz, 1H), 7.50 (s, 1H), 7.22 (dd, J=13.2, 8.1 Hz, 4H), 6.90 (dd, J=11.4, 7.3Hz, 4H), 6.71 (s, 2H), 4.71 (s, 1H), 4.55 (dd, J=21.0, 12.4Hz, 1H), 4.33 (d, J=25.3Hz, 3H), 4.12 (s, 2H), 3.76 (m, J=11.0, 7.3Hz, 2H), 3.56 (s, 2H), 3.38 (s , 2H), 3.18(s, 4H), 2.69(s, 4H), 2.47(s, 3H), 2.14(s, 4H), 1.35-1.22(m, 4H), 1.02(s, 9H).

[0138] Preparation of compound A3

[0139] Step A: tert-Butyl (2-(4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0140] To a solution of compound 1 (900 mg, 1.38 mmol) in N,N'-dimethylformamide (10 mL) was added WH-INT-01 (437 mg, 1.38 mmol) and potassium carbonate (191 mg, 2.76 mmol). The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 hours. The reaction solution was extracted with ethyl acetate, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with PE / EA (100 / 0 to 1 / 2) to obtain a yellow solid compound 2 (650 mg, yield: 49%). LCMS [M+H] + m / z:792.4.

[0141] Step B: 2-(6-amino-5-(4-(4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0142] To a solution of compound 2 (650 mg, 0.2 mmol) in methanol (5 mL) was added HCl / EA (1 M, 5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain compound 3 (250 mg, yield: 31%) as a yellow solid. LCMS [M+H] + m / z:648.3.

[0143] Step C: (2S,4R)-N-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0144] To a solution of compound 3 (200 mg, 0.30 mmol), VHL-INT-02 (105 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 mg, 0.60 mmol) in N,N'-dimethylformamide (5 mL) at 0°C was added HATU (105 mg, 0.30 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 35 / 65) to obtain the title compound A3 as a white solid. LCMS [M+H] + m / z:960.5. 1 H NMR (400MHz, MeOD): δ8.91(s,1H),7.69(s,1H),7.59(m,2H),7.51(s,1H),7.42(d,J=9.1Hz,3H),7.24(d,J=8.4Hz,2H),7.13(d,J=8.8Hz,2H),7. 04(t,J=8.5Hz,2H),4.64(m,5H),4.36(s,2H),3.82(m,4H),3.46(m,9H) ,3.14(m,5H),2.50(s,3H),2.33–2.00(m,2H),1.31(m,4H),1.04(s,9H).

[0145] Preparation of compound A4

[0146] Step A: tert-Butyl (2-((3-((tert-Butyldimethylsilyl)oxy)ethoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0147] To a solution of SM2 (260 mg, 1.5 mmol) in N,N'-dimethylformamide (10 mL) was added NaH (60%, 60 mg, 1.5 mmol) at 0°C under nitrogen. The mixture was stirred at 0°C for 30 minutes, and then INT-01 (800 mg, 1.5 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was then quenched with saturated NH4Cl solution (aq) (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography with PE / EA (1 / 2) to give a yellow solid compound 2 (500 mg, yield: 62%). LCMS[M+H] + m / z:536.3.

[0148] Step B: tert-Butyl (2-((3-(2-hydroxyethoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0149] To a solution of compound 2 (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added TBAF-tetrahydrofuran solution (1 M, 3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with water (30 mL) and extracted with EA (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN=30 / 70) to obtain compound 3 (300 mg, yield: 75%) as a yellow solid. LCMS [M+H] + m / z:422.2.

[0150] Step C: Synthesis of 2-(3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propoxy)ethyl 4-methylbenzenesulfonate

[0151] To a solution of compound 3 (300 mg, 0.71 mmol) and TEA (200 mg, 2.0 mmol) in dichloromethane (10 mL) at 0°C was added TsCl (190 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was then concentrated under reduced pressure and purified using a silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 4 (250 mg, yield: 61%) as a yellow solid. LCMS [M+H] + m / z:576.2.

[0152] Step D: tert-Butyl (2-((3-(2-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)ethoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0153] A solution of compound 4 (250 mg, 0.43 mmol), WH-INT-01-MOM (137 mg, 0.43 mmol) and potassium carbonate (119 mg, 0.86 mmol) in N,N'-dimethylformamide (10 mL) was stirred at 70 ° C for 6 hours. The reaction solution was quenched with water (30 mL) and extracted with EA (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (dichloromethane / methanol = 25 / 1) to give compound 5 (160 mg, yield: 10%) as a yellow solid oil. LCMS [M+H] + m / z:825.4.

[0154] Step E: 2-(6-amino-5-(4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyloxy)ethoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0155] To a solution of compound 5 (160 mg) in methanol (5 mL) was added HCl / dioxane (4 M, 2 mL) at 0°C. The resulting mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the target compound 6 (150 mg) as an oil, which was used directly in the next step. LCMS [M+H] + m / z:681.3.

[0156] Step F: (2S,4R)-N-(2-((3-(2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)ethoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0157] To a solution of compound 6 (150 mg, 0.22 mmol, 25% purity), VHL-INT-02 (105 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 mg, 0.60 mmol) in N,N'-dimethylformamide (5 mL) was added HATU (105 mg, 0.30 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A4 as a white solid (4 mg, yield: 8%). LCMS [M+H] +m / z:993.5. 1 H NMR (400MHz, MeOD): δ8.78(s,1H),7.79(s,1H),7.37(m,6H),6.90(s,4H),6.68(s,2H),4.70–4.04(m,7H) ,3.87–3.51(m,8H),3.18(m,4H),2.71(m,4H),2.47(s,3H),2.27–1.81(m,4H),1.29(m,4H),1.02(s,9H).

[0158] Preparation of Compound A5

[0159] Step A: tert-Butyl (2-((3-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)naphthalen-1-yl)oxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0160] To a solution of compound 1 (250 mg, 0.53 mmol) in N,N'-dimethylformamide (10 mL) were added INT-01 (281 mg, 0.53 mmol) and potassium carbonate (140 mg, 1.06 mmol). The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 hours. The reaction solution was extracted with ethyl acetate, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with PE / EA (100 / 0 to 1 / 2) to obtain a yellow solid compound 2 (150 mg, yield: 34%). LCMS [M+H] + m / z:831.4.

[0161] Step B: 2-(6-amino-5-(4-((3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propoxy)naphthalen-1-yl)methyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0162] To a solution of compound 2 (150 mg, 0.18 mmol) in methanol (5 mL) was added HCl / EA (4 M, 5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 40 / 60) to obtain compound 3 (120 mg, yield: 95%) as a yellow solid. LCMS [M+H] + m / z:687.3.

[0163] Step C: (2S,4R)-N-(2-((3-((4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)naphthalen-1-yl)oxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0164] To a solution of compound 3 (130 mg, 0.18 mmol), VHL-INT-02 (105 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 mg, 0.60 mmol) in N,N'-dimethylformamide (5 mL) was added HATU (105 mg, 0.30 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A5 (28 mg, yield: 15%) as a white solid. LCMS [M+H] + m / z:999.5. 1 H NMR (400MHz, MeOD): δ8.74(s,1H),8.27(d,J=8.7Hz,2H),7.75(d,J=7.6Hz,1H),7.50(d m,2H),7.44–7.15(m,4H),6.80(m,5H),4.67(s,1H),4.51(t,J=8.3Hz,1H),4.33(m,5H) ,3.94(s,2H),3.81–3.61(m,2H),3.51(t,J=6.6Hz,2H),3.15(s,4H),2.75(s,4H),2.40 (d,J=4.7Hz,3H),2.34–2.25(m,2H),2.20–1.97(m,2H),1.33–1.20(m,4H),1.00(s,9H).

[0165] Preparation of Compound A6

[0166] Step A: 3-Aminocyclobutane-1-ol hydrochloride

[0167] To compound 1 (8 g, 42.78 mmol) was added a solution of HCl / dioxane (4 M, 10 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to afford compound 2 (5.0 g), which was used in the next step without further purification.

[0168] Step B: 2-((3-Hydroxycyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0169] To a solution of compound 2 (0.7 g, 5.691 mmol) in DMSO (10 mL) were added 2-fluoro-4-(4-methylthiazol-5-yl)benzonitrile (1.246 g, 5.691 mol) and N,N-diisopropylethylamine (2.21 g, 17.073 mmol). The resulting mixture was stirred at 100°C for 5 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography, eluted with PE / EA (100 / 0 to 85 / 15) to obtain a yellow solid compound 3 (900 mg, yield: 56%). LCMS [M++H] + m / z:286.4.

[0170] Step C: 2-((3-((tert-Butyldiphenylsilyl)oxy)cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0171] To a solution of compound 3 (900 mg, 3.15 mmol) in dichloromethane (6 mL) were added TBDPSCl (1.038 g, 3.79 mmol) and imidazole (321 mg, 4.73 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 3 / 1) to obtain compound 4 (1.13 g, yield: 68%). LCMS [M+H] +m / z:524.3.

[0172] Step D: tert-Butyl (2-((3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0173] To a solution of compound 4 (1.03 g, 1.97 mmol) in tetrahydrofuran (20 mL) was slowly added BH3-tetrahydrofuran solution (1 M, 10 mL) at 0°C. The resulting mixed solution was stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction solution. The reaction solution was extracted with tetrahydrofuran (20 mL×3). A solution of TEA (596.7 mg, 5.91 mmol) and Boc2O (1.28 g, 5.91 mmol) in tetrahydrofuran (10 mL) was added to the above extract at 0°C under N2. The resulting mixed solution was stirred at room temperature for 4 hours. Water (50 mL) was added to the reaction solution. The reaction solution was extracted with EA (3×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain compound 5 (690 mg, yield: 56%). LCMS: [M+H] + M / z=628.3.

[0174] Step E: tert-Butyl (2-((3-hydroxycyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0175] To a solution of compound 5 (690 mg, 1.10 mmol) in tetrahydrofuran (10 mL) was added TBAF-tetrahydrofuran solution (1 M, 1.66 mL) under nitrogen at 0°C. The resulting mixture was stirred at room temperature for 18 hours. Water (20 mL) was added to the reaction solution and extracted with EA (3×30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 6 (401 mg, yield: 93%). LCMS: [M+H] + M / z=390.2.

[0176] Step F: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)amino)cyclobutyl 4-methylbenzenesulfonate

[0177] To a solution of compound 6 (401 mg, 1.03 mmol) in dichloromethane (10 mL) was added TsCl (234 mg, 1.24 mmol) and Et3N (156 mg, 1.55 mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours under nitrogen protection. Water (20 mL) was added to the reaction solution, which was extracted with EA (3×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain compound 7 (302 mg, yield: 54%). LCMS: [M+H] + M / z=544.3.

[0178] Step G: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0179] To a solution of compound 7 (300 mg, 0.55 mmol) in N,N'-dimethylformamide (3 mL) were added WH-INT-02 (278 mg, 0.66 mmol) and potassium carbonate (152 mg, 1.1 mmol). The resulting mixture was stirred at 90 ° C under a N2 atmosphere for 2 hours. The reaction solution was extracted with ethyl acetate, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with PE / EA (100 / 0 to 1 / 2) to obtain a yellow solid compound 8 (220 mg, yield: 50%). LCMS [M+H] + m / z:793.4.

[0180] Step H: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)cyclobutyloxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0181] To a solution of compound 8 (220 mg, 0.2 mmol) in methanol (5 mL) was added HCl / EA (3 M, 5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product, compound 9 (150 mg), which was used in the next step without further purification. LCMS [M+H] + m / z:649.4.

[0182] Step I: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0183] To a solution of compound 9 (150 mg, 0.23 mmol), VHL-INT-02 (76 mg, 0.23 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) in N,N'-dimethylformamide (2 mL) at 0°C was added HATU (95 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 3 hours. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: 0.1% NH4HCO3 aqueous solution / CH3CN = 20 / 80) to obtain the target compound A6 (10 mg, yield: 4.5%) as a white solid. LCMS [M+H] + m / z:961.5. 1 H NMR (400MHz, MeOD): δ8.84(s,1H),8.44–8.37(m,1H),7.78(d,J=8.0Hz,1H),7.52(s,1H),7.25(t,J=6.4H z,2H),7.04(s,1H),6.98–6.87(m,4H),6.72(d,J=9.6Hz,2H),4.72(s,1H),4.55(d,J=8.4Hz,1H),4.51(d, J=8.4Hz,1H),4.35(s,2H),3.83(s,1H),3.63(s,2H),3.33-3.15(m,5H),3.17–3.10(m,3H),3.06(s,3H), 2.56-2.43(m,4H),2.49(s,3H),2.20(d,J=8.0Hz,1H),2.10-2.02(m,3H),1.43–1.20(m,4H),1.02(s,9H).

[0184] Preparation of Compound A7

[0185] Step A: 3-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenol

[0186] A solution of compound 1 (1.0 g, 3.175 mmol) and 3-hydroxybenzaldehyde (465 mg, 3.810 mmol) in dichloroethane (30 mL) was stirred at room temperature for 30 minutes. Sodium acetate borohydride (2.02 g, 9.252 mmol) was then slowly added. The resulting mixture was stirred at room temperature for 18 hours. The reaction solution was filtered through a celite pad. The filtrate was concentrated to obtain a residue, which was purified by silica gel chromatography using dichloromethane / methanol (100 / 1 to 9 / 1) as the eluent to obtain compound 2 (421 mg). LCMS: m / z = 422.1 [M+H] + .

[0187] Step B: tert-Butyl (2-((3-((3-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0188] Potassium carbonate (207 mg, 1.5 mmol) was added to a solution of compound 2 (210 mg, 0.5 mmol) and INT-01 (319 mg, 0.6 mmol) in N,N'-dimethylformamide (5 mL). The resulting mixture was stirred at 100 ° C for 18 hours. After the reaction was completed, water (30 mL) was added to the reaction solution and extracted with EA (3×20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue. The residue was purified by silica gel chromatography (PE / EA=0 / 100 to 30 / 70) to obtain compound 3 (130 mg, yield: 33%). LCMS: m / z=781.4[M+H] + .

[0189] Step C: 2-(6-amino-5-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0190] To a solution of compound 3 (130 mg, 0.167 mmol) in methanol (5 mL) was added HCl / Diox (4 M, 2.5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product, compound 4 (110 mg), which was used in the next step without further purification. LCMS [M+H] + m / z:637.4.

[0191] Step D: (2S,4R)-N-(2-((3-((3-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0192] To a solution of compound 4 (110 mg, 0.162 mmol), VHL-INT-02 (64 mg, 0.194 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) in N,N'-dimethylformamide (2 mL) at 0°C was added HATU (74 mg, 0.194 mmol). The resulting mixture was stirred at room temperature for 3 hours. The concentrated crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 40 / 60) to obtain the target compound A7 (12 mg, yield: 7.8%) as a white solid. LCMS [M+H] + m / z: 949.4. 1HNMR (400MHz, MeOD): δ8.83 (s, 1H), 7.78 (d, J=7.5Hz, 1H), 7.51 (s, 1H), 7.24 (dd, J=21.0, 8.0Hz, 4H), 6.9 1 (dd, J=9.6, 6.7Hz, 4H), 6.69 (d, J=8.0Hz, 2H), 5.01 (t, J=8.4Hz, 1H), 4.74 (d, J=8.6Hz, 1H), 4.59 (d, J=14.8Hz, 1H), 4 .46 (d, J=14.7Hz, 2H), 4.11 (t, J=6.0Hz, 2H), 3.85 (d, J=11.2Hz, 1H), 3.77–3.70 (m, 1H), 3.65 (s, 2H), 3.21 (s, 4H), 2.9 0–2.71 (m, 5H), 2.48 (s, 3H), 2.33–2.23 (m, 1H), 2.17–2.05 (m, 2H), 1.96 (s, 1H), 1.40–1.20 (m, 5H), 1.14–0.99 (m, 9H).

[0193] Preparation of Compound A8

[0194] Step A: tert-Butyl (2-((3-hydroxypropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)(methyl)carbamate

[0195] To a solution of compound 1 (1.7 g, 2.69 mmol) in tetrahydrofuran (10 mL) was added a TBAF-tetrahydrofuran solution (1 M, 3.0 mL). The resulting mixture was stirred at 25 ° C for 18 hours. Water was added to the reaction solution and extracted with EA (3×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 50 / 50) as the eluent to obtain compound 2 (1.1 g). LCMS: m / z=392.1[M+H] + .

[0196] Step B: 2-(6-amino-5-(4-(4-(3-((2-((methylamino)methyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0197] To a solution of compound 2 (1.1 g, 2.81 mmol) in dichloromethane (10 mL) was added TsCl (640.5 mg, 3.37 mmol) and TEA (851 mg, 8.43 mmol) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was quenched with saturated brine (20 mL), extracted with EA (3×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain compound 3 (800 mg). LCMS: m / z=546.2[M+H] + .

[0198] Step C: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)(methyl)carbamate

[0199] To a solution of compound 3 (800 mg, 1.46 mmol) in N,N'-dimethylformamide (10 mL) was added WH-INT-02 (741 mg, 1.76 mmol) and potassium carbonate (604 mg, 4.38 mmol). The resulting mixture was stirred at 80°C for 8 hours. Water was then added to the reaction solution and extracted with EA (3×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography, eluting with PE / EA (100 / 0 to 50 / 50) to give compound 4 (130 mg). LCMS: m / z=795.1[M+H] + .

[0200] Step D: 2-(6-amino-5-(4-(4-(3-((2-((methylamino)methyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0201] To a solution of compound 4 (130 mg, 0.16 mmol) in EA (3 mL) was added HCl / EA (3 M, 1 mL). The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to give compound 5 (130 mg). LCMS: m / z = 651.4 [M+H] + .

[0202] Step E: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide

[0203] Compound 5 (130 mg, 0.2 mmol), VHL-INT-02 (79.2 mg, 0.24 mmol), and N,N-diisopropylethylamine (77.4 mg, 0.6 mmol) were dissolved in N,N'-dimethylformamide (2 mL) at 0°C under nitrogen, followed by the addition of HATU (91.2 mg, 0.24 mmol). The resulting mixture was stirred at room temperature for 12 hours. The concentrated residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 20 / 80) to obtain the target compound A8 (20 mg). LCMS: m / z = 963.6 [M+H] + . 1H NMR (400MHz, MeOD): δ8.83(s,1H),7.78(d,J=7.5Hz,1H),7.51(s,1H),7.24(dd,J=21.0,8.0Hz,4H),6.91(dd,J=9.6,6. 7Hz, 4H), 6.69 (d, J = 8.0Hz, 2H), 5.01 ( t, J = 8.4Hz, 1H), 4.74 ( d, J = 8.6Hz, 1H), 4.59 ( d, J = 14.8Hz, 1H), 4.46 ( d, J = 14.7Hz, 2H),4.11(t,J=6.0Hz,2H),3.85(d,J=11.2Hz,1H),3.77–3.70(m,1H),3.65(s,2H),3.21(s,4H),3.09(d,J=9.6Hz,3H),2 .90–2.71(m,5H),2.48(s,3H),2.33–2.23(m,1H),2.17–2.05(m,2H),1.96(s,1H),1.40–1.20(m,5H),1.14–0.99(m,9H).

[0204] Preparation of Compound A9

[0205] Step A: 2-(4-Hydroxypiperidin-1-yl)-4-(4-methylthiazol-5-yl)benzonitrile

[0206] Compound 1 (3 g, 13.75 mmol), SM2 (2.8 g, 27.50 mmol) and DIEA (6.8 mL, 41.25 mmol) were dissolved in DMF (40 mL). The mixture was stirred at 110 ° C overnight, diluted with water, extracted with EA (50 mL x 3), dried over sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (PE / EA from 100 / 0 to 50 / 50) to give a white solid product (2 g, yield: 48%). LCMS [M+H] + :m / z=300.2.

[0207] Step B: 2-(4-((tert-Butyldiphenylsilyl)oxy)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzonitrile

[0208] To a solution of compound 2 (2 g, 6.68 mmol) and imidazole (0.91 g, 12.76 mmol) in dichloromethane (60 mL) was added TDBPSCl (2.8 g, 9.57 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water and extracted with EA (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, eluted with PE / EA (100 / 0 to 90 / 10) to obtain a white solid compound 3 (3.5 g, yield: 85%). LCMS [M+H] + :m / z=537.2.

[0209] Step C: tert-Butyl(2-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0210] To a solution of compound 3 (3.5 g, 6.51 mmol) in tetrahydrofuran (20 mL) was added BH3-tetrahydrofuran solution (1 M, 40 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction solution was quenched with water. (Boc)2O (2.1 g, 13.02 mmol) was then added. The resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, extracted with EA (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography, eluting with PE / EA 100 / 0-50 / 50 to give a light green solid compound 4 (2.7 g, yield: 64%). LCMS [M+H] + :m / z=642.3.

[0211] Step D: tert-Butyl (2-(4-hydroxypiperidin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0212] To a solution of compound 4 (2.7 g, 4.21 mmol) in tetrahydrofuran (20 mL) at 0°C was added TBAF-tetrahydrofuran solution (1 M, 3 mL). The resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water (50 mL), extracted with EA (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0-25 / 75) as the eluent to obtain compound 5 (620 mg, yield: 36%) as a colorless oil. LCMS [M+H] + :m / z=404.2.

[0213] Step E: 1-(2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methyl)thiazol-5-yl)phenyl)piperidin-4-yl 4-methylbenzenesulfonate

[0214] To a solution of compound 5 (620 mg, 1.54 mmol) in dichloromethane (10 mL) were added TEA (1 mL) and TsCl (393 mg, 2.06 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water, extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA 100 / 0-90 / 10 as the eluent to obtain compound 6 (476 mg, yield: 55%) as a green solid. LCMS [M+H] + :m / z=558.2.

[0215] Step F: tert-Butyl (2-(4-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)piperidin-1-yl)-4-(4-methylisothiazol-5-yl)benzyl)carbamate

[0216] Compound 6 (300 mg, 0.53 mmol), WH-INT-02 (476 mg, 0.63 mmol) and potassium carbonate (295 mg, 1.56 mmol) were dissolved in N,N'-dimethylformamide (5 mL). The resulting mixture was stirred at 70 ° C overnight. After the reaction solution was cooled to room temperature, it was diluted with water, extracted with EA (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, eluting with PE / EA (100 / 0-0 / 100) and dichloromethane / methanol (100 / 0-90 / 10) in sequence to obtain compound 7 (320 mg, yield: 73%) as a yellow solid. LCMS [M+H] + :m / z=807.4.

[0217] Step G: 2-(6-amino-5-(4-((1-(2-(aminomethyl)-5-(4-methylthio)oxazol-5-yl)phenyl)piperidin-4-yl)methoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0218] To a solution of compound 7 (320 mg, 0.39 mmol) in methanol (5 mL) was added a solution of HCl / dioxane (4 M, 5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 8 (258 mg, yield: 100%) as a yellow solid. LCMS [M+H] + :m / z=663.3.

[0219] Step H: (2S,4R)-N-(2-(4-(4-(3-amino-6-(2-hydroxyphenyl))pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide To a solution of compound 8 (258 mg, 0.39 mmol), VHL-INT-02 (300 mg, 0.72 mmol), and N,N-diisopropylethylamine (0.5 mL, 0.35 mmol) in N,N'-dimethylformamide (3 mL) was added HATU (56 mg, 0.14 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 30 / 70) to obtain the target compound A9 (12.7 mg, yield: 2.7%) as a white solid. LCMS [M+H] + m / z=975.4. 1 H NMR(400MHz,MeOD)δ8.87(s,1H),7.78(d,J=7.9Hz,1H),7.59–7.49(m,2H),7.30(d,J=8.1Hz,2H ),7.24(s,2H),7.18(d,J=8.3Hz,1H),6.97(d,J=8.4Hz,2H),6.93–6.87(m,2H),4.75(s,1H),4.6 8–4.59(m,2H),4.50(d,J=15.5Hz,3H),3.94–3.79(m,2H),3.59(s,2H),3.19(s,7H),3.00–2.81( m,2H),2.72(s,4H),2.49(s,3H),2.15(d,J=13.4Hz,4H),1.97(s,2H),1.33(m,6H),1.05(s,9H).

[0220] Preparation of compound A10

[0221] Step A: 4-(4-((4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine

[0222] To a solution of compound 1 (500 mg, 2.35 mmol) and VHL-INT-01-MOM (1 g) in dichloroethane (20 mL) were added AcOH (3 drops) and NaBH(OAC)3 (1.43 g, 6.75 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give compound 2 (1.741 g). LCMS: m / z = 512.2 [M+H] + .

[0223] Step B: 2-(6-amino-5-(4-((4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0224] To a solution of compound 2 (1.741 g, crude product) in EA (10 mL) was added HCl / EA (3 M, 5 mL) solution at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to the reaction solution and extracted with EA (3×20 mL). The organic phase was washed with saturated NaHCO3 aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue. The residue was purified by silica gel chromatography (methanol / dichloromethane=0 / 100 to 12 / 88) to obtain compound 3 (800 mg, yield: 46%). LCMS: m / z=467.57[m / 2+1] + .

[0225] Step C: 4'((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ol

[0226] To a solution of compound 3 (800 mg, 1.71 mmol) dissolved in dichloromethane (10 mL) was added BBr3-dichloromethane solution (1 M, 5 mL) at -78 ° C. The resulting mixture was warmed to room temperature and stirred at room temperature until compound 3 was almost completely consumed. After the reaction was completed, water (30 mL) was added to the reaction solution and extracted with dichloromethane (3×30 mL). The organic phase was washed with saturated NaHCO3 aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4 (500 mg), which was used directly in the next reaction without further purification. LCMS: m / z=454.2[M+H] + .

[0227] Step D: tert-Butyl (2-((3-((4'-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)oxy)propyl)amino)-5-(4-methylthiazol-5-yl)benzyl)carbamate

[0228] To a solution of compound 4 (1.741 g, 3.775 mmol) in N,N'-dimethylformamide (10 mL) were added potassium carbonate (1.56 g, 11.324 mmol) and INT-01 (2.4 g, 4.53 mmol). The resulting mixture was stirred at 75 ° C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (30 mL) was added, and extracted with EA (3×30 mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue. The residue was purified by silica gel chromatography (methanol / dichloromethane=0 / 100 to 12 / 88) to obtain compound 5 (800 mg, yield: 17%). LCMS: m / z=813.3[m / 2+1] + .

[0229] Step E: 2-(6-amino-5-(4-((4'-(3-((2-(aminomethyl)-4-(4-methylthiazol-5-yl)phenyl)amino)propoxy)-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0230] To a solution of compound 5 (100 mg) in EA (3.0 mL) was added HCl / EA solution (1 M, 1.5 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give crude compound 6 (100 mg), which was used directly in the next step without further purification. LCMS: m / z = 713.4 [m / 2+H] + .

[0231] Step F: (2S,4R)-N-(2-((3-((4'-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)oxy)propyl)amino)-5-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0232] To a solution of compound 6 (100 mg, 0.137 mmol) in N,N'-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (0.7 mL), HATU (106 mg), and VHL-INT-02 (45 mg, 0.137 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 20 / 80) to obtain the target compound A10 (4.5 mg, yield: 3.2%). LCMS: m / z = 1025.5 [m / 2+H] + . 1 H NMR (400MHz, CD3OD): δ7.88(s,3H),7.33-7.25(m,7H),6.79(d,J=8.8Hz,2H),5.11(s,6H),4.53-4.48(m,8H),4.35(d,J=8 .4Hz,3H),3.94-3.73(m,22H),3.60-3.31(m,12H),3.21(t,J=6.8Hz,6H),1.96(s,9H),1.60–1.48(m,12H),1.33(m,32H).

[0233] Preparation of compound A11

[0234] Step A: 2-((3-((tert-Butyldiphenylsilyl)oxy)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0235] To a solution of compound 1 (3 g, 5 mmol) in N,N'-dimethylformamide (3 mL) was added NaH (300 mg, 7.6 mmol, 60% purity in mineral oil). The resulting mixture was stirred at room temperature for 30 minutes, and then CH3I (1.08 g, 7.6 mmol) was added. The resulting reaction solution was stirred at 25°C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with EA (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, eluting with PE / EA (100 / 0-80 / 20) to obtain compound 2 (3.2 g). LCMS: m / z=526.2 [M+H] + .

[0236] Step B: tert-Butyl (2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0237] Under nitrogen protection at 0°C, BH3-tetrahydrofuran solution (1M, 30mL) was slowly added to a solution of compound 2 (3.2g, 6mmol) in tetrahydrofuran (20mL). The resulting mixture was warmed to room temperature and stirred under nitrogen protection at room temperature for 4 hours. The reaction solution was quenched with saturated brine (20mL). The reaction solution was extracted with tetrahydrofuran (50mL×3). The extract was used directly in the next reaction. TEA (5mL) and Boc2O (9.0g, 9mmol) were added to the tetrahydrofuran extract at 0°C. The resulting mixture was stirred at room temperature for 18 hours. The reaction solution was quenched with saturated brine (50mL), extracted with EA (3×100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain the target compound 3 (1.7g). LCMS: m / z=630.4[M+H] + .

[0238] Step C: tert-Butyl (2-((3-hydroxypropyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0239] To a solution of compound 3 (1.7 g, 2.69 mmol) in tetrahydrofuran (3 mL) was added TBAF-tetrahydrofuran solution (1 M, 3 mL). The resulting mixture was stirred at 25°C for 8 hours. Water was added to the reaction solution and extracted with EA (3×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (10 / 0-2 / 1) as the eluent to obtain compound 4 (1.1 g). LCMS: m / z = 392.2 [M+H] + .

[0240] Step D: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl 4-methylbenzenesulfonate

[0241] Under a nitrogen atmosphere at 0°C, compound 4 (1.1 g, 2.8 mmol) and TsCl (0.5 g, 2.5 mmol) were dissolved in dichloromethane (10 mL). TEA (1.2 g, 1.2 mmol) was added to the above solution. The resulting mixture was warmed to room temperature and stirred under nitrogen for 4 hours. Water (20 mL) was added to the reaction solution and extracted with EA (3×30 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA=2 / 1) to obtain compound 5 (800 mg). LCMS: m / z=546.2[M+H] + .

[0242] Step E: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0243] To a solution of compound 5 (800 mg, 1.46 mmol) in N,N'-dimethylformamide (2 mL) were added WH-INT-02 (741 mg, 1.76 mmol) and potassium carbonate (604 mg, 4.38 mmol). The resulting mixture was stirred at 80°C for 8 hours. The reaction solution was cooled to room temperature. Water was added to the reaction solution and extracted with EA (3×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was eluted by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 6 (130 mg). LCMS: m / z=796.4[M+H] + .

[0244] Step F: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0245] To a solution of compound 6 (130 mg, 0.16 mmol) in EA (3 mL) was added HCl / EA (4 M, 1 mL). The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to give compound 7 (130 mg). LCMS: m / z = 651.4 [M+H] + .

[0246] Step G: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0247] Under nitrogen protection at 0°C, compound 7 (130 mg, 0.2 mmol), VHL-INT-02 (79.2 mg, 0.24 mmol), HATU (91.2 mg, 0.24 mmol), and N,N-diisopropylethylamine (77.4 mg, 0.6 mmol) were added sequentially to N,N'-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 40 / 60). Freeze-dried to obtain the target compound A11 (20 mg, yield: 10.4%) as a white solid. LCMS: m / z = 963.5 [M+H] + . 1H NMR (400MHz, MeOD): δ8.85 (s, 1H), 7.78 (d, J=8.2Hz, 1H), 7.58–7.46 (m, 2H), 7.24 (d, J=6.9H z, 4H), 7.15 (d, J = 7.9Hz, 1H), 6.96–6.82 (m, 4H), 4.75 (s, 1H), 4.61 (d, J = 16.0Hz, 2H), 4.50 (s , 2H), 4.06(s, 2H), 3.82(m, 2H), 3.55(s, 2H), 3.21–3.09(m, 5H), 2.74(s, 3H), 2.68(s, 4H), 2 .47 (s, 3H), 2.28–2.17 (m, 1H), 2.10 (m, 1H), 2.01 (s, 2H), 1.30 (d, J=7.6Hz, 5H), 1.05 (s, 9H).

[0248] Preparation of compound A12

[0249] Step A: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0250] To a solution of compound 1 (180 mg, 0.973 mmol) in N,N'-dimethylformamide (5 mL) were added INT-01 (517 mg, 0.973 mmol) and potassium carbonate (403 mg, 2.919 mmol). The resulting mixed solution was stirred at 75 ° C for 4 hours. After the reaction was completed, ice water (30 mL) was added to the reaction solution and extracted with EA (3×20 mL). The organic phase was washed with saturated NaHCO3 aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue. The residue was purified by silica gel chromatography (methanol: dichloromethane = 0 / 100 to 12 / 88) to obtain compound 2 (50 mg, yield: 17%). LCMS: m / z = 805.4 [M+H] + .

[0251] Step B: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0252] To a solution of compound 2 (50 mg) in EA (3.0 mL) was added HCl / EA solution (4 M, 1.5 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford compound 3 (40 mg, yield: 40%). LCMS: m / z = 705.4 [M+H] + .

[0253] Step C: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0254] N,N-Diisopropylethylamine (0.7 mL), HATU (106 mg), VHL-INT-02 (22.5 mg, 0.061 mmol), and compound 3 (40 mg, 0.057 mmol) were added sequentially to N,N'-dimethylformamide (1 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 20 / 80) to obtain the target compound A12 as a white solid (5 mg, yield 8.8%). LCMS: m / z = 1017.4 [M+H] + . 1 H NMR (400MHz, CD3OD): δ7.88 (s, 3H), 7.33-7.25 (m, 7H), 6.79 (d, J=8.8Hz, 2H), 5.11 (s, 6H), 4.53-4.48 (m, 8H), 4.35 (d, J=8. 4Hz, 3H), 3.94-3.73 (m, 22H), 3.60-3.31 (m, 12H), 3.21 (t, J=6.8Hz, 6H), 1.96 (s, 9H), 1.60-1.48 (m, 12H)h), 1.33 (m, 32H).

[0255] Preparation of compound A13

[0256] Step A: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0257] To a solution of compound 3 (900 mg, 2.02 mmol) in N,N'-dimethylformamide (10 mL) were added SM2 (1.21 g, 2.22 mmol) and potassium carbonate (207 mg, 1.5 mmol). The resulting mixture was stirred at 90°C for 3 hours under a nitrogen atmosphere. The reaction solution was extracted with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to obtain compound 4 (120 mg, yield: 26%) as a yellow solid.

[0258] Step B: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0259] To a solution of compound 4 (120 mg, 0.147 mmol) in EA (1.0 mL) was added a HCl / EA solution (4 M, 0.5 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then concentrated under reduced pressure to afford compound 5 as a yellow solid, which was used directly in the next step without further purification. LCMS: m / z = 706.3 [M+H] + .

[0260] Step C: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0261] To a solution of compound 5 (95 mg, 0.132 mmol), N,N-diisopropylethylamine (20.0 mg, 0.159 mmol), and HATU (60.0 mg, 0.159 mmol) in N,N'-dimethylformamide (2 mL) was added VHL-INT-02 (43.6 mg, 0.132 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A13 (12.0 mg, yield: 8.8%) as a white solid. LCMS: m / z = 1031.5 [M+H] + . 1 H NMR (400MHz, MeOD): δ8.86 (s, 1H), 7.77 (s, 1H), 7.59–7.48 (m, 2H), 7.28–7.14 (m, 3H), 7.10 (d, J=14.2 Hz, 2H), 6.99 (s, 1H), 6.94–6.88 (m, 3H), 4.75 (s, 1H), 4.57 (dd, J=36.3, 15.5Hz, 4H), 3.85 (s, 2H), 3.5 7(s, 2H), 3.19(s, 4H), 3.04(dd, J=17).6, 10.5Hz, 6H), 2.84–2.57(m, 12H), 2.50(d, J=10.3Hz, 5H), 2. 25 (dd, J=13.4, 7.6Hz, 1H), 2.12 (m, 1H), 1.88–1.71 (m, 2H), 1.31 (dd, J=7.8, 4.4Hz, 4H), 1.05 (s, 9H).

[0262] Preparation of compound A14

[0263] Step A: tert-Butyl 3-(4-formylphenoxy)azetidine-1-carboxylate

[0264] To a solution of compound 1 (2.48 g, 20.0 mmol) in N,N'-dimethylformamide (18 mL) at 0°C, SM2 (3.43 g, 20.0 mmol) and KOH (2.67 g, 47.6 mmol) were added. The resulting mixture was stirred at room temperature for 8 hours. The reaction solution was then diluted with water (50 mL) and extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain compound 2 (3.0 g, yield: 54.1%) as a white solid.

[0265] Step B: tert-Butyl 3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)azetidine-1-carboxylate

[0266] A solution of compound 2 (420 mg, 1.51 mmol) and VHL-INT-MOM-01 (400 mg, 1.27 mmol) in dichloroethane (5 mL) was stirred at room temperature for 2 hours. Sodium acetate borohydride (538 mg, 2.54 mmol) was then added. The resulting mixed solution was stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane (50 mL) and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) to give compound 3 (500 mg, yield: 65.0%) as a yellow solid. LCMS: m / z=578.0[M+H] + .

[0267] Step C: 2-(6-amino-5-(4-(azetidin-3-yloxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0268] To a solution of compound 3 (250 mg, 0.434 mmol) in EA (6 mL) was added HCl / EA solution (4 M, 3 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give compound 4 (200 mg), which was used directly in the next reaction without purification. LCMS: m / z = 433.1 [M+H] + .

[0269] Step D: tert-Butyl (2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)azetidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0270] Compound 4 (86.0 mg, crude product), SM3 (130 mg, 0.239 mmol), potassium carbonate (81.8 mg, 0.639 mmol) and sodium iodide (59.3 mg, 0.395 mmol) were added to N,N'-dimethylformamide (3 mL) in sequence. The resulting mixture was stirred at 70 ° C for 16 hours. After cooling to room temperature, water (20 mL) was added to dilute the reaction solution and extracted with EA (20 mL × 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 5 (50.0 mg, yield: 32.5%) as a yellow solid. LCMS: m / z = 806.4 [M+H] + .

[0271] Step E: 2-(6-amino-5-(4-((1-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)azetidin-3-yl)oxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0272] To a solution of compound 5 (50.0 mg, 0.062 mmol) in EA (1.0 mL) was added a HCl / EA solution (4 M, 0.5 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then concentrated under reduced pressure to afford a yellow solid compound 6 (45.0 mg), which was used directly in the next reaction. LCMS: m / z = 706.3 [M+H] + .

[0273] Step F: (2S,4R)-N-(2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)azetidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0274] Compound 6 (45.0 mg) was added to a solution of VHL-INT-02 (42.1 mg, 0.128 mmol), N,N-diisopropylethylamine (24.7 mg, 0.191 mmol), and HATU (29.1 mg, 0.077 mmol) in N,N'-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A14 (4.0 mg, yield: 6.33%) as a white solid. LCMS: m / z = 1018.6 [M+H] + . 1 H NMR (400MHz, MeOD): δ8.87 (s, 1H), 7.77 (d, J = 8.0Hz, 1H), 7.57–7.49 (m, 2H), 7.32 (d, J = 8.4Hz, 2H ), 7.27–7.16 (m, 3H), 6.95–6.88 (m, 2H), 6.81 (d, J=8.4Hz, 2H), 4.73 (s, 1H), 4.65–4.46 (m, 6H), 4. 18(s, 2H), 3.89–3.56(m, 7H), 3.20(s, 4H)h), 3.05(d, J=6.4Hz, 3H), 2.78–2.62(m, 8H), 2.47(s, 3 H), 2.28–2.19 (m, 1H), 2.09 (dd, J=15.7, 6.8Hz, 1H), 1.74 (s, 2H), 1.35–1.26 (m, 4H), 1.02 (s, 9H).

[0275] Preparation of compound A15

[0276] Step A: tert-Butyl 3-((4-formylphenyl)amino)pyrrolidine-1-carboxylate

[0277] Compound 1 (1.00 g, 4.33 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (967 mg, 5.19 mmol), Cs2CO3 (4.23 g, 13.0 mmol), Pd2(dba)3 (206 mg, 0.225 mmol) and Xantphos (250 mg, 0.432 mmol) were added to 1,4-dioxane (10 mL). The resulting mixture was replaced with nitrogen three times, heated to 80°C under a nitrogen atmosphere and stirred for 8 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (20 mL × 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain compound 2 (500 mg, yield: 39.8%) as a yellow solid. LCMS: m / z=235[M+H] + .

[0278] Step B: tert-Butyl 3-((4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)pyrrolidine-1-carboxylate

[0279] A solution of compound 2 (500 mg, 1.72 mmol) and WH-INT-01-MOM (452 ​​mg, 1.43 mmol) in dichloroethane (5 mL) was stirred at room temperature for 2 hours. Sodium acetate borohydride (609 mg, 2.87 mmol) was then added. The resulting mixed solution was stirred at room temperature for 16 hours. Water (30 mL) was added to dilute the reaction solution and extracted with dichloromethane (3×20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) to obtain compound 3 (660 mg, yield: 65.0%) as a yellow solid. LCMS: m / z=590.8[M+H] + .

[0280] Step C: 2-(6-amino-5-(4-(4-(pyrrolidin-3-ylamino)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0281] To a solution of compound 3 (330 mg, 0.560 mmol) in EA (6 mL) was added HCl / EA solution (4 M, 3 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then concentrated under reduced pressure to afford compound 4 (300 mg), which was used directly in the next reaction without further purification. LCMS: m / z = 446.2 [M+H] + .

[0282] Step D: tert-Butyl (2-((3-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)pyrrolidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0283] Sodium iodide (59.3 mg, 0.395 mmol) was added to a solution of compound 4 (88.0 mg), SM4 (130 mg, 0.239 mmol) and potassium carbonate (81.8 mg, 0.639 mmol) in N,N'-dimethylformamide (3 mL). The resulting mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (20 mL × 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 5 (66.0 mg, two-step yield: 55.9%) as a yellow solid. LCMS: m / z = 819.4 [M+H] + .

[0284] Step E: 2-(6-amino-5-(4-((1-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)pyrrolidin-3-yl)amino)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0285] To a solution of compound 5 (66.0 mg, 0.806 mmol) in EA (1.5 mL) was added HCl / EA solution (4 M, 0.6 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then concentrated under reduced pressure to afford compound 6 (75.0 mg) as a yellow solid, which was used directly in the next reaction without further purification. LCMS: m / z = 719.3 [M+H] + .

[0286] Step F: (2S,4R)-N-(2-((3-((3-((4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)pyrrolidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0287] Compound 6 (75.0 mg, crude) was added to a solution of VHL-INT-02 (68.9 mg, 0.209 mmol), N,N-diisopropylethylamine (40.4 mg, 0.313 mmol), and HATU (47.6 mg, 0.125 mmol) in N,N'-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A15 (18.6 mg, yield: 55.9%) as a white solid. LCMS: m / z = 1031.7 [M+H] + . 1H NMR (400MHz, MeOD): δ8.86 (s, 1H), 7.78 (d, J=7.5Hz, 1H), 7.56–7.49 (m, 2H), 7.24 (t, J=7.5Hz, 2H), 7.15 (dd, J=17.6, 8 .1Hz, 3H), 6.91 (dd, J=7.7, 4.7Hz, 2H), 6.60 (d, J=8.2Hz, 2H), 4.74 (s, 1H), 4.57 (dd, J=26.2, 16.5, 10.1Hz, 4H), 4.04 ( s, 1H), 3.81 (dt, J = 11.3, 7.3Hz, 2H), 3.50 (d, J = 15.1Hz, 2H), 3.06 (dd, J = 46.7, 39.9Hz, 8H), 2.85–2.65 (m, 11H), 2.46 ( s, 3H), 2.38–2.29 (m, 1H), 2.27–2.20 (m, 1H), 2.11 (t, J=9.2Hz, 1H), 1.85–1.73 (m, 3H), 1.38–1.25 (m, 4H), 1.03 (s, 9H).

[0288] Preparation of compound A16

[0289] Step A: tert-Butyl 3-((4-formylphenyl)amino)azetidine-1-carboxylate

[0290] Compound 1 (4 g, 17.316 mmol), SM2 (3.6 g, 20.792 mmol), Cs2CO3 (4.2 g, 12.883 mmol), XantPhos (1 g, 1.728 mmol) and Pd2(dba)3 (800 mg, 0.864 mmol) were added to anhydrous dioxane (40 mL). The resulting mixture was purged with nitrogen three times and stirred at 80°C overnight under nitrogen protection. LCMS showed that the reaction was complete. After cooling to room temperature, water (100 mL) was added to dilute the reaction solution, which was extracted three times with ethyl acetate (60 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was eluted by silica gel column chromatography (PE / EA=6 / 1-4 / 1) to obtain compound 2 (2.9 g, yield: 48.5%). LCMS [M+H] + m / z:435.2.

[0291] Step B: tert-Butyl 3-((4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)azetidine-1-carboxylate

[0292] Compound 2 (500 mg, 1.811 mmol) and SM3 (648 mg, 2.173 mmol) were dissolved in dry dichloroethane (15 mL), and acetic acid (1 drop) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. After cooling to 0°C, NaBH(HOAc)3 (1.15 g, 1.906 mmol) was slowly added, the mixture was warmed to room temperature and stirred overnight. Water (50 mL) was added to dilute the reaction solution, and the mixture was extracted three times with dichloromethane (30 mL). Anhydrous sodium sulfate was added to the combined organic phase for drying, filtration, and concentration were performed to obtain a crude product. Compound 3 (833 mg, yield: 83.3%) was obtained by elution with silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88). LCMS[M+H] + m / z:576.4.

[0293] Step C: 2-(6-amino-5-(4-(azetidin-3-ylamino)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0294] To a solution of compound 3 (500 mg, 0.899 mmol) in EA (10 ml) was added HCl / EA solution (4 M, 2.5 mL) at 0°C. The resulting mixture was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure to afford compound 4 (387 mg, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z:432.2.

[0295] Step D: tert-Butyl (2-((3-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)azetidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0296] Compound 4 (140 mg, 0.324 mmol) was dissolved in dry N,N'-dimethylformamide (5 mL), and potassium carbonate (134 mg, 0.646 mmol), 3-((2-((tert-butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl 4-methylbenzenesulfonate (213 mg, 0.390 mmol) and sodium iodide (97 mg, 0.917 mmol) were added. The resulting mixed solution was stirred at 70 ° C overnight. Cooled to room temperature. Water (50 mL) was added to dilute the reaction solution and extracted three times with EA (10 mL). Anhydrous sodium sulfate was then added to the combined organic phase for drying, filtration and concentration to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to obtain compound 5 (25 mg, yield: 9.5%). LCMS[M+H] + m / z:805.4.

[0297] Step E: 2-(6-amino-5-(4-((1-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)azetidin-3-yl)amino)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0298] To a solution of compound 5 (25 mg, 0.899 mmol) in EA (1 mL) was added HCl / EA solution (4 M, 0.5 mL) at 0°C. The resulting mixture was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure to afford compound 6 (21 mg, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z:705.4.

[0299] Step F: (2S,4R)-N-(2-((3-((3-((4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)azetidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0300] VHL-INT-02 (21 mg, 0.030 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), cooled to 0°C, and HATU (14 mg, 0.037 mmol), N,N-diisopropylethylamine (12 mg, 0.093 mmol), and compound 6 (21 mg, 0.030 mmol) were slowly added. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A16 (8 mg, yield: 4.3%). LCMS [M+H] + m / z:1017.8. 1 H NMR (400MHz, DMSO): δ8.98 (s, 1H), 8.54 (s, 1H), 7.90 (d, J=8.5Hz, 1H), 7.49 (s, 2H), 7.30–7.22 (m, 2H), 7.02 (dd, J=57.4, 49. 0Hz, 6H), 6.46 (d, J=8.4Hz, 2H), 6.22 (s, 2H), 5.91 (d, J=6.4Hz, 1H), 5.17 (d, J=3.4Hz, 1H), 4.60 (d, J=8.7Hz, 1H) 4.50 (t, J=8 .1Hz, 1H), 4.36 (s, 3H), 3.90 (s, 1H), 3.60 (s, 5H), 3.38 (s, 9H), 3.08 (s, 3H), 2.89 (s, 2H), 2.69 (d, J=15.2Hz, 4H), 2.63 (s, 3H ), 2.45 (s, 3H), 2.09 (s, 1H), 1.92 (d, J=8.9Hz, 1H), 1.50 (s, 2H), 1.34 (d, J=18.1Hz, 2H), 1.21 (d, J=8.7Hz, 2H), 0.96 (s, 9H).

[0301] Preparation of compound A17

[0302] Step A: tert-Butyl 4-(4-formylphenyl)piperidine-1-carboxylate

[0303] At -78°C, compound 1 (1.02 g, 2.99 mmol) was dissolved in tetrahydrofuran, then replaced with nitrogen. n-BuLi-n-hexane solution (2.5 M, 9.4 mL) was slowly added dropwise over 10 minutes. After the addition was complete, the mixture was stirred at -78°C for 10 minutes, and then N,N'-dimethylformamide (3 mL) was added. The resulting mixture was slowly warmed to room temperature and stirred for 0.5 hours. Ice water was added to quench the reaction. The reaction solution was extracted three times with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound 2 (860 mg, yield: 100%). 1 H NMR (400MHz, DMSO) δ9.82 (d, J=121.0Hz, 1H), 8.34–7.69 (m, 2H), 7.46 (t, J=23.4Hz, 2H), 3.01–2. 60 (m, 4H), 2.62–2.29 (m, 3H), 1.76 (t, J=12.2Hz, 2H), 1.63–1.48 (m, 2H), 1.42 (d, J=1.3Hz, 11H).

[0304] Step B: tert-Butyl 4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidine-1-carboxylate

[0305] At 0 ° C, compound 2 (400 mg, 3.17 mmol) and WH-INT-01-MOM (440 mg, 1.52 mmol) were dissolved in dichloroethane (2 mL) and stirred for 0.5 hours. Then, sodium acetate borohydride (810 mg, 3.82 mmol) was added. The resulting mixed solution was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 3 (240 mg, yield: 32%). LCMS[M+H] + m / z:589.3.

[0306] Step C: 2-(6-amino-5-(4-(piperidin-4-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0307] To a solution of compound 3 (240 mg, 0.4 mmol) in EA (1 mL) was added HCl / EA solution (4 M, 1 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain compound 4, which was used directly in the next reaction. LCMS [M+H] + m / z:444.3.

[0308] Step D: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0309] To a solution of compound 4 (0.15 g, 0.337 mmol) in N,N'-dimethylformamide (2 mL) were added 3-((2-((tert-butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl 4-methylbenzenesulfonate (0.222 g, 0.407 mmol), potassium carbonate (0.14 g, 1.04 mmol) and sodium iodide (0.105 g, 0.7 mmol). The resulting mixed solution was stirred at 70 ° C. under nitrogen for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 5 (174 mg, yield: 65%). LCMS[M+H] + m / z:818.4.

[0310] Step E: 2-(6-amino-5-(4-(4-(1-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)piperidin-4-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0311] To a solution of compound 5 (174 mg, 0.212 mmol) in EA (2 mL) was added HCl / EA solution (4 M, 1 mL) at 0°C. The resulting mixture was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure to afford compound 6 (152 mg, 100%), which was used directly in the next reaction. LCMS [M+H] + m / z:718.4.

[0312] Step F: 2S,4R)-N-(2-((3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0313] VHL-INT-02 (140 mg, 0.424 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), cooled to 0°C, and HATU (96 mg, 0.253 mmol), N,N-diisopropylethylamine (82 mg, 0.635 mmol), and compound 6 (152 mg, 0.211 mmol) were slowly added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The mixture was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A17 (30 mg, yield: 14.0%) as a white solid. LCMS [M+H] + m / z:1030.6. 1H NMR (400MHz, CD3OD) δ8.86 (s, 1H), 7.78 (dd, J=8.3, 1.4Hz, 1H), 7.50 (s, 2H), 7.29 (s, 2H), 7.25 (d, J=1. 8Hz, 2H), 7.21 (d, J=8.1Hz, 3H), 6.93–6.87 (m, 2H), 4.75 (s, 1H), 4.65–4.58 (m, 2H), 4.51 (d, J=15.8Hz, 2H), 3.82 (dt, J=11.2, 7.5Hz, 2H), 3.60 (s, 2H), 3.18 (s, 3H), 3.07 (ddd, J=28.8, 8.5, 4.3Hz, 5H), 2.71 ( d, J=6.0Hz, 7H), 2.48 (s, 6H), 2.29–2.06 (m, 4H), 1.80 (s, 6H), 1.36–1.26 (m, 4H), 1.04 (d, J=8.5Hz, 9H).

[0314] Preparation of compound A18

[0315] Step A: tert-Butyl 4-(2-fluoro-4-formylphenyl)piperazine-1-carboxylate

[0316] Under nitrogen protection, a DMSO (50 mL) solution of compound 1 (5.0 g, 26.9 mmol), SM2 (4.6 g, 32.4 mmol) and N, N-diisopropylethylamine (10.4 g, 80.6 mmol) was stirred at 100 ° C for 18 hours. After the reaction solution was cooled to room temperature, it was diluted with water (200 mL) and extracted with ethyl acetate three times. The combined organic phase was washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 80 / 20) to obtain a yellow solid compound 2 (7.4 g, yield: 89%). LCMS [M+H] + m / z: 309.2.

[0317] Step B: tert-Butyl 4-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)piperazine-1-carboxylate

[0318] A solution of compound 2 (822 mg, 2.67 mmol) and WH-INT-01-MOM (700 mg, 2.23 mmol) in dichloroethane (10 mL) was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (1.42 g, 6.7 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water (100 mL), extracted with EA (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, first purified with PE / EA (100 / 0 to 0 / 100), and then eluted with dichloromethane / methanol (100 / 0 to 80 / 20) to give a yellow solid compound 3 (1.0 g, yield: 62%). LCMS [M+H] + m / z:608.4.

[0319] Step C: 2-(6-amino-5-(4-(3-fluoro-4-(piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0320] To a solution of compound 3 (200 mg, 0.33 mmol) in methanol (2 mL) was added HCl / dioxane solution (2 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The solution was concentrated to afford compound 4, which was used in the next step without further purification. LCMS [M+H] + m / z:464.4.

[0321] Step D: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0322] Compound 4 (0.33 mmol), SM3 (216 mg, 0.39 mmol), potassium carbonate (91 mg, 0.66 mmol) and sodium iodide (5 mg, 0.03 mmol) were added sequentially to a solution of N,N'-dimethylformamide (2 mL). The resulting mixture was stirred overnight at 70 ° C under N2 protection. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the organic layer was concentrated to obtain a crude product. The crude product was eluted by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give a yellow solid compound 5 (100 mg, yield: 36%). LCMS [M+H] + m / z:837.5.

[0323] Step E: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)piperazin-1-yl)-3-fluorobenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0324] To a solution of compound 5 (100 mg, 0.12 mmol) in methanol (2 mL) was added HCl / dioxane solution (2 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford crude compound 6, which was used directly in the next reaction without further purification. LCMS [M+H] + m / z:737.5.

[0325] Step F: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0326] To a solution of compound 6 (0.12 mmol), VHL-INT-02 (47.5 mg, 0.18 mmol), and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in N,N'-dimethylformamide (2 mL) at 0°C was added HATU (55 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was then poured into ice water, whereupon a yellow solid precipitated. This solid was filtered, and the filter cake was washed with water and dried to obtain a residue. The residue was purified by silica gel column chromatography, eluting first with PE / EA (100 / 0 to 0 / 100) and then with dichloromethane / methanol (90 / 10) to obtain a yellow crude product. The crude product was then purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 35 / 65) to obtain the target compound A18 (83 mg, yield: 66%) as a pale yellow solid. LCMS [M+H] + m / z: 1049.6. 1H NMR (400MHz, MeOD) δ8.86 (s, 1H), 7.77 (s, 1H), 7.59–7.48 (m, 2H), 7.28–7.14 (m, 3H), 7.10 (d, J=1 4.2Hz, 2H), 6.99 (s, 1H), 6.94–6.88 (m, 2H), 4.75 (s, 1H), 4.57 (dd, J=36.3, 15.5Hz, 4H), 3.85 (s, 2H), 3.57(s, 2H), 3.19(s, 4H), 3.04(dd, J=17.6, 10.5Hz, 6H), 2.84–2.57(m, 12H), 2.50(d, J=10. 3Hz, 5H), 2.25 (dd, J=13.4, 7.6Hz, 1H), 2.12 (m, 1H), 1.88–1.71 (m, 2H), 1.31 (m, 4H), 1.05 (s, 9H).

[0327] Preparation of compound A19

[0328] Step A: tert-Butyl (2-((3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0329] A solution of compound 1 (200 mg, 0.432 mol), SM2 (344 mg, 0.648 mol), potassium carbonate (120 mg, 0.868 mol) and sodium iodide (130 mg, 0.867 mmol) in N,N'-dimethylformamide (2 mL) was stirred at 70 ° C for 18 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and washed three times with saturated brine. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by silica gel column chromatography with dichloromethane / methanol (100 / 0 to 90 / 10) to give a yellow solid compound 2 (100 mg, yield: 56%). LCMS [M+H] + m / z:823.7.

[0330] Step B: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)piperazin-1-yl)-3-fluorobenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0331] To a solution of compound 2 (237 mg, 0.288 mmol) in methanol (5 mL) was added HCl / dioxane solution (2 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The crude product, compound 3, was concentrated and used directly in the next reaction. LCMS [M+H] + m / z:723.5.

[0332] Step C: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0333] To a solution of compound 3 (0.277 mmol), VHL-INT-02 (110 mg, 0.334 mmol) and N,N-diisopropylethylamine (143 mg, 1.108 mmol) in N,N'-dimethylformamide (2 mL) was added HATU (127 mg, 0.334 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water to precipitate a yellow solid, which was filtered, and the filter cake was washed with water and dried to obtain a residue. The residue was purified by silica gel chromatography, eluting first with PE / EA (100 / 0 to 0 / 100) and then with dichloromethane / methanol (90 / 10) to obtain a yellow crude product. The crude product was then purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A19 as a pale yellow solid (85 mg, yield: 30%). LCMS [M+H] + m / z: 1035.6. 1H NMR (400MHz, MeOD): δ8.83 (s, 1H), 7.79 (d, J=6.9Hz, 1H), 7.52 (s, 1H), 7.23 (d, J=7.4Hz, 2H), 7.14–7.06 (m, 2H), 6.9 9 (s, 1H), 6.94–6.87 (m, 2H), 6.70 (d, J = 7.0Hz, 2H), 4.73 (s, 1H), 4.52 (d, J = 22.5Hz, 2H), 4.34 (dd, J = 38.7, 15.0Hz, 2 H), 3.81 (d, J = 22.5Hz, 2H) d, J = 3.8Hz, 2H), 3.57 (s, 2H), 3.26 (t, J = 6.6Hz, 2H), 3.20 (s, 4H), 3.09 (s, 4H), 2.70 (s, 8H) ), 2.60 (t, J=7.2Hz, 2H), 2.49 (s, 3H), 2.25–2.15 (m, 1H), 2.08 (m, 1H), 1.93 (s, 2H), 1.38–1.23 (m, 4H), 1.04 (s, 9H).

[0334] Preparation of compound A20

[0335] Step A: 2-Fluoro-4-(4-methylthiazol-5-yl)benzonitrile

[0336] Compound 1 (30.0 g, 149 mmol), 4-methylthiazole (30.0 g, 303 mmol), KOAc (30.0 g, 306 mmol) and Pd(OAc)2 (3.0 g, 13.4 mmol) were added sequentially to a solution of N,N'-dimethylformamide (300 mL). The obtained mixed solution was replaced with nitrogen three times and stirred at 100 ° C for 18 hours under nitrogen protection. After cooling to room temperature, the reaction solution was diluted with water (500 mL) and extracted three times with ethyl acetate (300 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 85 / 15) to give a yellow solid compound 2 (28 g, yield: 86%). LCMS [M+H] + m / z:219.1.

[0337] Step B: 2-(Cyclopropylamino)-4-(4-methylthiazol-5-yl)benzonitrile

[0338] To a solution of compound 2 (21 g, 96.2 mmol) in DMSO (200 mL) was added cyclopropylamine (8.2 g, 144 mmol). The resulting mixture was stirred at 50 ° C overnight. After cooling to room temperature, the reaction solution was diluted with water (200 mL) and extracted three times with ethyl acetate. The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 85 / 15) to obtain a yellow solid compound 3 (11.8 g, yield: 48%). LCMS [M+H] + m / z:297.1.

[0339] Step C: 2-((3-((tert-Butyldimethylsilyl)oxy)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0340] To a solution of compound 3 (11.8 g, 46.2 mmol) in N,N'-dimethylformamide (200 mL) was added NaH (5.5 g, 231 mmol) at 0°C in a N2 atmosphere. After stirring at 0°C for 30 minutes, (3-bromopropoxy)(tert-butyl)dimethylsilane (17.6 g, 69.3 mmol) was added. The resulting mixed solution was warmed to room temperature and stirred overnight. Water (200 mL) was added to the reaction solution for dilution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 80 / 20) to give compound 4 (16.9 g, yield: 85%) as a yellow solid. LCMS [M+H] + m / z:469.3.

[0341] Step D and Step E: tert-Butyl (2-((3-((tert-butyldimethylsilyl)oxy)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0342] At -15 ° C in N2 atmosphere, LiAlH4-THF solution (1M, 119 mL) was added to a solution of compound 4 (16.9 g, 39.6 mmol) in tetrahydrofuran (200 mL). The resulting mixed solution was warmed to room temperature and stirred overnight. The reaction was quenched with ice water (20 mL) and used directly in the next step. Ethanol (20 mL), NaHCO3 (5.5 g, 119 mmol) and (Boc)2O (17.3 g, 79.2 mmol) were added to the above reaction solution and stirred at room temperature for 6 hours. Then water was added to the dilution solution, extracted with ethyl acetate 3 times, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was passed through a silica gel column chromatography and purified with PE / EA (100 / 0 to 50 / 50) to obtain compound 6 (9.6 g, yield: 46%) as a yellow oil. LCMS [M+H] + m / z:532.4.

[0343] Step F: tert-Butyl (2-(cyclopropyl(3-hydroxypropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0344] To a solution of compound 6 (9.6 g, 18.1 mmol) in tetrahydrofuran (100 mL) was added TBAF-tetrahydrofuran solution (1 M, 21.7 mL). The resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 50 / 50) to obtain compound 7 (6.8 g, yield: 91%) as a yellow oil. LCMS [M+H] + m / z:418.3.

[0345] Step G: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)propyl 4-methylbenzenesulfonate

[0346] To a solution of compound 7 (6.8 g, 16.3 mmol) in dichloromethane (50 mL) was added Et3N (4.9 g, 48.9 mmol) and TsCl (3.7 g, 19.6 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel flash chromatography with PE / EA (100 / 0 to 50 / 50) to obtain a yellow oily compound 8 (2.5 g, yield: 27%). LCMS [M+H] + m / z:572.4.

[0347] Step H: tert-Butyl (2-(cyclopropyl(3-(4-formylphenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0348] To a solution of compound 8 (2.50 g, 4.4 mmol) in N,N'-dimethylformamide (25 mL) were added 4-hydroxybenzaldehyde (0.64 g, 5.2 mmol) and potassium carbonate (1.82 g, 13.2 mmol). The resulting mixture was stirred at 70 ° C under nitrogen for 0.5 hours, and sodium iodide (1.32 g, 8.8 mmol) was added. After stirring for 2 hours, LCMS showed that the reaction was complete. The reaction solution was extracted with ethyl acetate, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel flash chromatography with PE / EA (100 / 0 to 50 / 50) to obtain a yellow solid compound 9 (2.12 g, yield: 93%). LCMS [M+H] + m / z:522.4.

[0349] Step I: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0350] A solution of compound 9 (2.12 g, 4.1 mmol) and WH-INT-01-MOM (1.55 g, 4.9 mmol) in dichloroethane (25 mL) was stirred at room temperature for 30 minutes. Sodium acetate borohydride (2.61 g, 12.3 mmol) was then added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water (25 mL), extracted with EA (25 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, eluted with PE / EA (100 / 0 to 10 / 90), and then eluted with dichloromethane / methanol (99 / 1 to 90 / 10) to give compound 10 (2.52 g, yield: 75%) as a yellow solid. LCMS[M+H] + m / z:821.6.

[0351] Step J: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0352] To a solution of compound 10 (2.52 g, 3.1 mmol) in methanol (15 mL) was added a 2 M HCl / dioxane solution (15 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 11 (2.81 g, yield: 100%) as a white solid. LCMS [M+H] + m / z:677.5.

[0353] Step K: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0354] To a solution of compound 11 (2.81 g, 4.2 mmol), VHL-INT-02 (1.39 g, 4.2 mmol), and N,N-diisopropylethylamine (2.17 g, 16.8 mmol) in N,N'-dimethylformamide (15 mL) was added HATU (1.90 g, 5.0 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water to precipitate a yellow solid, which was filtered. The filter cake was washed with water and dried to obtain a residue. The residue was purified by silica gel chromatography, eluting first with PE / EA (100 / 0 to 10 / 90) and then with dichloromethane / methanol (90 / 10) to obtain a crude product as a yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 30 / 70) to obtain the target compound A20 (1.06 g, yield: 26%) as a light yellow solid. LCMS [M+H] + m / z:989.6. 1H NMR (400MHz, MeOD) δ8.86 (s, 1H), 7.78 (dd, J=8.3, 1.5Hz, 1H), 7.52-7.45 (m, 2H), 7.40 (d, J=1.7Hz, 1H), 7.25 (dd, J=10.7, 4.9Hz, 3H), 7.11 (dd, J=8.0, 1.8Hz, 1H), 6.95-6.88 (m, 2H), 6.86 (d, J=8.6Hz, 2H), 4.75 (s, 1H), 4.63-4.44 (m, 3H) (d, J=15.9Hz, 1H), 4.01 (dd, J=1 3.6, 7.7Hz, 2H), 3.82 (dt, J=11.1, 7.5Hz, 2H), 3.55 (s, 2H), 3.27 (d, J=7.6Hz, 2H), 3.22-3.08 (m, 4H), 2.77-2.57 (m, 5H), 2.48 (s, 3H), 2.30-1.98 (m, 5H), 1.43-1.17 (m, 5H), 1.04 (d, J=10.9Hz, 10H), 0.87 (dt, J=35.8, 7.4Hz, 1H), 0.67 (d, J=6.3Hz, 2H), 0.54-0.35 (m, 2H).

[0355] Preparation of compound A21

[0356] Step A: 2-(Isopropylamino)-4-(4-methylthiazol-5-yl)benzonitrile

[0357] To a solution of compound 1 (40.0 g, 183.3 mmol) in DMSO (500 mL) were added propan-2-amine (27.63 g, 467.4 mmol) and N,N-diisopropylethylamine (71.1 g, 550.3 mmol). The resulting mixture was stirred at 70 ° C overnight. After cooling to room temperature, the reaction solution was diluted with water (200 mL) and extracted 3 times with ethyl acetate. The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 85 / 15) to give a yellow solid compound 2 (31.5 g, yield: 66.8%). LCMS [M+H] + m / z:297.1.

[0358] Step B: 2-((3-((tert-Butyldimethylsilyl)oxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0359] To a solution of compound 2 (31.5 g, 123 mmol) in N,N'-dimethylformamide (300 mL) was added NaH (9.8 g, 246 mmol) at 0°C in a nitrogen atmosphere. After stirring at 0°C for 30 minutes, (3-bromopropoxy)(tert-butyl)dimethylsilane (62 g, 246 mmol) was added. The resulting mixed solution was warmed to room temperature and stirred overnight. Water (200 mL) was added to the reaction solution and diluted, and extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 80 / 20) to give a yellow solid compound 3 (45 g, yield: 85%). LCMS [M+H] + m / z:469.3.

[0360] Step C and Step D: tert-Butyl (2-((3-((tert-butyldimethylsilyl)oxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0361] At -15 ° C under N2 atmosphere, LiAlH4-tetrahydrofuran solution (1M, 185 mL) was added to a solution of compound 3 (45 g, 123 mmol) in tetrahydrofuran (500 mL). The resulting mixed solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with ice water (20 mL) and used directly in the next step. Ethanol (200 mL), NaHCO3 (31 g, 369 mmol) and (Boc)2O (53.6 g, 246 mmol) were added to the above reaction solution in sequence and stirred at room temperature for 6 hours. Diluted with water, extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 50 / 50) as eluent to give compound 5 (25 g, yield: 46%) as a yellow oil. LCMS[M+H]+m / z: 532.4.

[0362] Step E: tert-Butyl (2-((3-hydroxypropyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0363] To a solution of compound 5 (25 g, 46.9 mmol) in tetrahydrofuran (250 mL) was added TBAF-tetrahydrofuran solution (1 M, 94 mL). The resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 50 / 50) as the eluent to obtain compound 6 (8.1 g, yield: 41%) as a yellow oil. LCMS [M+H] + m / z:420.2.

[0364] Step F: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(isopropyl)amino)propyl 4-methylbenzenesulfonate

[0365] To a solution of compound 6 (8.1 g, 19.3 mmol) in dichloromethane (50 mL) was added Et3N (5.9 g, 58.3 mmol) and TsCl (5.5 g, 29.0 mmol). The resulting mixture was stirred at room temperature overnight. A saturated aqueous NaHCO3 solution was added to the reaction solution, and the mixture was extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 50 / 50) to obtain compound 7 (5.4 g, yield: 49%) as a yellow oil. LCMS [M+H] + m / z:574.2.

[0366] Step G: tert-Butyl (2-((3-(4-formylphenoxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0367] To a solution of compound 7 (5.4 g, 9.4 mmol) in N,N'-dimethylformamide (25 mL) were added 4-hydroxybenzaldehyde (1.4 g, 11.3 mmol) and potassium carbonate (3.9 g, 28.2 mmol) in sequence. The resulting mixture was stirred at 70 ° C for 0.5 hours, and sodium iodide (2.8 g, 18.8 mmol) was added. After stirring for 2 hours, the reaction solution was poured into ice water, extracted with ethyl acetate, washed 3 times with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 50 / 50) to obtain a yellow solid compound 8 (4.5 g, yield: 91%). LCMS [M+H] + m / z:524.4.

[0368] Step H: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0369] A solution of compound 8 (4.5 g, 8.6 mmol) and WH-INT-01-MOM (3.2 g, 10.3 mmol) in dichloroethane (25 mL) was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (5.5 g, 25.8 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, first eluted with PE / EA (100 / 0 to 10 / 90), and then eluted with dichloromethane / methanol (99 / 1 to 90 / 10) to give a yellow solid compound 9 (5.1 g, yield: 72%). LCMS [M+H] + m / z:823.4.

[0370] Step I: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(isopropyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0371] To a solution of compound 9 (5.1 g, 9.8 mmol) in methanol (20 mL) was added a 2M HCl / dioxane solution (20 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 10 (8.3 g, yield: 100%) as a white solid. LCMS [M+H] + m / z:679.5.

[0372] Step J: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0373] To a solution of compound 10 (8.3 g, 12.1 mmol), VHL-INT-02 (4.8 g, 14.5 mmol), and N,N-diisopropylethylamine (6.3 g, 48.4 mmol) in N,N'-dimethylformamide (20 mL) was added HATU (5.5 g, 14.5 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water to precipitate a yellow solid, which was filtered and the filter cake washed with water and dried to obtain a residue. The residue was purified by silica gel chromatography, eluting first with PE / EA (100 / 0 to 10 / 90) and then with dichloromethane / methanol (90 / 10) to obtain the crude product as a yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 ml / min, mobile phase: H2O (0.1% NH4HCO3) / CH3CN = 30 / 70) to obtain the target compound A21 (2.1 g, yield: 17.5%) as a pale yellow solid. LCMS [M+H] + m / z:991.5. 1 H NMR (400MHz, MeOD): δ8.86 (s, 1H), 7.77 (d, J=7.3Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.48 (s, 1H), 7.31 (s, 1H), 7.27-7.13 (m, 4H), 6 .95-6.87 (m, 2H), 6.83 (d, J=8.5Hz, 2H), 4.76 (s, 1H), 4.58 (ddd, J=42.4, 17.4, 9.8Hz, 4H), 3.95 (d, J=5.5Hz), 2H), 3.83 (dt, J=1 1.1, 7.3Hz, 2H), 3.53 (s, 2H), 3.28 (d, J=2.5Hz, 2H), 3.16 (d, J=5.7Hz, 5H), 2.67 (s, 4H), 2.47 (s, 3H), 2.24 (d, J=7.5Hz, 1H), 2. 12 (ddd, J=13.3, 9.3, 4.3Hz, 1H), 1.78 (d, J=5.7Hz, 2H), 1.43-1.20 (m, 4H), 1.12 (dd, J=12.8, 6.5Hz, 6H), 1.05 (d, J=9.1Hz, 9H).

[0374] Preparation of compound A22

[0375] Step A: tert-Butyl (2-(cyclopropyl(3-(4-(4-formylphenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0376] Under nitrogen protection, 4-(piperazine-1-yl)benzaldehyde (2.19 g, 11.5 mmol) and potassium carbonate (3.98 g, 28.8 mmol) were added to a solution of compound 8 (5.50 g, 9.6 mmol) in N,N'-dimethylformamide (25 mL). The resulting mixture was stirred at 70 ° C under nitrogen protection for 0.5 hours, and then sodium iodide (2.88 g, 19.2 mmol) was added. Stirring was continued for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography using PE / EA (100 / 0 to 50 / 50) to obtain a yellow solid compound 9 (2.32 g, yield: 41%). LCMS [M+H] + m / z: 590.4.

[0377] Step B: tert-Butyl (2-((3-(4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0378] Compound 9 (2.32 g, 3.9 mmol) and WH-INT-01-MOM (1.48 g, 4.7 mmol) were dissolved in dichloroethane (25 mL) and stirred at room temperature for 30 minutes. Sodium acetate borohydride (2.48 g, 11.7 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated and diluted with water (330 mL), extracted with EA (30 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, first eluted with PE / EA (100 / 0 to 10 / 90), then eluted with dichloromethane / methanol (99 / 1 to 90 / 10) to give a yellow solid compound 10 (2.63 g, yield: 75%). LCMS [M+H] + m / z: 889.6.

[0379] Step C: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)propyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0380] To a solution of compound 10 (2.63 g, 3.0 mmol) in methanol (20 mL) was added a 4 M HCl / dioxane solution (10 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 11 (2.81 g, 100% yield) as a white solid. LCMS [M+H] + m / z: 745.6.

[0381] Step D: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0382] To a solution of compound 11 (2.81 g, 3.8 mmol), VHL-INT-02 (1.26 g, 3.8 mmol), and N,N-diisopropylethylamine (1.96 g, 15.2 mmol) in N,N'-dimethylformamide (20 mL) was added HATU (1.75 g, 4.6 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water to precipitate a yellow solid, which was filtered and the filter cake washed with water. The filter cake was purified by silica gel chromatography, eluting first with PE / EA (100 / 0 to 10 / 90) and then with dichloromethane / methanol (90 / 10). The resulting yellow solid was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 40 / 60) to obtain the target compound A22 (1.04 g, yield: 26%) as a light yellow solid. LCMS [M+H] + m / z: 1057.7. 1H NMR (400MHz, MeOD) δ8.87 (s, 1H), 7.78 (d, J=7.0Hz, 1H), 7.57-7.47 (m, 2H), 7.40 (s, 1H), 7.24 (t, J=6.2Hz, 3H), 7.15(d, J=8.0Hz, 1H), 7.00-6.85(m, 4H), 4.75(s, 1H), 4.65-4.34(m, 4H), 3.90-3.76(m, 2H), 3.55(s, 2H), 3.15( d, J=15.1)Hz, 10H), 2.65 (d, J=41.2Hz, 9H), 2.50 (s, 3H), 2.47-2.36 (m, 2H), 2.22 (d, J=7.2Hz, 1H), 2.11 (d, J=8 .9Hz, 1H), 1.89 (s, 2H), 1.46-1.19 (m, 6H), 1.05 (d, J=9.6Hz, 9H), 0.67 (d, J=6.3Hz, 2H), 0.45 (d, J=13.8Hz, 2H).

[0383] Preparation of compound A23

[0384] Step A: tert-Butyl 3-(4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0385] Under nitrogen protection, a Tol (150 mL) solution of compound 1 (5 g, 26 mmol), 2-(4-bromophenyl)-1,3-dioxolane (6.1 g, 28.6 mmol), Pd2(dba)3 (1.2 g, 1.3 mmol), t-BuONa (7.5 g, 78 mmol) and BINAP (809 mg, 1.3 mmol) was stirred at 100 ° C for 18 hours. After the reaction solution was cooled to room temperature, it was diluted with water (100 mL) and extracted with EA (80 mL) three times. The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 80 / 10) to give a brown oily compound 2 (7.2 g, yield: 87.8%). LCMS [M+H] + m / z: 317.2.

[0386] Step B: tert-Butyl 3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0387] A solution of compound 2 (1.81 g, 5.76 mmol) and WH-INT-01-MOM (1.5 g, 4.8 mmol) in dichloroethane (35 mL) was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (5 g, 24 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water (50 mL), extracted with EA (30 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography and eluted with PE / EA (100 / 0 to 10 / 90) to give a light yellow oily compound 3 (1 g, yield: 34.5%). LCMS [M+H] + m / z: 616.4.

[0388] Step C: 2-(5-(4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzyl)piperazin-1-yl)-6-aminopyridazin-3-yl)phenol

[0389] To a solution of compound 3 (1 g, 1.63 mmol) in methanol (10 mL) was added HCl / dioxane solution (2 M, 10 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 4 (1.5 g, yield: 100%) as a white solid. LCMS [M+H] + m / z: 472.4.

[0390] Step D: tert-Butyl (2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0391] To a solution of compound 4 (150 mg, 0.32 mmol) in N,N'-dimethylformamide (10 mL) was added INT-01 (204 mg, 0.384 mmol) and potassium carbonate (133 mg, 0.96 mmol) under a N2 atmosphere. The resulting mixture was stirred at 70°C for 0.5 hours, and sodium iodide (96 mg, 0.64 mmol) was added. After stirring for 2 hours, the reaction solution was poured into ice water, extracted with ethyl acetate, washed 3 times with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product, which was eluted by silica gel flash chromatography with PE / EA (100 / 0 to 30 / 70) to give a yellow solid compound 5 (170 mg, yield: 64.2%). LCMS [M+H] + m / z: 831.5.

[0392] Step E: 2-(6-amino-5-(4-(8-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0393] To a solution of compound 5 (170 mg, 0.2 mmol) in methanol (2 mL) was added HCl / dioxane solution (4 M, 2.0 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 6 (170 mg, yield: 100%) as a white solid. LCMS [M+H] + m / z: 731.4.

[0394] Step F: (2S,4R)-N-(2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0395] To a solution of compound 6 (170 mg, 0.23 mmol), VHL-INT-02 (84 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.5 mL) in N,N'-dimethylformamide (1 mL) at 0°C was added HATU (104 mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and a white solid precipitated. The solid was filtered, and the filter cake was washed with water and dried to obtain a residue. The residue was purified by silica gel column chromatography, eluting first with PE / EA (100 / 0 to 10 / 90) and then with dichloromethane / methanol (90 / 10) to obtain the crude product as a yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain Compound A23 (28 mg, yield: 12%) as a white solid. LCMS [M+H] + m / z: 1043.5. 1 H NMR (400MHz, MeOD): δ8.80 (s, 1H), 7.78 (d, J=8.1Hz, 1H), 7.51 (s, 1H), 7.21 (t, J=8.0Hz, 5H), 6.95-6.87 (m, 2H), 6.80 (d , J=8.7Hz, 2H), 6.69 (d, J=7.6Hz, 2H), 4.72 (s, 1H), 4.52 (dd, J=18.4, 10.4Hz, 2H), 4.32 (dd, J=42.4, 14.9Hz, 2H), 3.87- 2.24 –2.11 (m, 1H), 2.04 (dd, J=13.2, 4.4Hz, 4H), 1.97–1.86 (m, 2H), 1.79 (d, J=7.6Hz, 3H), 1.42–1.22 (m, 5H), 1.03 (s, 10H).

[0396] Preparation of compound A24

[0397] Step A: tert-Butyl (2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0398] Under nitrogen protection, 3-((2-(((tert-butyloxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl-4-methylbenzenesulfonate (204 mg, 0.384 mmol) and potassium carbonate (133 mg, 0.96 mmol) were added to a solution of compound 4 (150 mg, 0.32 mmol) in N,N'-dimethylformamide (10 mL). The resulting mixed solution was stirred at 70 ° C for 0.5 hours, and then sodium iodide (96 mg, 0.64 mmol) was added. Stirring was continued for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed 3 times with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography and eluted with PE / EA (100 / 0 to 30 / 70) to give a yellow solid compound 5 (128 mg, yield: 47.4%). LCMS [M+H] + m / z: 846.5.

[0399] Step E: 2-(6-amino-5-(4-(8-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0400] To a solution of compound 5 (128 mg, 0.15 mmol) in methanol (2 mL) was added HCl / dioxane solution (2 M, 3 mL) at 0°C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated to afford compound 6 (128 mg, yield: 100%) as a white solid, which was used directly in the next step. LCMS [M+H] + m / z: 745.4.

[0401] Step F: (2S,4R)-N-(2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0402] To a solution of compound 6 (128 mg, 0.17 mmol), VHL-INT-02 (62 mg, 0.19 mmol), and N,N-diisopropylethylamine (0.5 mL) in N,N'-dimethylformamide (1 mL) was added HATU (78 mg, 0.2 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, whereupon a white solid precipitated. The solid was filtered, the filter cake washed with water, and dried to obtain a residue. The residue was purified by silica gel column chromatography, eluting first with PE / EA (100 / 0 to 10 / 90) and then with dichloromethane / methanol (90 / 10) to obtain the crude product as a yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A24 (38 mg, yield: 21%) as a white solid. LCMS [M+H] + m / z:1057.6. 1 HNMR (400MHz, MeOD) δ8.86 (s, 1H), 7.78 (dd, J=8.3, 1.5Hz, 1H), 7.56–7.46 (m, 2H), 7.28–7.14 (m, 6H), 6.96–6.87 (m, 2H), 6.79 (d, J=8.7 Hz, 2H), 4.75 (s, 1H), 4.61 (dd, J=16.3, 8.3Hz, 2H), 4.51 (d, J=15.9Hz, 2H), 3.82 (dt, J=11.1, 7.5Hz, 2H)), 3.54 (s, 2H), 3.39 (d, J=10.5H z, 4H), 3.23–3.12 (m, 4H), 3.04 (t, J=6.9Hz, 2H), 2.92 (d, J=10.7Hz, 2H), 2.73 (s, 3H), 2.69 (s, 3H), 2.57–2.50 (m, 2H), 2.48 (s, 3H), 2.24 (dd, J=13.1, 7.6Hz, 1H), 2.10 (ddd, J=13.3, 9.3, 4.5Hz, 1H), 1.98 (s, 2H), 1.85–1.70 (m, 4H), 1.42–1.23 (m, 5H), 1.05 (d, J=6.8Hz, 10H).

[0403] Preparation of compound A25

[0404] Step A: tert-Butyl 4-(4-formyl-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0405] To a solution of compound 1 (1 g, 5.369 mmol) in DMSO (10 mL) was added N,N-diisopropylethylamine (2.08 g, 16.124 mmol) and 4-bromo-3-(trifluoromethyl)benzaldehyde (1.14 g, 5.934 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 120°C and stirred for 12 hours. The reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was purified by flash chromatography on a silica gel column (PE / EA=2 / 1) to obtain compound 2 (1.6 g, yield: 84%). LCMS[M+H] + m / z: 259.2.

[0406] Step B: tert-Butyl 4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0407] Compound 2 (0.7 g, 2.222 mmol) and WH-INT-01-MOM (0.955 g, 2.667 mmol) were dissolved in dichloroethane (10 mL). The resulting mixture was stirred at room temperature for 1 hour, and then sodium acetate borohydride (1.414 g, 6.669 mmol) was added and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 3 (0.8 g, yield: 57%). LCMS[M+H] + m / z: 658.3.

[0408] Step C: 2-(6-amino-5-(4-(piperazin-1-yl)-3-(trifluoromethyl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0409] Under nitrogen protection, HCl / dioxane solution (2M, 2 mL) was added to a solution of compound 3 (0.8 g) in methanol (1 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain compound 4, which was used directly in the next reaction. LCMS [M+H] + m / z: 514.3.

[0410] Step D: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0411] To a solution of compound 4 (0.1 g, 0.184 mmol) in N,N'-dimethylformamide (2 mL) were added 3-((2-((tert-butyloxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl 4-methylbenzenesulfonate (0.128 g, 0.234 mmol), potassium carbonate (0.081 g, 0.586 mmol) and sodium iodide (0.059 g, 0.393 mmol) in sequence. The atmosphere was purged with nitrogen three times, and the resulting mixture was stirred at 70 ° C for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 5 (75 mg, yield: 43%), LCMS [M+H] + m / z: 887.4.

[0412] Step E: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)piperazin-1-yl)-3-(trifluoromethyl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0413] To a solution of compound 5 (0.075 g) in methanol (1 mL) was added a hydrochloric acid / dioxane solution (4 M, 1 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain compound 6, which was used directly in the next reaction. LCMS [M+H] + m / z: 787.3.

[0414] Step F: (2S,4R)-N-(2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0415] To a solution of compound 6 (0.104 g, 0.132 mmol) in N,N'-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (0.052 g, 0.403 mmol), VHL-INT-02 (0.088 g, 5.934 mmol), and HATU (0.061 g, 0.160 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to obtain the target compound A25 (3.1 mg) as a white solid. LCMS [M+H] + m / z: 1099.5.

[0416] Preparation of compound A26

[0417] Step A: tert-Butyl (2-((3-(4-(4-formylphenyl)piperazin-1-yl)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0418] To a solution of compound 1 (500 mg, 0.87 mmol) in N,N'-dimethylformamide (10 mL) were added 4-(piperazine-1-yl)benzaldehyde (200 mg, 1.05 mmol) and potassium carbonate (361 mg, 2.61 mmol). The resulting mixture was stirred at 70 ° C under nitrogen protection for 0.5 hours, and then sodium iodide (260 mg, 1.74 mmol) was added. Stirring was continued for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed 3 times with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography using PE / EA (100 / 0 to 50 / 50) to obtain a yellow solid compound 2 (130 mg, yield: 25%). LCMS [M+H] + m / z: 592.5.

[0419] Step B: tert-Butyl (2-((3-(4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0420] Compound 2 (130 mg, 0.22 mmol) and WH-INT-01-MOM (83 mg, 0.26 mmol) were dissolved in dichloroethane (5 mL). Stirred at room temperature for 30 minutes, then sodium acetate borohydride (140 mg, 0.66 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water (20 mL), extracted with EA (20 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, first eluted with PE / EA (100 / 0 to 10 / 90), then eluted with dichloromethane / methanol (99 / 1 to 90 / 10) to give a yellow solid compound 3 (170 mg, yield: 72%). LCMS [M+H] + m / z: 891.6.

[0421] Step C: 4-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(isopropyl)amino)propyl)piperazin-1-yl)benzyl)piperazin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine

[0422] To a solution of compound 3 (170 mg, 0.19 mmol) in methanol (2 mL) was added HCl / dioxane solution (2 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 4 (150 mg, yield: 93%) as a white solid. LCMS [M+H] + m / z: 747.6.

[0423] Step D: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0424] To a solution of compound 4 (150 mg, 0.20 mmol), VHL-INT-02 (80 mg, 0.24 mmol) and N,N-diisopropylethylamine (103 mg, 0.8 mmol) in N,N'-dimethylformamide (5 mL) was added HATU (91 mg, 0.24 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water to precipitate a yellow solid, which was filtered and the filter cake washed with water and dried to obtain a residue. The residue was purified by silica gel chromatography, eluting first with PE / EA (100 / 0 to 10 / 90) and then with dichloromethane / methanol (90 / 10) to obtain a crude product as a yellow solid. The crude product was then purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain compound A26 (20 mg, yield: 17.5%) as a light yellow solid. LCMS [M+H] + m / z: 1059.7. 1 H NMR (400MHz, MeOD): δ8.87 (s, 1H), 7.78 (d, J=6.9Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 7.2 4(d, J=8.5Hz, 3H), 7.19 (d, J=8.0Hz, 1H), 6.92 (dd, J=6.6, 2.2Hz, 4H), 4.57 (s, 3H), 3.85 (dd, J=15.1, 6.9Hz, 1 H), 3.55 (s, 1H) 2H), 3.15 (d, J = 21.8Hz, 10H), 2.69 (s, 3H), 2.57 (s, 4H), 2.49 (s, 3H), 2.25 (d, J = 6.9Hz, 1H), 2. 22-2.15 (m, 1H), 2.02 (s, 1H), 1.59 (s, 3H), 1.31 (d, J=17.2Hz, 12H), 1.16 (dd, J=15.1, 6.5Hz, 6H), 1.07 (s, 9H).

[0425] Preparation of compound A27

[0426] Step A: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0427] Under nitrogen protection, INT-01 (0.25 g, 0.564 mmol), potassium carbonate (0.165 g, 3.586 mmol) and sodium iodide (0.12 g, 1.6 mmol) were added to a solution of compound 4 (0.2 g, 0.389 mmol) in N, N'-dimethylformamide (2 mL). The resulting mixed solution was stirred at 70 ° C for 12 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 5 (105 mg, yield: 30%). LCMS[M+H] + m / z:873.4.

[0428] Step E: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)piperazin-1-yl)-3-(trifluoromethyl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0429] To a solution of compound 5 (0.105 g) in methanol (1 mL) was added a hydrochloric acid / dioxane solution (4 M, 1.0 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound 6, which was used directly in the next reaction. LCMS [M+H] + m / z: 773.3.

[0430] Step F: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0431] To a solution of compound 6 (0.104 g, 0.132 mmol) in N,N'-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (0.052 g, 0.403 mmol), VHL-INT-02 (0.088 g, 5.934 mmol), and HATU (0.061 g, 0.160 mmol). The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A27 (4.2 mg) as an off-white solid. LCMS [M+H] + m / z: 1085.6. 1 H NMR (400MHz, MeOD) δ8.84 (s, 1H), 7.79 (d, J=6.8Hz, 1H), 7.69–7.58 (m, 2H), 7.59–7.41 (m, 3H), 7.35– 7.18(m, 2H), 6.96–6.86(m, 2H), 6.70(d, J=6.8Hz, 2H), 4.73(s, 5H), 4.50(s, 1H), 4.35(dd, J=35.3, 1 5.0Hz, 3H), 3.82 (d, J=6.8Hz, 3H)), 3.66 (s, 3H), 3.21–3.15 (m, 2H), 2.95 (s, 5H), 2.78–2.56 (m, 11H) , 2.50 (s, 5H), 2.19 (t, J=7.6Hz, 3H), 1.92 (d, J=12.5Hz, 2H), 1.60 (s, 1H), 1.28 (s, 6H), 1.04 (s, 11H).

[0432] Preparation of compound A28

[0433] Step A: tert-Butyl (2-((3-(3-(4-formylphenoxy)pyrrolidin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0434] To a solution of compound 1 (40 mg, 0.2 mmol) in N,N'-dimethylformamide (2 mL) were added INT-01 (120 mg, 0.24 mmol) and potassium carbonate (86 mg, 0.6 mmol). The resulting mixture was stirred at 80 ° C for 8 h. After cooling to room temperature, the reaction solution was diluted with water and extracted with EA (3x30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 50 / 50) as eluent to obtain compound 2 (80 mg). LCMS [M+H] + m / z: 551.3.

[0435] Step B: tert-Butyl (2-((3-(3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)pyrrolidin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0436] Compound 2 (80 mg, 0.15 mmol) and WN-INT-01-MOM (54 mg, 0.17 mmol) were dissolved in dichloroethane (2 mL). Stirred at 25 ° C for 2 hours, and then sodium acetate borohydride (92 mg, 0.45 mmol) was added. The resulting mixed solution was continued to stir at 25 ° C for 18 hours. The reaction solution was diluted with water and extracted with EA (3x30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography, eluted with PE / EA (100 / 0 to 50 / 50) to give compound 3 (60 mg). LCMS [M+H] + m / z: 850.4.

[0437] Step C: 2-(6-amino-5-(4-((1-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)pyrrolidin-3-yl)oxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0438] To a solution of compound 3 (60 mg, 0.07 mmol) in methanol (1 mL) was added HCl / dioxane solution (2 M, 0.5 mL). The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to obtain compound 4 (80 mg).

[0439] Step D: (2S,4R)-N-(2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)pyrrolidin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0440] At 0°C under a nitrogen atmosphere, compound 4 (80 mg, 0.11 mmol), VHL-INT-02 (44 mg, 0.13 mmol), HATU (51 mg, 0.13 mmol), and N,N-diisopropylethylamine (0.2 mL) were added sequentially to N,N'-dimethylformamide (1 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A28 (3.0 mg, yield: 2.7%) as a white solid. LCMS [M+H] + m / z: 1018.5. 1 H NMR (400MHz, MeOD): δ8.82 (s, 1H), 7.78 (d, J=6.9Hz, 1H), 7.51 (s, 1H), 7.31–7.20 (m, 4H), 6.95–6.83 (m, 4H), 6.75–6. 61 (m, 2H), 4.71 (s, 1H), 4.55 (dd, J=17.6, 8.6Hz, 4H), 4.47 (s, 1H), 4.32 (dd, J=13.5, 5.2Hz, 2H), 3.79 (d, J=8.4Hz, 1H )3.57 (s, 2H), 3.22 (dd, J=15.5, 8.8Hz, 6H), 2.90 (s, 3H), 2.70 (s, 5H), 2.59 (s, 1H), 2.48 (s, 3H), 2.34 (d, J=7.2Hz, 1H ), 2.18 (s, 1H), 2.12–2.02 (m, 1H), 1.91 (dd, J=12.5, 4.9Hz, 3H), 1.31 (dd, J=20.6, 9.2Hz, 4H), 1.02 (d, J=2.6Hz, 9H).

[0441] Preparation of compound A29

[0442] Step A: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-methoxyphenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0443] Compound 1 (150 mg, 0.347 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), and potassium carbonate (131 mg, 1.041 mmol), SM2 (207 mg, 0.417 mmol) and sodium iodide (95 mg, 0.694 mmol) were added in sequence. The resulting mixture was stirred at 70 ° C overnight. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate 3 times, washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 50 / 50) to give a yellow oily compound 2 (164 mg, 61.42%). LCMS [M+H] + m / z: 849.7.

[0444] Step B: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)piperazin-1-yl)-3-methoxybenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0445] To a solution of compound 2 (164 mg, 0.193 mmol) in methanol (1 mL) was slowly added HCl-dioxane solution (2 M, 5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain compound 3 (144.7 mg). LCMS [M+H] + m / z: 749.4.

[0446] Step C: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-methoxyphenyl)piperazin-1-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0447] Compound 3 (144 mg, 0.192 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), cooled to 0°C, and HATU (88 mg, 0.230 mmol), N,N-diisopropylethylamine (74 mg, 0.576 mmol), and VHL-INT-02 (127 mg, 0.385 mmol) were slowly added. The resulting mixture was warmed to room temperature and stirred overnight. The reaction solution was diluted with water (10 mL) and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using PE / EA (100 / 0 to 80 / 20) as the eluent to obtain the target compound A29 as a yellow solid (9.13 mg, 4.5%). LCMS [M+H] + m / z: 1062.6. 1 H NMR (400MHz, MeOD): δ8.88 (s, 1H), 8.47 (s, 2H), 7.78 (d, J=7.4Hz, 1H), 7.63–7.39 (m, 2H), 7.27 (s, 1H), 7.22 (dd, J=12.0, 8.3Hz, 2H), 7.0 4 (s, 1H), 6.92 (d, J = 8.0Hz, 4H), 4.75 (s, 1H), 4.68–4.59 (m, 1H), 4.56 (d, J = 3.6Hz, 2H), 4.50 (s, 1H), 3.88 (s, 4H), 3.85 (s, 1H), 3.82–3.76 (m, 1H), 3.61 (s, 2H), 3.48 (s, 1H), 3.21 (s, 5H), 3.10 (dd, J=12, 8.2Hz, 6H), 3.01 (s, 3H), 2.90 (s, 2H), 2.70 (d, J=16Hz, 7H), 2.49 (s, 3H), 2 .24 (d, J=8.4Hz, 1H), 2.13 (dd, J=8.8, 4.2Hz, 1H), 1.88 (s, 2H), 1.42-1.33 (m, 1H), 1.35-1.29 (m, 2H), 1.28 (d, J=4.0Hz, 2H), 1.04 (s, 9H).

[0448] Preparation of compound A30

[0449] Step A: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0450] Under nitrogen protection, INT-01 (190 mg, 0.358 mmol), potassium carbonate (81 mg, 0.587 mmol) and sodium iodide (88 mg, 0.587 mmol) were added to a solution of compound 3 (130 mg, 0.293 mmol) in N,N'-dimethylformamide (5 mL). The resulting mixed solution was stirred at 70 ° C overnight. After cooling to room temperature, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol (100 / 0 to 90 / 10) to give a yellow solid compound 4 (100 mg, yield: 42%). LCMS [M+H] + m / z: 804.4.

[0451] Step B: 2-(6-amino-5-(4-(4-(1-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)piperidin-4-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0452] To a solution of compound 4 (110 mg, 0.137 mmol) in methanol (5 mL) was added HCl / dioxane solution (2 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 5, which was used in the next reaction without further purification. LCMS [M+H] + m / z: 704.5.

[0453] Step C: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0454] To a solution of compound 5 (0.284 mmol), VHL-INT-02 (113 mg, 0.342 mmol) and N,N-diisopropylethylamine (147 mg, 1.136 mmol) in N,N'-dimethylformamide (5 mL) was added HATU (130 mg, 0.342 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water to precipitate a yellow solid, which was filtered and the filter cake washed with water and dried to obtain a residue. The residue was purified by silica gel chromatography, eluting first with PE / EA (100 / 0 to 0 / 100) and then with dichloromethane / methanol (90 / 10) to obtain the crude product as a yellow solid. The crude product was purified by reverse phase chromatography (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 20 / 80) to obtain the target compound A30 (60 mg, yield: 20%) as a white solid. LCMS [M+H] + m / z: 1016.8. 1 H NMR (400MHz, MeOD): δ8.84 (d, J=2.6Hz, 1H), 7.78 (dd, J=8.3, 1.4Hz, 1H), 7.51 (s, 1H), 7.31 (d, J=8.1Hz, 2H), 7. 27–7.19 (m, 4H), 6.96–6.87 (m, 2H), 6.73–6.66 (m, 2H), 4.73 (s, 1H), 4.58–4.48 (m, 2H), 4.34 (dd, J=40.6, 14.9H z, 2H), 3.89–3.74 (m, 2H), 3.61 (s, 2H), 3.26–3.10 (m, 8H), 2.71 (s, 4H), 2.58 (dd, J=18.2, 10.7Hz, 3H), 2.50 (s, 3H), 2.24–2.05 (m, 4H), 1.93 (dd, J=17.1, 10.5Hz, 2H), 1.79 (d, J=20.8Hz, 4H), 1.41–1.26 (m, 4H), 1.04 (s, 9H).

[0455] Preparation of compound A31

[0456] Step A: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-3-fluorophenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0457] To a solution of compound 1 (0.1 g, 0.22 mmol) in N,N'-dimethylformamide (5 mL) were added INT-01 (148 mg, 0.27 mmol), potassium carbonate (94 mg, 0.68 mmol) and sodium iodide (20.8 mg, 0.11 mmol). The resulting mixture was stirred at 80 ° C for 8 h. The reaction solution was cooled to room temperature, diluted with water and extracted with EA (3x30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography, eluted with PE / EA (100 / 0 to 50 / 50) to give compound 2 (100 mg).

[0458] Step B: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propoxy)-2-fluorobenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0459] To a solution of compound 2 (0.1 g, 0.1 mmol) in methanol (2 mL) was added HCl / dioxane solution (2 M, 1 mL) at 0°C. The resulting mixture was stirred for 2 hours. The reaction mixture was concentrated to afford compound 3 (100 mg). LCMS [M+H] + m / z: 655.3.

[0460] Step C: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-3-fluorophenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0461] Compound 3 (0.1 g, 0.15 mmol), VHL-INT-02 (60 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol), and N,N-diisopropylethylamine (0.1 mL) were added sequentially to N,N'-dimethylformamide (1 mL) at 0°C. After nitrogen substitution, the resulting mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A31 (5.0 mg, yield: 3.4%) as an off-white solid. LCMS [M+H] + m / z: 967.4. 1H NMR (400MHz, MeOD): δ8.82 (s, 1H), 7.78 (d, J=7.9Hz, 1H), 7.50 (s, 1H), 7.31–7.15 (m, 3H), 7.00–6.84 (m, 2H) , 6.71 (s, 4H), 4.70 (d, J = 7.4Hz, 1H), 4.51 (dd, J = 24.1, 16.2Hz, 3H), 4.39 (d, J = 14.9Hz, 1H), 4.28 (d, J = 14.4 Hz, 1H), 4.13 (d, J=5.7Hz, 1H), 3.78 (dd, J=25.0, 11.0Hz, 3H), 3.64 (s, 2H), 3.39 (d, J=6.5Hz, 2H), 3.18 (s, 3 H), 2.73 (s, 3H), 2.44 (d, J=20.9Hz, 4H), 2.19–2.02 (m, 4H), 1.30 (d, J=9.3Hz, 6H), 1.02 (s, 9H), 0.88 (s, 1H).

[0462] Preparation of compound A32

[0463] Step A: tert-Butyl 3-((4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)azetidine-1-carboxylate

[0464] Compound 1 (380 mg, 1.207 mmol) and SM2 (400 mg, 1.449 mmol) were dissolved in dry dichloroethane (5 mL), and acetic acid (1 drop) was added dropwise. Stir at room temperature for 2 hours. Cool to 0 ° C, and slowly add sodium acetate borohydride (767 mg, 3.62 mmol). The resulting mixture was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with dichloromethane (10 mL). Then, anhydrous sodium sulfate was added to the organic phase for drying, and purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to obtain the target compound 2 (442 mg, yield: 63.7%). LCMS: m / z: [M+H] + =576.4.

[0465] Step B: 2-(6-amino-5-(4-(azetidin-3-ylamino)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0466] To a solution of compound 2 (440 mg, 0.765 mmol) in ethanol (2 mL) was slowly added HCl / dioxane solution (4 M, 5 mL) at 0°C. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to afford compound 3 (329.8 mg, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z: 432.2.

[0467] Step C: tert-Butyl (2-(3-(3-((3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)phenyl)amino)azetidin-1-yl)propyl)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0468] Compound 3 (150 mg, 0.348 mmol) was dissolved in dry N, N'-dimethylformamide (1 mL), potassium carbonate (144 mg, 1.04 mmol) and INT-01 (223 mg, 0.416 mmol) were added, followed by sodium iodide (104 mg, 0.693 mmol). The resulting mixture was stirred at 70 ° C overnight. The reaction solution was concentrated, diluted with water (25 mL), extracted with EA (25 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, first eluted with PE / EA (100 / 0 to 10 / 90), and then eluted with dichloromethane / methanol (99 / 1 to 90 / 10) to give a yellow solid compound 4 (69 mg, yield: 25%). LCMS [M+H] + m / z: 791.4.

[0469] Step D: 2-(6-amino-5-(4-((1-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)azetidin-3-yl)amino)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0470] To a solution of compound 4 (69 mg, 0.087 mmol) in methanol (2.0 mL) was slowly added HCl / dioxane solution (4.0 M, 2.0 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to afford compound 5 (60 mg, yield: 100%). LCMS [M+H] + m / z: 691.4.

[0471] Step E: (2S,4R)-N-(2-((3-((3-((4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)amino)azetidin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0472] Compound 5 (60 mg, 0.086 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), cooled to 0°C, and HATU (39 mg, 0.104 mmol), N,N-diisopropylethylamine (34 g, 0.26 mmol), and VHL-INT-02 (57, 0.17 mmol) were slowly added. The resulting mixture was warmed to room temperature and stirred overnight. The reaction solution was diluted with water, extracted with EA (3x30 mL), washed twice with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 35 / 65) to obtain A32 (8.0 mg, yield: 4.3%) as a white solid. LCMS [M+H] + m / z: 1004.2. 1 H NMR (400MHz, MeOD): δ8.83 (s, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.51 (s, 1H), 7.26–7.20 (m, 2H), 7.14 (d, J = 8.0Hz, 2H), 6.95 –6.88(m, 2H), 6.72–6.65(m, 2H), 6.56(d, J=8.4Hz, 2H), 4.71(s, 1H), 4.54(dd, J=23.8, 16.2Hz, 2H), 4.33(d, J=3.0Hz , 2H) 4.16–4.05 (m, 1H), 3.84 (s, 2H), 3.81 (s, 2H), 3.52 (s, 3H), 3.48 (s, 1H), 3.20 (d, J=8.4Hz, 6H), 3.13 (s, 1H), 2.79 –2.73 (m, 2H), 2.70 (s, 5H), 2.49 (s, 3H), 2.23–2.15 (m, 1H), 2.08 (s, 1H), 1.79 (s, 2H), 1.35–1.22 (m, 5H), 1.01 (s, 9H).

[0473] Preparation of compound A33

[0474] Step A: tert-Butyl (2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-methoxyphenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate Compound 1 (150 mg, 0.315 mmol) was dissolved in dry N, N'-dimethylformamide (2 mL), and potassium carbonate (131 mg, 0.946 mmol), INT-01 (203 mg, 0.378 mmol) and sodium iodide (95 mg, 631 mmol) were added. The resulting mixed solution was stirred at 70 ° C overnight. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted 3 times with EA (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography, eluted with dichloromethane / methanol (99 / 1 to 90 / 10) to give a yellow solid compound 2 (157 mg, yield: 60%). LCMS [M+H] + m / z: 481.4.

[0475] Step B: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)piperazin-1-yl)-3-methoxybenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0476] To a solution of compound 2 (153 mg, 0.179 mmol) in methanol (1 mL) was slowly added HCl-dioxane solution (2 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford compound 3 (134 mg, yield: 100%) as a white solid. LCMS [M+H] + m / z: 735.4.

[0477] Step C: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-methoxyphenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0478] Compound 3 (153 mg, 0.182 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), cooled to 0 ° C, and HATU (83 mg, 0.219 mmol), N,N-diisopropylethylamine (71 mg, 0.547 mmol) and VHL-INT-02 (120 mg, 0.364 mmol) were slowly added. The resulting mixture was stirred at room temperature overnight. The reaction solution was poured into ice water to precipitate a yellow solid, which was filtered and the filter cake was washed with water and dried to obtain a residue. The residue was purified by silica gel chromatography, first eluting with PE / EA (100 / 0 to 10 / 90) and then eluting with dichloromethane / methanol (90 / 10) to obtain a crude product as a yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A33 (14 mg, yield: 7.3%) as a pale yellow solid. LCMS [M+H] + m / z: 1047.5. 1 H NMR (400MHz, MeOD): δ8.84 (s, 1H), 8.44–8.37 (m, 1H), 7.78 (d, J=8.0Hz, 1H), 7.52 (s, 1H), 7.25 (t, J=6.4Hz, 2H ), 7.04(s, 1H), 6.98–6.87(m, 4H), 6.72(d, J=9.6Hz, 2H), 4.72(s, 1H), 4.55(d, J=8.4Hz, 1H), 4.51(d, J=8.4Hz, 1H), 4.35(s, 2H)), 3.89(s, 3H), 3.83(s, 1H), 3.63(s, 2H), 3.22(s, 6H), 3.17–3.10(m, 3H), 3.06(s, 3H), 2.98(s , 2H), 2.75(s, 4H), 2.49(s, 3H), 2.20(d, J=8.0Hz, 1H), 2.08(dd, J=12.8, 8.7Hz, 3H), 1.43–1.20(m, 4H), 1.02(s 9H).

[0479] Preparation of compound A34

[0480] Step A: tert-Butyl (2-((2-(3-(4-formylphenoxy)pyrrolidin-1-yl)ethyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0481] To a solution of compound 1 (40 mg, 0.2 mmol) in N,N'-dimethylformamide (2 mL) was added SM2 (120 mg, 0.24 mmol) and potassium carbonate (86 mg, 0.6 mmol) in sequence. The resulting mixture was stirred at 80 ° C for 8 hours. The reaction solution was poured into ice water and extracted with EA (3x30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography and eluted with PE / EA (100 / 0 to 50 / 50) to give compound 2 (86 mg). LCMS [M+H] + m / z: 551.3.

[0482] Step B: tert-Butyl (2-((2-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)pyrrolidin-1-yl)ethyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0483] To a solution of compound 2 (80 mg, 0.15 mmol) in dichloroethane (2 mL) was added WH-INT-01-MOM (54 mg, 0.17 mmol). After stirring at 25 ° C for 2 hours, sodium acetate borohydride (92 mg, 0.45 mmol) was added. The resulting mixed solution was stirred for 18 hours at 25 ° C. Water was added to the reaction solution and extracted with dichloromethane (3x30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography and eluted with PE / EA (100 / 0 to 50 / 50) to give compound 3 (60 mg, yield: 50%). LCMS [M+H] + m / z: 806.4.

[0484] Step C: 2-(6-amino-5-(4-((1-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)ethyl)pyrrolidin-3-yl)oxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0485] To a solution of compound 3 (60 mg, 0.07 mmol) in methanol (1 mL) was added a 4 M HCl / dioxane solution (0.5 mL). The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to afford compound 4 (80 mg). LCMS [M+H] + m / z: 706.4.

[0486] Step D: (2S,4R)-N-(2-((2-(3-(4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)pyrrolidin-1-yl)ethyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0487] Compound 4 (80 mg, 0.11 mmol), VHL-INT-02 (44 mg, 0.13 mmol), HATU (51 mg, 0.13 mmol), and N,N-diisopropylethylamine (0.2 mL) were added sequentially to a solution of N,N'-dimethylformamide (1 mL) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A34 as a white solid (3.1 mg, yield: 2.8%). LCMS [M+H] + m / z: 1018.2. 1 H NMR (400MHz, MeOD) δ8.86 (s, 1H), 7.78 (d, J=7.3Hz, 1H), 7.52 (d, J=10.8Hz, 2H), 7.25 (dd, J=14.4, 8.1Hz, 4H) , 7.17 (d, J=8.2Hz, 1H), 6.95–6.88 (m, 2H), 6.85 (d, J=6.8Hz, 2H), 4.74 (s, 1H), 4.63–4.43 (m, 6H), 3.83 (d, J= 11.7Hz, 1H), 3.57 (s, 2H), 3.23–3.12 (m, 6H), 2.91 (s, 3H), 2.79–2.65 (m, 9H), 2.58 (s, 1H), 2.48 (d, J=6.6Hz, 3H), 2.37–2.19 (m, 2H), 2.16–2.06 (m, 1H), 1.91 (d, J=18.8Hz, 1H), 1.40–1.22 (m, 4H), 1.04 (d, J=3.8Hz, 9H).

[0488] Preparation of compound A35

[0489] Step A: tert-Butyl 8-(4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0490] To a solution of compound 1 (5 g, 23.552 mmol) in Tol (100 mL) were added 2-(4-bromophenyl)-1,3-dioxolane (6 g, 26.192 mmol), t-BuONa (6.8 g, 70.833 mmol), BINAP (0.75 g, 1.205 mmol) and Pd2(dba)3 (1.1 g, 1.202 mmol). The atmosphere was purged with nitrogen three times, and the resulting mixture was stirred at 100°C for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a crude product, compound 2 (7 g, yield: 94%). LCMS [M+H] + m / z: 317.2.

[0491] Step B: tert-Butyl 8-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0492] To a solution of compound 2 (1 g, 3.174 mmol) in dichloroethane (10 mL) was added WH-INT-01-MOM (1.2 g, 3.797 mmol). The mixture was stirred at room temperature for 1 hour, and then sodium acetate borohydride (2.1 g, 9.905 mmol) was added. The resulting mixed solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 3 (0.96 g, yield: 50%). LCMS[M+H] + m / z: 616.4.

[0493] Step C: 2-(5-(4-(4-(3,8-diazabicyclo[3.2.1]octan-8-yl)benzyl)piperazin-1-yl)-6-aminopyridazin-3-yl)phenol

[0494] To a solution of compound 3 (0.96 g) in methanol (10 mL) was added a hydrochloric acid / dioxane solution (4 M, 5 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain crude compound 4 (0.735 g, yield: 100%), which was used directly in the next reaction. LCMS [M+H] +m / z: 472.2.

[0495] Step D: tert-Butyl (2-((3-(8-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0496] Under nitrogen protection, INT-01 (0.203 g, 0.381 mmol), potassium carbonate (0.132 g, 0.956 mmol) and sodium iodide (0.096 g, 0.640 mmol) were added to a solution of compound 4 (0.15 g, 0.318 mmol) in N,N'-dimethylformamide (2 mL). The resulting mixed solution was stirred at 70 ° C for 12 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 5 (120 mg, yield: 46%). LCMS[M+H] + m / z: 831.4.

[0497] Step E: 2-(6-amino-5-(4-(3-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0498] To a solution of compound 5 (0.1 g) in methanol (1 mL) was added a 4 M hydrochloric acid / dioxane solution (2 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain crude compound 6, which was used directly in the next reaction.

[0499] Step F: (2S,4R)-N-(2-((3-(8-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0500] Under nitrogen protection, N,N'-dimethylformamide (1 mL) solution of compound 6 (0.12 g, 0.164 mmol) was added with N,N-diisopropylethylamine (0.056 g, 0.434 mmol), VHL-INT-02 (0.096 g, 0.290 mmol), and HATU (0.072 g, 0.189 mmol). The resulting mixture was stirred at room temperature for 12 hours under nitrogen protection. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to obtain the target compound A35 (4 mg, yield: 2.3%) as a white solid. LCMS [M+H] + m / z: 1043.5. 1 H NMR (400MHz, CD3OD) δ8.85 (s, 1H), 7.64 (d, J = 8.6Hz, 2H), 7.50–7.35 (m, 4H), 7.22 (d, J = 7.6Hz, 1H), 7.02 (dd, J=11.3, 8.4Hz, 4H), 6.73 (d, J=7.7Hz, 1H), 6.64 (s, 1H), 4.68 (d, J=8.5Hz, 1H), 4.56 (s, 2H) , 4.49 (d, J = 9.4Hz, 2H), 4.41–4.19 (m, 5H), 3.81 (dd, J = 14.4, 7.2Hz, 3H), 3.63–3.40 (m, 9H), 3.25 (d, J=6.7Hz, 6H), 2.46 (s, 3H), 2.21 (s, 3H), 2.04 (d, J=7.9Hz, 6H), 1.32 (d, J=31.2Hz, 5H), 0.94 (s, 9H).

[0501] Preparation of compound A36

[0502] Step A: tert-Butyl (2-((3-(8-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0503] To a solution of compound 4 (0.15 g, 0.318 mmol) in N,N'-dimethylformamide (2 mL) were added 3-((2-((tert-butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl 4-methylbenzenesulfonate (0.210 g, 0.384 mmol), potassium carbonate (0.132 g, 0.956 mmol) and sodium iodide (0.096 g, 0.640 mmol). The resulting mixed solution was purged with nitrogen and stirred at 70 ° C under nitrogen protection for 12 hours. The reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to give compound 5 (80 mg, yield: 30%). LCMS [M+H] + m / z: 845.4.

[0504] Step B: 2-(6-amino-5-(4-(3-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0505] To a solution of compound 5 (0.1 g) in methanol (1 mL) was added a 4 M hydrochloric acid / dioxane solution (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness to afford crude compound 6, which was used directly in the next reaction.

[0506] Step C: (2S,4R)-N-(2-((3-(8-(4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0507] To a solution of compound 6 (0.12 g, 0.164 mmol) in N,N'-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (0.056 g, 0.434 mmol), VHL-INT-02 (0.096 g, 0.290 mmol), and HATU (0.072 g, 0.189 mmol). The resulting mixture was stirred at room temperature under N2 for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A36 (4 mg, yield: 2.3%) as a white solid. LCMS [M+H] + m / z: 1057.6. 1 H NMR (400MHz, MeOD): δ8.87 (s, 1H), 7.78 (d, J=7.4Hz, 1H), 7.54 (d, J=8.1Hz, 3H), 7.36–7.12 (m, 6H), 7.00–6.77 (m , 5H), 4.75 (d, J=6.8Hz, 2H), 4.62 (t, J=8.4Hz, 1H), 4.50 (t, J=13.7Hz, 3H), 4.29 (s, 2H), 3.80 (dt, J=11.0, 7.4Hz, 2H), 3.66 (d, J=26.1Hz, 3H), 3.25 (s, 4H), 3.02 (t, J=6.5Hz, 3H), 2.88 (s, 7H), 2.74–2.57 (m, 8H), 2.48 (d, J=3.9Hz , 4H), 2.33–2.17 (m, 1H), 2.18–2.01 (m, 2H), 1.95 (d, J=9.8Hz, 4H), 1.75 (s, 2H), 1.50–1.21 (m, 5H), 1.05 (s, 10H).

[0508] Preparation of compound A37

[0509] Step A: tert-Butyl 3-(2-fluoro-4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0510] To a solution of compound 1 (5 g, 23.585 mmol) and 3,4-difluorobenzaldehyde (3.68 g, 25.915 mmol) in N,N'-dimethylformamide (50 mL) were added potassium carbonate (9.7 g, 70.289 mmol) and sodium iodide (354 mg, 2.360 mmol). The resulting mixture was stirred at 120°C for 12 hours. The reaction solution was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (EA / PE = 0 / 100-40 / 60) to obtain compound 2 (2.1 g, yield: 27%). LCMS [M+H] + m / z: 335.2.

[0511] Step B: tert-Butyl 3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0512] Compound 2 (2.6 g, 7.784 mmol) and WH-INT-01-MOM (2.1 g, 6.666 mmol) were dissolved in dichloroethane (10 mL). After stirring at room temperature for 2 hours, the mixture was cooled to 0 ° C and sodium acetate borohydride (4.2 g, 19.811 mmol) was slowly added. The resulting mixed solution was stirred at room temperature overnight. Saturated brine (100 mL) was added to quench the reaction, and then extracted three times with dichloromethane, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was eluted by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 3 (2.2 g, yield: 52%). LCMS[M+H] + m / z: 634.4.

[0513] Step C: 2-(5-(4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorobenzyl)piperazin-1-yl)-6-aminopyridazin-3-yl)phenol

[0514] To a solution of compound 3 (400 mg, 0.632 mmol) in methanol (4 mL) was slowly added HCl / dioxane solution (4 M, 1.0 mL) at 0°C. The resulting mixture was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure to afford compound 4 (309 mg, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z: 490.2.

[0515] Step D: tert-Butyl (2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0516] Compound 4 (150 mg, 0.306 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), and potassium carbonate (92 mg, 0.613 mmol), INT-01 (195 mg, 0.367 mmol) and sodium iodide (127 mg, 0.920 mmol) were added. The resulting mixture was stirred at 70 ° C overnight. The reaction solution was poured into ice water (50 mL), extracted with EA (10 mL × 3), and then anhydrous sodium sulfate was added to the organic phase for drying, filtration and concentration to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to obtain compound 5 (223 mg, yield: 85.7%). LCMS [M + H] + m / z: 849.4.

[0517] Step E: 2-(6-amino-5-(4-(8-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)amino)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorobenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0518] To a solution of compound 5 (223 mg, 0.262 mmol) in methanol (2 mL) was slowly added HCl / dioxane solution (4 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to afford compound 6 (196 mg, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z: 749.4.

[0519] Step F: (2S,4R)-N-(2-((3-(3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0520] Compound VHL-INT-02 (173 mg, 0.524 mmol) was dissolved in dry N,N'-dimethylformamide (1 mL), cooled to 0°C, and HATU (119 mg, 0.313 mmol), N,N-diisopropylethylamine (101 mg, 0.782 mmol), and compound 6 (196 mg, 0.262 mmol) were slowly added. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water. Extraction was performed with ethyl acetate (3 x 30 mL), washed with saturated brine (50 mL), and filtered and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 40 / 60) to obtain the target compound A37 (39 mg, yield: 7.0%) as a white solid. LCMS [M+H] + m / z: 1061.6. 1 H NMR (400MHz, MeOD): δ8.82 (s, 1H), 7.78 (d, J=7.5Hz, 1H), 7.51 (s, 1H), 7.24 (t, J=7.9Hz, 2H), 7.05 (d, J=6. 9Hz, 2H), 6.95–6.84 (m, 3H), 6.70 (d, J=9.1Hz, 2H), 4.73 (s, 1H), 4.60–4.47 (m, 2H), 4.34 (dd, J=35.7, 14.7 Hz, 2H), 3.81 (s, 2H), 3.56 (s, 2H), 3.48 (s, 4H), 3.16 (d, J=26.7Hz, 6H), 3.04 (s, 2H), 2.66 (d, J=30.1Hz, 6H ), 2.49 (s, 3H), 2.13 (d, J=42.5Hz, 2H), 1.97 (d, J=31.3Hz, 6H), 1.32 (dd, J=20.3, 8.3Hz, 4H), 1.03 (s, 9H).

[0521] Preparation of compound A38

[0522] Step A: tert-Butyl (2-((3-(2-fluoro-4-formylphenoxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0523] Under nitrogen protection, SM2 (59 mg, 0.42 mmol), sodium iodide (105 mg, 0.7 mmol) and potassium carbonate (145 mg, 1.05 mmol) were added to a solution of compound 1 (200 mg, 0.35 mmol) in N,N'-dimethylformamide (3 mL). The resulting mixture was stirred at 70 ° C overnight. After cooling to room temperature, the reaction solution was diluted with water, extracted with ethyl acetate 3 times, washed with saturated brine 3 times, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to obtain a yellow oily compound 2 (100 mg, yield: 52.9%). LCMS[M+H] + m / z: 542.3.

[0524] Step B: tert-Butyl (2-((3-(5-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenoxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0525] Compound 2 (100 mg, 0.185 mmol) and WH-INT-01-MOM (70 mg, 0.222 mmol) were dissolved in dichloroethane (2 mL) solution, and sodium acetate borohydride (118 mg, 0.555 mmol) was added. The resulting mixed solution was stirred at room temperature for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give a yellow oily compound 3 (87 mg, yield: 56.2%). LCMS[M+H] + m / z: 841.5.

[0526] Step C: 2-(6-amino-5-(4-(3-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(isopropyl)amino)propoxy)-4-fluorobenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0527] To a solution of compound 3 (87 mg, 0.104 mmol) in methanol (1.5 mL) was added HCl / dioxane solution (4 M, 1.5 mL). The resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain crude compound 4, which was used directly in the next reaction. LCMS [M+H] + m / z: 697.5.

[0528] Step D: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenoxy)propyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0529] To a solution of VHL-INT-02 (43 mg, 0.13 mmol) in N,N'-dimethylformamide (2 mL) at 0°C under nitrogen was added N,N-diisopropylethylamine (57 mg, 0.44 mmol) and HBTU (50 mg, 0.13 mmol). After stirring for 30 minutes, a solution of compound 4 (76 mg, 0.11 mmol) in N,N'-dimethylformamide (1 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A38 (15 mg, yield: 8.2%) as a white solid. LCMS [M+H] + m / z: 1009.7. 1 H NMR (400MHz, MeOD): δ8.86 (s, 1H), 7.79 (d, J=7.9Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.51 (s, 1H), 7.32 (s, 1H), 7.24 (t, J=7.7Hz, 1H), 7. 17 (d, J=6.7Hz, 1H), 7.10 (d, J=12.2Hz, 1H), 7.03 (d, J=8.6Hz, 1H), 6.97 (d, J=8.5Hz, 1H), 6.95–6.87 (m, 1H)2H), 4.76 (s, 1H), 4.67– 4.59 (m, 1H), 4.58–4.45 (m, 3H), 4.05 (s, 2H), 3.83 (dt, J=11.0, 7.1Hz, 2H), 3.55 (s, 2H), 3.24–3.10 (m, 5H), 2.68 (s, 4H), 2.47 (s, 3H) ), 2.30–2.20 (m, 1H), 2.12 (ddd, J=13.4, 9.2, 4.5Hz, 1H), 1.81 (s, 2H), 1.43–1.20 (m, 5H), 1.13 (dd, J=11.7, 6.5Hz, 7H), 1.06 (s, 9H).

[0530] Preparation of compound A39

[0531] Step A: tert-Butyl (2-(cyclopropyl(3-(2-fluoro-4-formylphenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0532] To a solution of 3-((2-((tert-butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)propyl 4-methylbenzenesulfonate (200 mg, 0.350 mmol) in N,N'-dimethylformamide (5 mL) were added 3-fluoro-4-hydroxybenzaldehyde (58.8 mg, 0.420 mmol), potassium carbonate (145 mg, 1.050 mmol), and sodium iodide (105 mg, 0.700 mmol). The resulting mixture was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water, extracted with ethyl acetate (200 mL x 3), washed with saturated brine (200 mL x 3), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100 to 30 / 70) to obtain compound 1 (175 mg, yield: 92.9%) as a yellow solid. LCMS [M+H] + :m / z=540.4.

[0533] Step B: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenoxy)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0534] Compound 1 (175 mg, 0.324 mmol) and WH-INT-01-MOM (102 mg, 0.324 mmol) were dissolved in dichloroethane (10 mL). The mixture was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (206 mg, 0.972 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was diluted with water (25 mL) and extracted with dichloromethane (25 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol / EA=0 / 100~10 / 90) to obtain compound 2 (239 mg, yield: 88.1%) as a yellow solid. LCMS[M+H] + :m / z=839.5.

[0535] Step C: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)propoxy)-3-fluorobenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0536] To a solution of compound 2 (239 mg, 0.285 mmol) in methanol (5 mL) was added a 2 M HCl / dioxane solution (5 mL) at 0°C. The resulting mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to afford compound 3 (331 mg, yield: 100%) as a white solid, which was used directly in the next reaction. LCMS [M+H] + :m / z=695.4.

[0537] Step D: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenoxy)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0538] To a solution of compound 3 (331 mg, 0.476 mmol), VHL-INT-02 (189 mg, 0.572 mmol), and N,N-diisopropylethylamine (246 mg, 1.904 mmol) in N,N'-dimethylformamide (5 mL) was added HATU (217 mg, 0.572 mmol) at 0°C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water to precipitate a yellow solid, which was filtered. The filter cake was washed with water and dried to obtain a residue. The residue was purified by silica gel column chromatography (eluting first with EA / PE = 0 / 100 to 100 / 0, then with methanol / EA = 0 / 100 to 100 / 0) to obtain a crude product as a yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to give a pale yellow solid compound A39 (33 mg, yield: 6.9%). LCMS [M+H] + :m / z=1007.5. 1H NMR (400MHz, MeOD): δ8.87 (s, 1H), 7.79 (dd, J=8.2, 1.4Hz, 1H), 7.51 (s, 1H), 7.47 (d, J=8.0Hz, 1H), 7.40 (d, J=1.7Hz, 1H), 7.27-7.21 (m, 1H ), 7.12 (d, J=1.5Hz, 1H), 7.09 (dd, J=3.6, 1.8Hz, 1H), 7.05-6.88 (m, 4H), 4.75 (s, 1H), 4.64-4.55 (m, 1H), 4.50 (m, 2H), 4.38 (m, 1H), 4.07 (m 2H), 3.81 (m, 2H), 3.54 (s, 2H), 3.15 (m, 4H), 2.67 (d, J=3.4Hz, 5H), 2.48 (d, J=7.1Hz, 3H), 2.20 (s, 1H), 2.16-2.01 (m, 3H), 1.40-1.19 (m, 4H), 1.04 (s, 9H), 0.67 (d, J=6.4Hz, 2H), 0.46 (m, 2H).

[0539] Preparation of compound A40

[0540] Step A: 2-((2-((tert-Butyldimethylsilyl)oxy)ethyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0541] Under nitrogen protection, NaH (0.4 g, 16.666 mmol) was added to a solution of compound 2 (2 g, 7.832 mmol) in N,N'-dimethylformamide (20 mL). After stirring at room temperature for 1 hour, (2-bromoethoxy)(tert-butyl)dimethylsilane (2.3 g, 9.583 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours under nitrogen protection. The reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to obtain compound 3 (1 g, yield: 31%). LCMS [M+H] + m / z: 414.1.

[0542] Steps B and C: tert-Butyl (2-((2-((tert-Butyldimethylsilyl)oxy)ethyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0543] To a solution of compound 3 (1 g, 2.417 mmol) in tetrahydrofuran (40 mL) was added dropwise LiAlH4-tetrahydrofuran solution (1 M, 7.3 mL). The resulting mixed solution was stirred at room temperature for 2 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and ethanol (10 mL), NaHCO3 (0.61 g, 7.261 mmol) and Boc2O (1.32 g, 6.048 mmol) were added to the above reaction solution. The resulting mixed solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated to remove the organic solvent to obtain a residue. The residue was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to obtain compound 5 (0.37 g, yield: 30%). LCMS[M+H] + m / z: 516.3.

[0544] Step D: tert-Butyl (2-(cyclopropyl(2-hydroxyethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0545] To a solution of compound 5 (0.3 g, 0.579 mmol) in tetrahydrofuran (5 mL) was added TBAF-tetrahydrofuran solution (1 M, 0.7 mL). The resulting mixed solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 6 (0.23 g, yield: 98%). LCMS[M+H] + m / z: 404.2.

[0546] Step E: 2-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)ethyl 4-methylbenzenesulfonate

[0547] To a solution of compound 6 (0.23 g, 0.569 mmol) in dichloromethane (3 mL) was added TEA (0.175 g, 1.729 mmol) and TosCl (0.12 g, 0.629 mmol). The resulting mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 7 (130 mg, yield: 42%). LCMS[M+H] + m / z: 558.2.

[0548] Step F: tert-Butyl (2-(cyclopropyl(2-(4-(4-formylphenyl)piperazin-1-yl)ethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0549] To a solution of compound 7 (0.15 g, 0.268 mmol) in N,N'-dimethylformamide (2 mL) were added 4-(piperazin-1-yl)benzaldehyde (0.065 g, 0.341 mmol), potassium carbonate (0.11 g, 0.797 mmol) and sodium iodide (0.08 g, 0.533 mmol). The resulting mixture was stirred at 70 ° C for 12 hours under nitrogen. After the reaction was completed, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to obtain compound 8 (100 mg, yield: 66%). LCMS[M+H] + m / z: 576.4.

[0550] Step F: tert-Butyl (2-((2-(4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)ethyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0551] To a solution of compound 8 (100 mg, 0.173 mmol) in dichloroethane (1 mL) was added WH-INT-01-MOM (54.5 mg, 0.173 mmol). The mixture was stirred at room temperature under N2 for 1 hour, and then sodium acetate borohydride (0.115 g, 0.542 mmol) was added. The resulting mixed solution was stirred at room temperature under nitrogen protection for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 9 (100 mg, yield: 66%). LCMS[M+H] + m / z: 875.6.

[0552] Step G: 2-(6-amino-5-(4-(4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)ethyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0553] To a solution of compound 9 (0.1 g, 0.114 mmol) in methanol (1 mL) was added a 2 M HCl / dioxane solution (2 mL). The resulting mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction solution was concentrated to afford compound 10 (0.1 g, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + M / z: 677.3.

[0554] Step H: (2S,4R)-N-(2-((2-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)ethyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0555] To a solution of compound 10 (0.1 g, 0.136 mmol) in N,N'-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (0.055 g, 0.426 mmol), VHL-INT-02 (0.095 g, 0.287 mmol), and HATU (0.065 g, 0.171 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A40 (6 mg, yield: 4.2%) as a white solid. LCMS [M+H] + m / z: 1043.6. 1 H NMR (400MHz, MeOD): δ8.85 (s, 1H), 7.78 (d, J=7.6Hz, 1H), 7.49 (dd, J=14.2, 6.5Hz, 4H), 7.24 (d, J=8.6Hz, 4H), 7.15 (d , J=6.4Hz, 1H), 6.91 (d, J=8.3Hz, 5H), 4.85 (s, 2H), 4.75 (s, 1H), 4.60 (t, J=8.5Hz, 1H), 4.45 (dd, J=33.7, 13.0Hz, 3H), 3.84 (dd, J=15.9, 7.4Hz, 2H), 3.56 (s, 3H), 3.15 (d, J=31.2Hz, 10H), 2.71 (t, J=33.3Hz, 14H), 2.49 (s, 4H), 2.23 (d, J=7 .4Hz, 1H), 2.15–2.05 (m, 1H), 1.33 (dd, J=22.7, 7.7Hz, 5H), 1.06 (s, 9H), 0.67 (d, J=6.3Hz, 2H), 0.46 (d, J=6.6Hz, 2H).

[0556] Preparation of compound A41

[0557] Step A: tert-Butyl 4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidine-1-carboxylate

[0558] Compound 1 (0.500 g, 1.73 mmol) and WH-INT-01-MOM (367 mg, 1.73) were dissolved in dichloroethane (20 mL) solution and stirred at room temperature for 30 minutes, and then sodium acetate borohydride (1.467 g, 6.92 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated and diluted with water (10 mL), extracted with EA (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (methanol / EA=0 / 100-10 / 90) to give compound 2 (727 mg, yield: 71.5%) as a yellow solid. LCMS[M+H] + m / z=589.5.

[0559] Step B: 2-(6-amino-5-(4-(piperidin-4-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0560] To a solution of compound 2 (727 mg) in methanol (10 mL) was added a 2M HCl / dioxane solution (20 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to afford compound 3 (822 mg, yield: 93%) as a yellow powder. LCMS [M+H] + m / z=445.3.

[0561] Step C: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidin-1-yl)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0562] A solution of compound 3 (822 mg, 1.85 mmol), 3-((2-((tert-butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)propyl 4-methylbenzenesulfonate (1.268 g, 2.22 mmol) and potassium carbonate (307 mg, 2.22 mmol) in N,N'-dimethylformamide (10 mL) was stirred at 70 ° C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with EA (10 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (methanol / EA=0 / 100-10 / 90) to give compound 4 as a yellow solid (852 mg, yield: 54.6%). LCMS[M+H] + m / z=844.7.

[0563] Step D: 2-(6-amino-5-(4-(4-(1-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)propyl)piperidin-4-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0564] To a solution of compound 4 (852 mg, 1.01 mmol) in methanol (10 mL) was added HCl / dioxane solution (2 M, 10 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to afford compound 5 (955 mg, yield: 100%) as a yellow solid. LCMS [M+H] + m / z=744.5.

[0565] Step E: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperidin-1-yl)propyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0566] To a solution of compound 5 (955 mg, 1.28 mmol), VHL-INT-02 (0.509 g, 1.54 mmol), and N,N-diisopropylethylamine (2 mL) in N,N'-dimethylformamide (3 mL) was added HATU (586 mg, 1.54 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by Prep-HPLC (C18, flow rate: 30 ml / min, mobile phase: H2O (0.1% FA) / CH3CN = 20 / 80) to obtain the target compound A41 (124 mg, yield: 9.2%) as a pale yellow solid. LCMS [M+H] + m / z=1056.6. 1H NMR (400MHz, MeOD): δ8.87 (s, 1H), 7.85-7.72 (m, 1H), 7.50 (d, J=5.9Hz, 2H), 7.40 (d, J=1.7Hz, 1H), 7.30 (d, J=8.1Hz, 2H), 7.27-7.18 (m, 3H), 7.16 (dd, J=8.0, 1.7Hz, 1H), 6.97-6.82 (m, 2H), 4.76 (s, 1H), 4.61 (t, J=8.3Hz, 1H), 4.51 (d, J=15.7Hz, 2H), 4.42 (s, 1H), 4.3 8 (s, 1H), 3.83 (dt, J = 11.0, 7.5Hz, 2H), 3.63 (d, J = 20.2Hz, 2H), 3.24-3.00 (m, 8H), 2.79-2.61 (m, 5H), 2.49 (d, J = 10.5Hz, 5H), 2.14 (d d, J=12.3, 7.9Hz, 4H), 1.81 (dd, J=35.4, 25.6Hz, 6H), 1.47-1.16 (m, 4H), 1.05 (s, 9H), 0.66 (d, J=6.4Hz, 2H), 0.45 (d, J=11.5Hz, 2H).

[0567] Preparation of compound A42

[0568] Step A: tert-Butyl (2-((3-(4-(4-((4-(4-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)piperazin-1-yl)-2,2-dimethylpropyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0569] Under nitrogen protection at room temperature, Et3N (39 mg, 0.384 mmol) was added to a solution of compound 2 (213 mg, 0.461 mmol) and SM2 (160 mg, 0.384 mmol) in N,N'-dimethylformamide (2 mL). After stirring at room temperature for 8 hours, sodium acetate borohydride (244 mg, 1.152 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water to precipitate compound 3 (111 mg, yield: 48%). LCMS [M+H] + m / z: 865.7.

[0570] Step B: 2-(6-amino-5-(4-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(methyl)amino)-2,2-dimethylpropyl)piperazin-1-yl)-3-fluorobenzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0571] To a solution of compound 3 (111 mg, 0.13 mmol) in methanol (1 mL) was added HCl / dioxane solution (4 M, 2 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to afford crude compound 4, which was used directly in the next step. LCMS [M+H] + m / z: 765.5.

[0572] Step C: (2S,4R)-N-(2-((3-(4-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)-2-fluorophenyl)piperazin-1-yl)-2,2-dimethylpropyl)(methyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0573] To a solution of VHL-INT-02 (52 mg, 0.156 mmol) in N,N'-dimethylformamide (2 mL) at 0°C under nitrogen was added N,N-diisopropylethylamine (67 mg, 0.52 mmol) and HBTU (60 mg, 0.156 mmol). After stirring for 30 minutes, a solution of compound 4 (90 mg, 0.13 mmol) in N,N'-dimethylformamide (1 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 20 / 80) to obtain the target compound A42 (15 mg, yield: 8.2%) as a white solid. LCMS [M+H] + m / z: 1077.7. 1H NMR (400MHz, MeOD): δ8.86(s,1H),7.77(s,1H),7.59–7.48(m,2H),7.28–7.14(m,3H),7.10(d,J=1 4.2Hz,2H),6.99(s,1H),6.94–6.88(m,2H),4.75(s,1H),4.57(dd,J=36.3,15.5Hz,4H),3.85(s,2 H),3.57(s,2H),3.19(s,4H),3.04(dd,J=17.6,10.5Hz,6H),2.84–2.57(m,12H),2.50(d,J=10.3H z,5H),2.25(dd,J=13.4,7.6Hz,1H),2.12(m,1H),1.31(m,4H),1.05(s,9H),0.79(d,J=6.8Hz,6H).

[0574] Preparation of compound A43

[0575] Step A: 2-(4-(Hydroxymethyl)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzonitrile

[0576] To a solution of compound 1 (6 g, 27.522 mmol) in DMSO (50 mL) were added N,N-diisopropylethylamine (14 mL) and SM2 (4.2 g, 36.464 mmol). The resulting mixture was stirred at 110°C under nitrogen for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to obtain compound 2 (4 g, yield: 46%). LCMS [M+H] + m / z: 314.1.

[0577] Step B: 2-(4-(((tert-Butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzonitrile

[0578] To a solution of compound 2 (4 g, 12.762 mmol) in dichloromethane (40 mL) were added Im (1.5 g, 22.058 mmol) and TBDPSCl (3.6 g, 13.097 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-30 / 70) to obtain compound 3 (3.8 g, yield: 54%). LCMS [M+H] + m / z: 552.3.

[0579] Steps C and D: tert-Butyl (2-(4-(((tert-Butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0580] To a solution of compound 3 (3.5 g, 6.352 mmol) in tetrahydrofuran (60 mL) was added LiAlH4-tetrahydrofuran solution (1 M, 19 mL). The resulting mixture was stirred at room temperature under nitrogen protection for 2 hours. After the reaction was completed, ice water was added to quench the reaction, and the reaction solution was used directly in the next step. Ethanol (10 mL), NaHCO3 (1.6 g, 19.045 mmol) and Boc2O (3.5 g, 16.036 mmol) were added to the above reaction solution. The resulting mixture was stirred at room temperature for 12 hours. After the reaction was completed, the organic solvent in the reaction solution was removed under reduced pressure, poured into water and extracted with EA, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-50 / 50) to obtain compound 5 (1.2 g, yield: 30%). LCMS[M+H] + m / z: 655.4.

[0581] Step E: tert-Butyl (2-(4-(hydroxymethyl)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0582] To a solution of compound 5 (0.6 g, 0.914 mmol) in tetrahydrofuran (5 mL) was added TBAF-tetrahydrofuran solution (1 M, 1.1 mL). The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified using a silica gel column chromatography (PE / EA=60 / 40) to obtain compound 6 (300 mg, yield: 78%). LCMS [M+H] + m / z: 418.2.

[0583] Step F: (1-(2-(((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)piperidin-4-yl)methyl 4-methylbenzenesulfonate

[0584] To a solution of compound 6 (0.3 g, 0.718 mmol) in dichloromethane (3 mL) were added pyridine (0.17 g, 2.151 mmol) and TosCl (0.18 g, 0.944 mmol). The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to obtain compound 7 (235 mg, yield: 57%). LCMS [M+H] + m / z: 572.2.

[0585] Step G: tert-Butyl (2-(4-((4-formylphenoxy)methyl)piperidin-1-yl)-5-(4-methylthiazol-5-yl)benzyl)carbamate

[0586] To a solution of compound 7 (0.235 g, 0.411 mmol) in N,N'-dimethylformamide (2 mL) were added SM3 (0.070 g, 0.573 mmol), potassium carbonate (0.17 g, 1.231 mmol) and sodium iodide (0.125 g, 0.833 mmol). The resulting mixture was stirred at 70°C under nitrogen for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to obtain compound 8 (100 mg, yield: 46%). LCMS [M+H] + m / z: 522.4.

[0587] Step H: tert-Butyl (2-(4-((4-((4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)methyl)piperidin-1-yl)-5-(4-methylthiazol-5-yl)benzyl)carbamate

[0588] Under nitrogen protection at 0°C, compound 8 (100 mg, 0.191 mmol) and WH-INT-01-MOM (70 mg, 0.221 mmol) were dissolved in dichloroethane (1 mL) and stirred for 0.5 hours, followed by the addition of sodium acetate borohydride (115 mg, 0.542 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to give compound 9 (60 mg, yield: 38%). LCMS [M+H] + m / z: 821.4.

[0589] Step I: 2-(6-amino-5-(4-(4-((1-(2-(aminomethyl)-4-(4-methylthiazol-5-yl)phenyl)piperidin-4-yl)methoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0590] To a solution of compound 9 (0.1 g, 0.121 mmol) in methanol (1 mL) was added a 2 M HCl / Diox solution (2 mL). The resulting mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to obtain compound 10 (104 mg). LCMS [M+H] + m / z: 677.3.

[0591] Step J: (2S,4R)-N-(2-(4-(((4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)methyl)piperidin-1-yl)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0592] To a solution of compound 10 (0.06 g, 0.088 mmol) in N,N'-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (0.035 g, 0.271 mmol), VHL-INT-02 (0.095 g, 0.287 mmol), and HATU (0.065 g, 0.171 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A43 (6 mg) as a white solid. LCMS [M+H] + m / z: 989.5. 1 H NMR (400MHz, MeOD): δ8.86(d,J=7.0Hz,1H),7.78(d,J=8.3Hz,1H),7.46(dt,J=18.9,7.4Hz,2H),7.23(dd d,J=32.9,16.2,8.2Hz,5H),7.10–6.81(m,5H),4.75(s,1H),4.67–4.36(m,4H),4.08(s,1H),3.88(dd,J= 30.6,6.5Hz,3H),3.58(d,J=3.4Hz,2H),3.37(s,6H),3.26–3.02(m,7H),2.74(dd,J=44.2,25.8Hz,6H),2 .48(d,J=1.9Hz,4H),2.33–1.88(m,6H),1.65(s,2H),1.31(dd,J=17.2,12.8Hz,5H),1.17–0.98(m,10H).

[0593] Preparation of compound A44

[0594] Step A: 2-(Isobutylamino)-4-(4-methylthiazol-5-yl)benzonitrile

[0595] To a solution of 2-methylpropan-1-amine (2 g, 27.397 mmol) and compound 1 (7.7 g, 35.321 mmol) in DMSO (20 mL) was added N,N-diisopropylethylamine (14.1 g, 109.302 mmol). The resulting mixture was stirred at 110°C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (100 mL) and extracted three times with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-30 / 70) to obtain compound 2 (5.6 g, yield: 75.6%). LCMS [M+H] + m / z: 272.2.

[0596] Step B: 2-((3-((tert-Butyldimethylsilyl)oxy)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0597] Under nitrogen protection at 0°C, NaH (1.6 g, 39.999 mmol) was slowly added in batches to a solution of compound 2 (3.5 g, 12.915 mmol) in N,N'-dimethylformamide (35 mL), and the mixture was stirred at room temperature for 2 hours. Then the mixture was cooled to 0°C, (3-bromopropoxy)(tert-butyl)dimethylsilane (3.6 g, 14.229 mmol) was added, the mixture was slowly warmed to room temperature and stirred for 12 hours. Water was added to quench the reaction, the mixture was extracted with ethyl acetate (3x30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-40 / 60) to give compound 3 (1.2 g, yield 21%). LCMS[M+H] + m / z: 444.2.

[0598] Steps C and D: tert-Butyl (2-((3-((tert-butyldimethylsilyl)oxy)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0599] Compound 3 (1.2 g, 0.225 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to 0°C, and LiAlH4-tetrahydrofuran solution (1 M, 8.1 mL) was slowly added dropwise. After warming to room temperature and stirring for 2 hours, the mixture was cooled to 0°C and sodium sulfate decahydrate (870 mg, 2.701 mmol) was added to quench the reaction. Ethanol (10 mL), NaHCO3 (681 mg, 0.666 mmol), and Boc2O (1.47 g, 0.564 mmol) were then added. The resulting mixture was warmed to room temperature and stirred at room temperature overnight. The organic solvent was removed under reduced pressure, and water (100 mL) was added to dilute the reaction solution. The mixture was extracted three times with EA, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 (481 mg, yield: 32.5%). LCMS [M+H] + m / z: 548.4.

[0600] Step E: tert-Butyl (2-((3-hydroxypropyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0601] To a solution of compound 5 (481 mg, 0.875 mmol) in tetrahydrofuran (5 mL) was added TBAF-tetrahydrofuran solution (1 M, 1.1 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-30 / 70) to obtain compound 6 (229 mg, yield: 60.4%). LCMS [M+H] + m / z: 434.2.

[0602] Step F: 3-((2-(((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(isobutyl)amino)propyl 4-methylbenzenesulfonate

[0603] To a solution of compound 6 (229 mg, 0.528 mmol) in dichloromethane (3 mL) were added pyridine (125 mg, 1.582 mmol) and TosCl (130 mg, 0.682 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane (3 x 30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to obtain compound 7 (213 mg, yield: 68.7%). LCMS [M+H] +m / z: 749.4.

[0604] Step G: tert-Butyl (2-((3-(4-formylphenoxy)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0605] Compound 7 (100 mg, 0.170 mmol) was dissolved in dry N,N'-dimethylformamide (1 mL), followed by the addition of potassium carbonate (70 mg, 0.507 mmol), 4-hydroxybenzaldehyde (25 mg, 0.131 mmol), and sodium iodide (51 mg, 0.340 mmol). The resulting mixture was stirred at 70°C overnight. After cooling to room temperature, the reaction solution was diluted with water (50 mL) and extracted three times with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to give compound 8 (90 mg, yield: 98%). LCMS [M+H] + m / z: 538.4.

[0606] Step H: tert-Butyl (2-((3-(4-((4-((4-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0607] Compound 8 (90 mg, 0.167 mmol) and WH-TNT-01-MOM (68 mg, 0.215 mmol) were dissolved in dichloroethane (2 mL), stirred at room temperature for 2 hours, cooled to 0 ° C, and sodium acetate borohydride (115 mg, 0.542 mmol) was slowly added. After the addition was completed, the resulting mixture was slowly warmed to room temperature and stirred overnight. Saturated brine (100 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 9 (97 mg, yield: 65%). LCMS[M+H] + m / z: 837.4.

[0608] Step I: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(isobutyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0609] Under nitrogen protection at 0°C, a solution of compound 9 (97 mg, 0.116 mmol) in methanol (2 mL) was added with HCl-dioxane solution (2 M, 2 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain compound 10 (80 mg, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z: 693.4.

[0610] Step J: (2S,4R)-N-(2-((3-(4-((4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0611] Compound VHL-INT-02 (76 mg, 0.230 mmol) was dissolved in dry N,N'-dimethylformamide (1 mL), cooled to 0°C, and HATU (53 mg, 0.139 mmol), N,N-diisopropylethylamine (45 mg, 0.348 mmol), and compound 10 (80 mg, 0.115 mmol) were slowly added. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (50 mL), filtered, and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A44 (8 mg, 3.5%) as a white solid. LCMS [M+H] + m / z: 1005.1. 1H NMR (400MHz, MeOD): δ8.86(s,1H),7.78(d,J=8.4Hz,1H),7.53(s,2H),7.30(s,3H),7.25(d,J=7.6Hz,1H),7.17 (d,J=8.0Hz,1H),6.91(d,J=7.7Hz,4H),4.88(s,1H),4.83–4.82(m,1H),4.76(s,1H),4.62(s,2H),4.59–4.50(m ,2H),4.03(s,2H),3.83(s,4H),3.28–3.23(m,3H),3.16(s,3H),2.95(s,4H),2.83(dd,J=11.9,7.2Hz,2H),2.46 (s,3H),1.98(s,2H),1.82–1.76(m,1H),1.33(d,J=9.9Hz,2H),1.29(s,2H),1.07(s,9H),0.93(d,J=6.5Hz,6H).

[0612] Preparation of compound A45

[0613] Step A: tert-Butyl (2-((3-(4-(4-formylphenyl)piperazin-1-yl)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0614] Compound 7 (100 mg, 0.170 mmol) was dissolved in dry N,N'-dimethylformamide (1 mL), followed by the addition of potassium carbonate (70 mg, 0.507 mmol), 4-(piperazin-1-yl)benzaldehyde (40 mg, 0.210 mmol) and sodium iodide (51 mg, 0.340 mmol). The resulting mixture was stirred at 70°C overnight. After cooling to room temperature, water (50 mL) was added to dilute the reaction solution, which was extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was eluted by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to obtain compound 8 (86 mg, yield: 84%). LCMS [M+H] + m / z: 606.4.

[0615] Step B: tert-Butyl (2-((3-(4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0616] Compound 8 (86 mg, 0.141 mmol) and 6-(2-(methoxymethoxy)phenyl)-4-(piperazin-1-yl)pyridazin-3-amine (54 mg, 0.171 mmol) were dissolved in dichloroethane (2 mL). After stirring at room temperature for 2 hours, the mixture was cooled to 0°C and sodium acetate borohydride (90 mg, 0.424 mmol) was slowly added. The resulting mixture was stirred at room temperature overnight. Saturated brine (100 mL) was added to quench the reaction, followed by extraction with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was eluted by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 9 (116 mg, yield: 90.6%). LCMS[M+H] + m / z: 905.6.

[0617] Step C: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(isobutyl)amino)propyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0618] To a solution of compound 9 (116 mg, 0.128 mmol) in methanol (2 mL) was slowly added a 2M HCl / dioxane solution at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to afford compound 10 (97 mg, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z: 749.4.

[0619] Step D: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(isobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0620] VHL-INT-02 (84 mg, 0.254 mmol) was dissolved in dry N,N'-dimethylformamide (2 mL), cooled to 0°C, and HATU (58 mg, 0.153 mmol), DIEA (49 mg, 0.379 mmol), and compound 10 (97 mg, 0.127 mmol) were slowly added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A45 (12 mg) as a white solid. LCMS [M+H] + m / z: 1061.6. 1 H NMR (400MHz, MeOD): δ 8.88 (s, 1H), 8.43 (s, 1H), 7.78 (d, J = 7.9Hz, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.52 (s, 1H), 7.31 (d, J = 8.4Hz, 2H), 7.23 (dd, J =17.9, 9.0Hz, 2H), 6.97 (d, J = 8.5Hz, 2H), 6.92 (dd, J = 7.6, 4.3Hz, 2H), 4.75 (s, 1H), 4.64 (d, J = 7.5Hz, 1H), 4.60 (s, 1H), 4.50 (s, 1H), 3.83 (d d, J=23.9, 7.3Hz, 2H), 3.68 (s, 2H), 3.34 (s, 1H), 3.22 (s, 9H), 3.09 (t, J=7.3Hz, 2H), 2.97 (s, 3H), 2.79 (dd, J=21.3, 9.2Hz, 8H), 2.49 (s, 3H) , 2.14 (ddd, J=43.4, 41.9, 16.3Hz, 2H), 1.87 (d, J=29.6Hz, 3H), 1.37 (s, 2H), 1.28 (t, J=6.3Hz, 2H), 1.05 (s, 9H), 0.93 (dd, J=17.9, 6Hz, 6H).

[0621] Preparation of compound A46

[0622] Step A: 4-iodobutan-2-ol

[0623] To a solution of compound 1 (10.0 g, 111 mmol) in tetrahydrofuran (50 mL) were added imidazole (8.3 g, 122 mmol), triphenylphosphine (32.0 g, 122 mmol) and iodine (31.0 g, 122 mmol). The resulting mixed solution was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated Na2S2O3 solution (120 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 10 / 90) to give compound 2 (15.0 g, yield: 68%) as a colorless oil. LCMS [M+H] + m / z=201.0.

[0624] Step B: tert-Butyl((4-iodobutan-2-yl)oxy)diphenylsilane

[0625] A solution of compound 2 (5 g, 25.0 mmol), tert-butyldiphenylsilyl chloride (8.25 g, 30.0 mmol) and imidazole (2.04 g, 30.0 mmol) in dichloromethane (50 mL) was stirred at 25 ° C for 18 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 10 / 90) to give compound 3 (7.5 g, yield: 68.4%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ7.75-7.65(m, 4H), 7.46-7.30(m, 6H), 4.17-4.01(m, 1H), 3.95-3.76 (m, 2H), 1.74 (m, 1H), 1.62 (m, 1H), 1.20 (d, J=6.3Hz, 3H), 1.06 (s, 9H).

[0626] Step C: 2-((3-((tert-Butyldiphenylsilyl)oxy)butyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0627] To a solution of 2-(isopropylamino)-4-(4-methylthiazol-5-yl)benzonitrile (2g, 7.8mmol) in N,N'-dimethylformamide (20mL) was added NaH (1.57g, 39.2mmol) in batches at room temperature. After stirring at room temperature for 30 minutes, compound 3 (4.1g, 9.36mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was diluted with water (20mL), extracted with ethyl acetate (20mL x3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 10 / 90) to give a yellow solid compound 4 (3.81g, yield: 86.4%). LCMS [M+H] + m / z: 568.4.

[0628] Step D: 2-(Aminomethyl)-N-(3-((tert-butyldiphenylsilyl)oxy)butyl)-N-isopropyl-5-(4-methylthiazol-5-yl)aniline

[0629] To a solution of compound 4 (3.81 g, 6.7 mmol) in tetrahydrofuran (20 mL) was added dropwise a solution of LiAlH4-tetrahydrofuran (1 M, 13 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 5, which was used directly in the next reaction. LCMS [M+H] + m / z: 572.4.

[0630] Step E: tert-Butyl (2-((3-((tert-butyldiphenylsilyl)oxy)butyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0631] Compound 5 was dissolved in ethanol (30 mL), and sodium bicarbonate (1.69 g, 20.1 mmol) and di-tert-butyl dicarbonate (2.924 g, 13.4 mmol) were added in sequence. The resulting mixture was stirred at room temperature for 3 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 15 / 85) to obtain a yellow oily compound 6 (2.1 g, yield: 46.7%). LCMS [M+H] + m / z=672.5.

[0632] Step F: tert-Butyl (2-((3-hydroxybutyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0633] To a solution of compound 6 (2.1 g, 3.1 mmol) in tetrahydrofuran (20 mL) was added TBAF-tetrahydrofuran solution (1 M, 6.2 mL). The resulting mixed solution was stirred at room temperature for 16 hours. Water (20 mL) was added to dilute the reaction solution and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 50 / 50) to give compound 7 (755 mg, yield: 56.2%) as a yellow oil. LCMS [M+H] + m / z: 434.3.

[0634] Step G: tert-Butyl (2-((3-bromobutyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0635] Compound 7 (755 mg, 1.74 mmol) was dissolved in dichloromethane (30 mL), and carbon tetrabromide (0.693 g, 2.09 mmol) and triphenylphosphine (0.548 g, 2.09 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 15 / 85) to obtain compound 8 (0.522 g, yield: 60.4%) as a yellow oil. LCMS [M+H] + m / z=498.2.

[0636] Step H: tert-Butyl (2-((3-(4-formylphenoxy)butyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0637] To a solution of compound 8 (0.522 g, 1.05 mmol) in N,N'-dimethylformamide (30 mL) were added 4-hydroxybenzaldehyde (0.159 g, 1.3 mmol) and potassium carbonate (0.290 g, 2.1 mmol). The resulting mixture was stirred at 70 ° C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 50 / 50) to give a yellow solid compound 9 (0.432 g, yield: 76.5%). LCMS [M+H] + m / z=538.4.

[0638] Step I: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy))phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)butyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0639] Compound 9 (0.432 g, 0.8 mmol) and WH-INT-01-MOM (0.252 g, 0.8 mmol) were dissolved in dichloroethane (30 mL). Stirred at room temperature for 30 minutes. Then sodium acetate borohydride (0.678 g, 3.2 mmol) was added. The resulting mixed solution was stirred overnight at room temperature. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (methanol / ethyl acetate = 0 / 100 to 10 / 90) to give compound 10 (0.483 g, yield: 72.1%) as a yellow solid. LCMS [M+H] + m / z=837.5.

[0640] Step J: 2-(6-amino-5-(4-((4-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(isopropyl)amino)butan-2-yl)oxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0641] To a solution of compound 10 (0.483 g, 0.58 mmol) in methanol (3 mL) was added a 2 M HCl / dioxane solution (3 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford crude compound 11 as a yellow powder (0.611 g, yield: 100%), which was used directly in the next reaction. LCMS [M+H] + m / z=693.5.

[0642] Step K: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)butyl)(isopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0643] To a solution of compound 11 (0.611 g, 0.88 mmol) in N,N'-dimethylformamide (3 mL) at 0°C were added VHL-INT-02 (0.291 g, 0.88 mmol), N,N-diisopropylethylamine (2 mL), and HATU (0.403 g, 1.06 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A46 (0.015 g, yield: 1.8%) as a pale yellow solid. LCMS [M+H] + m / z=1005.5. 1 H NMR (400MHz, CD3OD): δ8.85 (d, J=3.1Hz, 1H), 7.79 (d, J=7.4Hz, 1H), 7.58 (d, J=7.1Hz, 1H), 7.51 (s, 1H), 7.32–7.09 (m, 5H), 6.92 (dd, J=7.6, 5 .4Hz, 2H), 6.76 (d, J=8.4Hz, 1H), 6.68 (d, J=8.3Hz, 1H), 4.76 (s, 1H), 4.70–4.59 (m, 1H), 4.50 (d, J=8.4Hz, 1H)dt, J=16.3, 12.0Hz, 4H), 3.83 (m 2H), 3.54(d, J=5.3Hz, 2H), 3.20(d, J=30.9Hz, 6H), 2.68(s, 4H), 2.53-2.40(m, 3H), 2.34–2.20(m, 1H), 2. 13(s, 1H), 1.81(s, 1H), 1.67-1.49(m, 1H), 1.44-1.20(m, 8H), 1.15(d, J=6.6Hz, 1H), 1.13-0.92(m, 14H).

[0644] Preparation of compound A47

[0645] Step A: 2-(Cyclobutylamino)-4-(4-methylthiazol-5-yl)benzonitrile

[0646] Compound 1 (5 g, 20.5 mmol), N,N-diisopropylethylamine (10 mL) and SM2 (3 g, 42 mmol) were dissolved in DMSO (7 mL). The resulting mixture was stirred at 50 ° C overnight under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted three times with ethyl acetate (50 mL). Anhydrous sodium sulfate was added to the combined organic phase and dried, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-50 / 50) and dried to obtain compound 2 (4.62 g). LCMS [M+H] + m / z=270.1.

[0647] Step B: 2-((3-((tert-Butyldimethylsilyl)oxy)propyl)(cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0648] To a solution of compound 2 (4.4 g, 16.3 mmol) in N,N'-dimethylformamide (20 mL) was added NaH (3.2 g, 80 mmol) in batches. After stirring for 30 minutes, SM3 (5 g, 19.7 mmol) was added. The resulting mixture was stirred at 25 ° C for 18 hours. Water was added to quench the reaction and extracted with ethyl acetate (3x30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography ((EA / PE=0 / 100-30 / 70)) to give compound 3 (4.07 g). LCMS[M+H] + m / z=442.2.

[0649] Step C and Step D: tert-Butyl (2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0650] To a solution of compound 3 (4.07 g, 9.25 mmol) in tetrahydrofuran (20 mL) at 0°C, slowly add LiH4-tetrahydrofuran solution (1 M, 30 mL). The resulting mixture is stirred at room temperature for 4 hours under nitrogen. The reaction solution is quenched with saturated brine (20 mL). The reaction solution is extracted with ethyl acetate (50 mL x 3), and the combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude target compound 4. The crude product is dissolved in ethanol, and sodium bicarbonate (2.39 g, 27.75 mmol) and di-tert-butyl carbonic anhydride (3.0 g, 13.7 mmol) are added. The resulting mixture is stirred at room temperature for 4 hours. Water (50 mL) is added to the reaction solution for dilution. The mixture is extracted with ethyl acetate (3 x 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 5 (2.37 g). LCMS [M+H] + m / z=670.3.

[0651] Step E: tert-Butyl (2-(cyclobutyl(3-hydroxypropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0652] To a solution of compound 5 (2.37 g, 4.3 mmol) in tetrahydrofuran (10 mL) was added TBAF-tetrahydrofuran solution (1 M, 10 mL). The resulting mixture was stirred at 25 ° C for 8 hours. The reaction solution was diluted with water and extracted with ethyl acetate (3x30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-30 / 70) to give compound 6 (0.85 g). LCMS [M+H] + m / z=432.2.

[0653] Step F: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclobutyl)amino)propyl 4-methylbenzenesulfonate

[0654] Under nitrogen protection at 0°C, compound 6 (0.85g, 2mmol), TsCl (0.75g, 5mmol) and triethylamine (0.6g, 6mmol) were added to dichloromethane (10mL). The resulting mixture was stirred at room temperature for 4 hours. Water (20mL) was added to the reaction solution and extracted with ethyl acetate (3x30mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 7 (800mg). LCMS [M+H] + m / z=586.2.

[0655] Step G: tert-Butyl (2-(cyclobutyl(3-(4-(4-formylphenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0656] To a solution of compound 7 (400 mg, 0.68 mmol) in N,N'-dimethylformamide (2 mL) were added SM4 (155 mg, 0.81 mmol) and potassium carbonate (282 mg, 2.04 mmol). The resulting mixed solution was stirred at 80 ° C for 8 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3x30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (100 / 0-50 / 50) to give compound 8 (240 mg, yield: 58%). LCMS [M+H] + m / z=604.3.

[0657] Step H: tert-Butyl (2-((3-(4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0658] A solution of compound 8 (240 mg, 0.4 mmol) and WH-INT-01-MOM (150 mg, 0.48 mmol) in dichloroethane (6 mL) was stirred at room temperature for 2 hours, and then sodium acetate borohydride (264 mg, 1.2 mmol) was added. The resulting mixed solution was stirred at room temperature for 18 hours. Water was added to the reaction solution and extracted with ethyl acetate (3x30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was subjected to silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 9 (235 mg). LCMS[M+H] + m / z=903.5.

[0659] Step I: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclobutyl)amino)propyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0660] To a solution of compound 9 (235 mg, 0.26 mmol) in methanol (5 mL) was added a HCl / dioxane solution (4 M, 2.5 mL). The resulting mixture was stirred at 0°C for 2 hours. The reaction solution was concentrated to afford compound 10 (240 mg), which was used directly in the next reaction. LCMS [M+H] + m / z=903.5.

[0661] Step J: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0662] Under nitrogen protection at 0°C, compound 10 (240 mg, 0.3 mmol), VHL-INT-02 (125 mg, 0.36 mmol), HATU (144 mg, 0.36 mmol), and N,N'-diisopropylethylamine (122 mg, 0.9 mmol) were added sequentially to N,N'-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 12 hours. The mixture was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A47 (30 mg) as a white solid. LCMS [M+H] + m / z=1071.6. 1 H NMR (400MHz, MeOD): δ8.87 (s, 1H), 7.77 (d, J=8.1Hz, 1H), 7.56 (d, J=8.5Hz, 1H), 7.50 (s, 1H), 7.25–7.18 (m, 5H), 6.94–6.89 (m, 4H), 4.76 (s, 1H), 4.63 (dd, J=15.5, 8.5Hz, 3H), 4.48 (d, J=21.0Hz, 1H), 3.91–3.74 (m, 3H ), 3.54 (s, 2H), 3.15 (d, J=16.6Hz, 9H), 3.04 (s, 2H), 2.68 (s, 4H), 2.55 (s, 4H), 2.39 (s, 2H), 2.26 (dd, J=13. 1, 7.6Hz, 1H), 2.17–2.00 (m, 3H), 1.90 (m, 2H), 1.73–1.53 (m, 5H), 1.31 (dd, J=5.9, 3.4Hz, 5H), 1.06 (m, 10H).

[0663] Preparation of compound A48

[0664] Step A: 2-(Cyclopentylamino)-4-(4-methylthiazol-5-yl)benzonitrile

[0665] To a solution of compound 1 (5 g, 22.9 mmol) in DMSO (60 mL) were added cyclopentylamine (2.15 g, 25.2 mmol) and N,N'-diisopropylethylamine (8.9 g, 68.7 mmol). The resulting mixed solution was stirred at 100 ° C overnight. After cooling to room temperature, the reaction solution was diluted with water (200 mL) and extracted three times with ethyl acetate. The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with petroleum ether / ethyl acetate (100 / 0 to 85 / 15) to give a yellow solid compound 2 (3.7 g, yield: 60%). LCMS [M+H] + m / z: 284.2.

[0666] Step B: 2-((3-((tert-Butyldimethylsilyl)oxy)propyl)(cyclopentyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0667] Under nitrogen protection at 0°C, NaH (1 g, 0.42 mmol) was added to a solution of compound 2 (2.4 g, 8.48 mmol) in N,N'-dimethylformamide (20 mL). After 30 minutes, (3-bromopropoxy)(tert-butyl)dimethylsilane (2.5 g, 10.17 mmol) was added. The resulting mixed solution was warmed to room temperature and stirred overnight. The reaction solution was diluted with water (200 mL) and extracted three times with ethyl acetate. The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with petroleum ether / ethyl acetate (100 / 0-80 / 20) to give a yellow solid compound 3 (2.7 g, yield: 71%). LCMS [M+H] + m / z: 456.2.

[0668] Step C and Step D: tert-Butyl (2-((3-((tert-butyldimethylsilyl)oxy)propyl)(cyclopentyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0669] At -15 ° C in a nitrogen atmosphere, LiAlH4-tetrahydrofuran solution (1M, 17 mL) was added to a solution of compound 3 (2.6 g, 5.7 mmol) in tetrahydrofuran (30 mL). The obtained mixed solution was warmed to room temperature and stirred overnight. The reaction solution was quenched with ice water (20 mL) at low temperature, and the obtained reaction solution was directly used for the next step reaction. Ethanol (20 mL), sodium bicarbonate (1.4 g, 17.1 mmol) and di-tert-butyl carbonic anhydride (2.5 g, 11.4 mmol) were added to the above reaction solution. The obtained mixed solution was stirred at room temperature for 6 hours. The organic solvent was removed under reduced pressure, water was added and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (100 / 0 to 50 / 50) to obtain compound 6 (1.18 g, yield: 35%) as a gray-brown oil. LCMS[M+H] + m / z: 560.4.

[0670] Step E: tert-Butyl (2-(cyclopentyl(3-hydroxypropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0671] To a solution of compound 5 (1.1 g, 2.1 mmol) in tetrahydrofuran (10 mL) was added TBAF-tetrahydrofuran solution (1 M, 6 mL). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (100 / 0 to 50 / 50) to obtain yellow oily compound 6 (445 mg, yield: 48%). LCMS [M+H] + m / z: 446.2.

[0672] Step F: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopentyl)amino)propyl 4-methylbenzenesulfonate

[0673] To a solution of compound 6 (400 mg, 0.98 mmol) in dichloromethane (10 mL) were added Et3N (272 mg, 2.94 mmol) and TsCl (204 mg, 1.17 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (100 / 0 to 60 / 40) to obtain compound 7 (381 mg, yield: 60%) as a yellow oil. LCMS [M+H] + m / z: 600.4.

[0674] Step G: tert-Butyl (2-(cyclopentyl(3-(4-(4-formylphenyl)piperazin-1-yl)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0675] To a solution of compound 7 (300 mg, 0.5 mmol) in N,N'-dimethylformamide (25 mL) were added 4-hydroxybenzaldehyde (80 mg, 0.52 mmol) and potassium carbonate (174 mg, 1.26 mmol). The mixture was stirred at 70 ° C under a nitrogen atmosphere for 0.5 hours, and then sodium iodide (125 mg, 0.84 mmol) was added. The resulting mixed solution was continued to react for 2 hours under a nitrogen atmosphere at 70 ° C. Then it was cooled to room temperature, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (100 / 0-50 / 50) to obtain a yellow solid compound 8 (135 mg, yield: 52%). LCMS [M+H] + m / z: 618.4.

[0676] Step H: tert-Butyl (2-((3-(4-((4-((3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(cyclopentyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0677] A solution of compound 8 (135 mg, 0.22 mmol) and WH-INT-01-MOM (63 mg, 0.2 mmol) in dichloroethane (4 mL) was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (127 mg, 0.6 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water (20 mL), extracted with ethyl acetate (20 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, first eluted with petroleum ether / ethyl acetate (100 / 0 to 10 / 90), then eluted with dichloromethane / methanol (99 / 1 to 90 / 10) to give compound 9 (147 mg, yield: 80%) as a white solid. LCMS[M+H] + m / z: 917.5.

[0678] Step I: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopentyl)amino)propyl)piperazin-1-yl)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0679] To a solution of compound 9 (147 mg, 0.16 mmol) in methanol (1.5 mL) was added HCl / dioxane solution (4 M, 2.0 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 10 (147 mg, yield: 100%) as a white solid, which was used directly in the next reaction. LCMS [M+H] + m / z: 773.5.

[0680] Step J: (2S,4R)-N-(2-((3-(4-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)propyl)(cyclopentyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0681] To a solution of compound 10 (147 mg, 0.19 mmol), VHL-INT-02, and N,N'-diisopropylethylamine (0.5 mL) in N,N'-dimethylformamide (20 mL) was added HATU (86 mg, 0.22 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and a white solid precipitated. The solid was filtered, and the filter cake was washed with water and dried to obtain a residue. The residue was purified by silica gel column chromatography, eluting first with petroleum ether / ethyl acetate (100 / 0 to 10 / 90) and then with dichloromethane / methanol (90 / 10) to obtain the crude product as a yellow solid. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 20 / 80) to obtain the target compound A48 (2.1 mg, yield: 17.5%) as a white solid. LCMS [M+H] + m / z: 1085.6. 1 H NMR (400MHz, MeOD) δ8.87 (s, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.59–7.48 (m, 2H), 7.38 (d, J = 9.6Hz, 1H), 7.28–7.18 (m, 4H), 6.96–6.86 (m, 4H), 4.76 (s, 1H), 4.69–4.56 (m, 3H), 4.48 (d, J=28.5Hz, 1H), 3.93–3.74 (m, 2H), 3.57– 3.46 (m, 3H), 3.13 (dd, J=20.0, 14.4Hz, 11H), 2.69 (s, 4H), 2.56 (s, 4H), 2.49 (s, 3H), 2.45–2.34 (m, 2H), 2.30 –2.21 (m, 1H), 2.18–2.06 (m, 1H), 1.74 (d, J=29.7Hz, 4H), 1.64–1.46 (m, 6H), 1.41–1.19 (m, 6H), 1.06 (s, 9H).

[0682] Preparation of compound A49

[0683] Step A: 4-iodobutan-2-ol

[0684] To a solution of compound 1 (10.0 g, 111 mmol) in tetrahydrofuran (50 mL) were added imidazole (8.3 g, 122 mmol), triphenylphosphine (32.0 g, 122 mmol) and iodine (31.0 g, 122 mmol). The resulting mixed solution was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated Na2S2O3 solution (120 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 10 / 90) to give compound 2 (15.0 g, yield: 68.0%) as a colorless oil. LCMS [M+H] + m / z=201.0.

[0685] Step B: tert-Butyl((4-iodobutan-2-yl)oxy)diphenylsilane

[0686] Compound 2 (5 g, 25.0 mmol), tert-butyldiphenylsilyl chloride (8.25 g, 30.0 mmol) and imidazole (2.04 g, 30.0 mmol) were dissolved in dichloromethane (50 mL) solution. The resulting mixed solution was stirred at 25 ° C for 18 hours. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100-10 / 90) to give a colorless liquid compound 3 (7.5 g, yield: 68.4%). 1 H NMR (400MHz, CDCl3) δ7.75-7.65 (m, 4H), 7.46-7.30 (m, 6H), 4.17-4.01 (m, 1H), 3 .95-3.76 (m, 2H), 1.74 (m, 1H), 1.62 (m, 1H), 1.20 (d, J=6.3Hz, 3H), 1.06 (s, 9H).

[0687] Step C: 2-((3-((tert-Butyldiphenylsilyl)oxy)butyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0688] To a solution of 2-(cyclopropylamino)-4-(4-methylthiazol-5-yl)benzonitrile (2g, 7.8mmol) in N,N'-dimethylformamide (20mL) was added NaH (1.57g, 39.2mmol) in batches at room temperature. After stirring for 30 minutes, compound 3 (4.1g, 9.36mmol) was added. The resulting mixed solution was stirred at room temperature overnight. Water (20mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20mL x3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100-10 / 90) to give compound 4 (3.75g, yield: 85.0%) as a yellow solid. LCMS [M+H] + m / z=566.4.

[0689] Step D: tert-Butyl(2-((3-((tert-butyldiphenylsilyl)oxy)butyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0690] To a solution of compound 4 (2.0 g, 3.53 mmol) in tetrahydrofuran (20 mL) was added LiAlH4-tetrahydrofuran solution (1 M, 11 mL). The resulting mixture was stirred at 25°C overnight. The reaction solution was quenched with ice water and used directly in the next reaction. LCMS [M+H] + m / z=570.4.

[0691] Step E: tert-Butyl (2-(cyclopropyl(3-hydroxybutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0692] To the reaction solution of the above compound 5, ethanol (30 mL), sodium bicarbonate (0.891 g, 10.59 mmol) and di-tert-butyl carbonic anhydride (1.54 g, 7.06 mmol) were added. The resulting mixed solution was stirred at room temperature for 6 hours. The organic solvent was removed under reduced pressure, diluted with water, extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 15 / 85) to obtain compound 6 (0.893 g, yield 18.9%) as a yellow oil. LCMS [M+H] + m / z=670.5.

[0693] Step F: tert-Butyl (2-(cyclopropyl-1(3-hydroxybutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0694] To a solution of compound 6 (0.892 g, 1.3 mmol) in tetrahydrofuran (20 mL) was added TBAF-tetrahydrofuran solution (1 M, 2.6 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 50 / 50) to obtain compound 7 (0.389 g, yield: 69.0%) as a yellow oil. LCMS [M+H] + m / z: 432.3.

[0695] Step G: tert-Butyl (2-((3-bromobutyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0696] To a solution of compound 7 (0.389 g, 0.90 mmol) in dichloromethane (30 mL) were added carbon tetrabromide (0.358 g, 1.08 mmol) and triphenylphosphine (0.283 g, 1.08 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 20 / 80) to obtain compound 8 (0.288 g, yield: 64.7%) as a yellow oil. LCMS [M+H] + m / z=494.3.

[0697] Step H: tert-Butyl (2-(cyclopropyl(3-(4-formylphenoxy)butyl))amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0698] To a solution of compound 8 (0.288 g, 0.58 mmol) in N,N'-dimethylformamide (20 mL) were added 4-hydroxybenzaldehyde (0.085 g, 0.70 mmol), sodium iodide (37.67 mg, 0.29 mmol) and potassium carbonate (0.240 g, 1.74 mmol). The resulting mixture was stirred at 70 ° C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 50 / 50) to obtain compound 9 (0.198 g, yield: 64%) as a yellow solid. LCMS [M+H] + m / z=536.4.

[0699] Step I: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy))phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)butyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0700] Compound 9 (0.198 g, 0.37 mmol) and WH-INT-01-MOM (0.177 g, 0.37 mmol) were dissolved in dichloroethane (30 mL) solution. Stirred at room temperature for 30 minutes, then sodium acetate borohydride (0.314 g, 1.48 mmol) was added. The resulting mixed solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100 to 10 / 90) to obtain a yellow solid compound 10 (0.211 g, yield: 68.3%). LCMS [M+H] + m / z=835.5.

[0701] Step J: 2-(6-amino-5-(4-((4-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)butan-2-yl)oxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0702] To a solution of compound 10 (0.211 g, 0.25 mmol) in methanol (3 mL) was added a 4 M HCl / dioxane solution (3 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford compound 11 (0.301 g, 100% yield) as a yellow solid, which was used directly in the next reaction. LCMS [M+H] + m / z=691.4.

[0703] Step K: (2S,4R)-N-(2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl))pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)butyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0704] Compound 11 (0.301 g, 0.44 mmol), VHL-INT-02 (0.175 g, 0.53 mmol), and N,N'-diisopropylethylamine (2 mL) were added to N,N'-dimethylformamide (3 mL) at 0°C, stirred until homogeneous, and then HATU (0.201 g, 0.53 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A49 (11 mg, yield: 2.49%) as a pale yellow solid. LCMS [M+H] + m / z=1003.5. 1 H NMR (400MHz, MeOD) δ8.85 (s, 1H), 7.77 (s, 1H), 7.50 (s, 1H), 7.45 (dd, J=8.0, 3.0Hz, 1H), 7.36 (s, 1H), 7.28-7.16 (m , 3H), 7.11 (s, 1H), 6.95-6.87 (m, 2H), 6.81 (d, J=7.7Hz, 2H), 4.75 (s, 1H), 4.58 (s, 1H), 4.53-4.29 (m, 4H), 3.89-3. 75 (m, 2H)), 3.54 (s, 2H), 3.22 (dd, J=21.0, 13.9Hz, 6H), 2.64 (dd, J=14.2, 10.6Hz, 5H), 2.47 (s, 3H), 2.22 (s, 1H), 2 .10 (s, 1H), 1.95 (dd, J=12.1, 5.3Hz, 2H), 1.37-1.22 (m, 7H), 1.10-1.00 (m, 9H), 0.64 (d, J=6.2Hz, 2H), 0.44 (s, 2H).

[0705] Preparation of compound A50

[0706] Step A: tert-Butyl (2-(cyclobutyl(3-(4-formylphenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0707] To a solution of compound 1 (300 mg, 0.5 mmol) in N,N'-dimethylformamide (2 mL) were added SM2 (75 mg, 0.6 mmol) and potassium carbonate (212 mg, 1.5 mmol). The resulting mixture was stirred at 80 ° C for 8 hours. Cooled to room temperature, water was added and extracted with ethyl acetate (3x30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (100 / 0-50 / 50) to obtain compound 2 (200 mg).

[0708] Step B: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(cyclobutyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0709] Compound 2 (200mg, 0.4mmol) and WH-INT-01-MOM (150mg, 0.48mmol) were dissolved in dichloroethane (2mL). The mixture was stirred at room temperature for 2 hours, and then sodium acetate borohydride (264mg, 1.2mmol) was added. The obtained mixed solution was continued to stir at room temperature for 18 hours. Water was added to the reaction solution and extracted with ethyl acetate (3x30mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (100 / 0-50 / 50) to obtain compound 3 (260mg). LCMS[M+H] + m / z=835.4.

[0710] Step C: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclobutyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0711] To a solution of compound 3 (260 mg, 0.31 mmol) in methanol (5 mL) was added a solution of HCl / dioxane (4 M, 2.5 mL). The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford compound 4 (260 mg), which was used directly in the next reaction.

[0712] Step D: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(cyclobutyl)amino)-4-(4-methylthiazol-5-yl)phenyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0713] Under nitrogen protection at 0°C, compound 4 (260 mg, 0.37 mmol), VHL-INT-02 (150 mg, 0.45 mmol), HATU (171 mg, 0.45 mmol), and N,N'-diisopropylethylamine (0.5 mL, 1.11 mmol) were added sequentially to N,N'-dimethylformamide (2 mL). The resulting mixture was warmed to room temperature and stirred for 12 hours. The mixture was concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 ml / min, mobile phase: H2O (0.1% FA) / CH3CN = 35 / 65) to obtain the target compound A50 (30 mg, yield: 8.2%) as a white solid. LCMS [M+H] + m / z=989.5. 1 H NMR (400MHz, MeOD): δ8.86 (s, 1H), 7.78 (d, J=8.2Hz, 1H), 7.61–7.43 (m, 2H), 7.28–7.14 (m, 5H), 6 .91 (dd, J=7.6, 4.2Hz, 2H), 6.83 (d, J=8.5Hz, 2H), 4.74 (d, J=13.7Hz, 1H), 4.67–4.55 (m, 3H), 4.50 (s, 1H), 3.95 (t, J=5.9Hz, 2H), 3.89–3.75 (m, 3H), 3.51 (d, J=25.2Hz, 2H), 3.25–3.07 (m, 6H), 2.67 (s, 4H), 2.29–1.99 (m, 5H), 1.99–1.75 (m, 4H), 1.74–1.57 (m, 2H), 1.42–1.19 (m, 5H), 1.05 (s, 9H).

[0714] Preparation of compound A51

[0715] Step A: 2-((Cyclopropylmethyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0716] To a DMSO (50 mL) solution of compound 1 (5 g, 22.935 mmol) and 2-methylpropan-1-amine (4.9 g, 69.014 mmol) was added N, N-diisopropylethylamine (11.8 g, 91.472 mmol). The resulting mixture was stirred at 80 ° C for 12 hours. After cooling to room temperature, water (150 mL) was added to quench the reaction, and ethyl acetate (100 mL) was added to extract three times. Then, anhydrous sodium sulfate was added to the organic phase and dried, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-50 / 50) to obtain compound 2 (6 g, yield: 98%). LCMS [M+H] + m / z: 270.2.

[0717] Step B: 2-((3-((tert-Butyldimethylsilyl)oxy)propyl)(cyclopropylmethyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0718] Under nitrogen protection at 0°C, NaH (3.5 g, 145.833 mmol) was added in batches to a solution of compound 2 (5.8 g, 21.561 mmol) in N,N-dimethylformamide (60 ml). After stirring for 2 hours, (3-bromopropoxy)(tert-butyl)dimethylsilane (10.9 g, 43.083 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction was quenched with water, extracted with ethyl acetate (3 x 100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-30 / 70) to obtain compound 3 (4.8 g, yield: 53%). LCMS [M+H] + m / z: 442.2.

[0719] Step C: tert-Butyl (2-((3-((tert-butyldimethylsilyl)oxy)propyl)(cyclopropylmethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0720] Compound 3 (2 g, 4.535 mmol) was dissolved in dry tetrahydrofuran (20 mL), cooled to 0°C, and a LiAlH4-tetrahydrofuran solution (1 M, 13.6 mL) was slowly added. The mixture was stirred at room temperature for 2 hours. After cooling to 0°C, sodium sulfate decahydrate (1.46 g, 4.534 mmol) was added to quench the reaction. The reaction mixture was filtered, and ethanol (20 mL), sodium bicarbonate (1.1 g, 13.095 mmol), and di-tert-butyl carbonic anhydride (2.5 g, 11.467 mmol) were added to the filtrate. The resulting mixture was warmed to room temperature and stirred overnight. The organic solvent was removed under reduced pressure, and the mixture was diluted with water (100 mL). The mixture was extracted three times with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-50 / 50) to obtain compound 4 (715 mg, yield: 28.9%). LCMS [M+H] + m / z: 548.4.

[0721] Step D: tert-Butyl (2-((cyclopropylmethyl)(3-hydroxypropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0722] To a solution of compound 4 (715 mg, 1.309 mmol) in tetrahydrofuran (5 mL) was added TBAF-tetrahydrofuran solution (1 M, 1.6 mL). The resulting mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water. The reaction solution was extracted with ethyl acetate (3x30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-50 / 50) to obtain compound 5 (411 mg, yield: 72%). LCMS [M+H] + m / z: 432.2.

[0723] Step E: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropylmethyl)amino)propyl 4-methylbenzenesulfonate

[0724] To a solution of compound 5 (411 mg, 0.953 mmol) in dichloromethane (6 mL) were added pyridine (225 mg, 2.848 mmol) and TosCl (236 mg, 1.242 mmol). The resulting mixture was stirred at room temperature under N2 for 12 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (3x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-30 / 70) to obtain compound 6 (400 mg, yield: 71.8%). LCMS[M+H] + m / z: 586.4.

[0725] Step F: tert-Butyl (2-((cyclopropylmethyl)(3-(4-formylphenoxy)propyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0726] Compound 6 (200 mg, 0.341 mmol) was dissolved in dry N,N-dimethylformamide (3 mL), and potassium carbonate (141 mg, 1.021 mmol), 4-(piperazin-1-yl)benzaldehyde (54 mg, 0.442 mmol) and sodium iodide (102 mg, 0.68 mmol) were added. The resulting mixture was stirred at 70 ° C overnight. Water (50 mL) was added to quench the reaction. The reaction solution was extracted three times with ethyl acetate (50 mL), and then anhydrous sodium sulfate was added to the organic phase for drying, filtration and concentration to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-60 / 40) to obtain compound 7 (170 mg, yield: 93%). LCMS[M+H] + m / z: 536.4.

[0727] Step G: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(cyclopropylmethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0728] To a solution of compound 7 (170 mg, 0.317 mmol) in dichloroethane (5 mL) was added WH-INT-01-MOM (109 mg, 0.346 mmol) and sodium acetate borohydride (202 mg, 0.952 mmol). The resulting mixed solution was stirred at room temperature under N2 for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to give compound 8 (200 mg, yield: 75%) LCMS[M+H] + m / z: 835.4.

[0729] Step H: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropylmethyl)amino)propoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0730] To a solution of compound 8 (200 mg, 0.239 mmol) in methanol (2 mL) was slowly added HCl / dioxane (4 M, 2 mL) at 0°C. The resulting mixture was stirred at room temperature for 4 hours. LCMS indicated a successful reaction. The reaction solution was spin-dried at low temperature to afford compound 9 (97 mg, yield: 100%). LCMS [M+H] + m / z: 691.4.

[0731] Step I: (2S,4R)-N-(2-((3-((4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)propyl)(cyclopropylmethyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0732] VHL-INT-02 (157 mg, 0.475 mmol) was dissolved in dry N,N-dimethylformamide (2 mL), cooled to 0°C, and HATU (108 mg, 0.284 mmol), N,N-diisopropylethylamine (92 mg, 0.713 mmol), and compound 9 (165 mg, 0.239 mmol) were slowly added. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water. The reaction solution was extracted with ethyl acetate (3 x 30 mL), washed with saturated brine (50 mL), and filtered and concentrated to obtain a residue. The residue was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A51 (10 mg, yield: 2.1%) as a white solid. LCMS [M+H] + m / z: 1003.5. 1 H NMR (400MHz, MeOD): δ8.86 (s, 1H), 7.78 (d, J = 7.0Hz, 1H), 7.55 (d, J = 8.0Hz, 1H), 7.50 (s, 1H), 7.35 (d, J = 1.5Hz, 1H), 7.26–7.18 (m, 4H) , 6.90 (m, 4H), 4.75 (s, 1H), 4.60 (dd, J=7.1, 4.2Hz, 2H), 4.50 (s, 1H), 4.03 (t, J=6.0Hz, 2H), 3.84 (dd, 1H)J=17.1, 7.4Hz, 2H), 3.55 (s, 2 H), 3.36 (t, J=6.8Hz, 2H), 3.17 (s, 4H), 2.84 (t, J=5.8Hz, 2H), 2.68 (s, 4H), 2.47 (s, 3H), 2.23 (d, J=7.7Hz, 1H), 2.13 (dd, J=9.1, 4.3Hz , 1H), 1.95–1.87 (m, 2H), 1.43–1.18 (m, 5H), 1.05 (d, J=9.0Hz, 9H), 0.90 (d, J=4.8Hz, 1H), 0.43 (d, J=8.0Hz, 2H), 0.06 (q, J=4.7Hz, 2H).

[0733] Preparation of compound A52

[0734] Step A: 2-((3-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0735] To a solution of compound 1 (5 g, 19.42 mmol) in N,N-dimethylformamide (50 mL) was added NaH (3.2 g, 80 mmol). The resulting mixed solution was stirred at 0 ° C under a nitrogen atmosphere for 1 hour. SM2 (9.3 g, 29.59 mmol) was then added. The resulting mixed solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-30 / 70) to obtain compound 2 (1.3 g, yield: 15%). LCMS[M+H] + m / z: 442.2.

[0736] Step B and Step C: tert-Butyl (2-((3-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0737] At -15 ° C in N2 atmosphere, to a solution of compound 2 (1.3 g, 2.94 mmol) in tetrahydrofuran (10 mL) was added LiAlH4-tetrahydrofuran solution (1M, 6 mL). The resulting mixed solution was heated to room temperature and stirred overnight. The reaction solution was quenched with ice water (5 mL), and ethanol (10 mL), sodium bicarbonate (0.76 g, 9.04 mmol) and di-tert-butyl carbonic anhydride (1.65 g, 7.56 mmol) were added to the reaction solution, and the resulting mixed solution was stirred at room temperature for 6 hours. Concentration gave a crude product. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (100 / 0-50 / 50) to give compound 4 (400 mg, yield: 25%) as a yellow oil. LCMS [M+H] + m / z: 546.3.

[0738] Step D: tert-Butyl (2-(cyclopropyl(3-hydroxy-2-methylpropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0739] To a solution of compound 4 (0.4 g, 0.732 mmol) in tetrahydrofuran (2 mL) was added TBAF-tetrahydrofuran solution (1 M, 1.1 mL). The resulting mixture was stirred at room temperature under N2 for 12 hours. After the reaction was completed, water was added to the reaction solution, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to obtain compound 5 (180 mg, yield: 57%). LCMS [M+H] + m / z: 432.2.

[0740] Step E: 3-((2-((tert-Butoxycarbonyl)amino)methyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)-2-methylpropyl 4-methylbenzenesulfonate

[0741] Under nitrogen protection at 0°C, pyridine (0.1 g, 1.26 mmol) and TsCl (0.11 g, 0.57 mmol) were added to a solution of compound 5 (0.18 g, 0.41 mmol) in dichloromethane (1 mL). The resulting mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 100-50 / 50) to obtain compound 6 (0.14 g, yield: 57%). LCMS [M+H] + m / z: 586.2.

[0742] Step F: tert-Butyl (2-(cyclopropyl(3-(4-formylphenoxy)-2-methylpropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0743] Under nitrogen protection, SM3 (0.045 g, 0.36 mmol), potassium carbonate (0.11 g, 0.797 mmol) and sodium iodide (0.075 g, 0.533 mmol) were added to a solution of compound 6 (0.14 g, 0.23 mmol) in N,N-dimethylformamide (2 mL). The resulting mixed solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE=0 / 100-50 / 50) to obtain compound 7 (90 mg, yield: 70%). LCMS[M+H] + m / z: 536.3.

[0744] Step G: tert-Butyl (2-((3-(4-((4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)-2-methylpropyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)carbamate

[0745] Under nitrogen protection at room temperature, WH-INT-01-MOM (0.08 g, 0.221 mmol) was added to a dichloroethane (1 mL) solution of compound 7 (90 mg, 0.168 mmol). Stir for 1 hour, then add sodium acetate borohydride (106.8 mg, 0.504 mmol). The resulting mixed solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM=0 / 100-12 / 88) to obtain compound 8 (70 mg, yield: 50%). LCMS[M+H] + m / z: 835.3.

[0746] Step H: 2-(6-amino-5-(4-(4-(3-((2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenyl)(cyclopropyl)amino)-2-methylpropoxy)benzyl)piperazin-1-yl)pyridazin-3-yl)phenol

[0747] Under nitrogen protection at room temperature, HCl / dioxane solution (4M, 2 mL) was added to a solution of compound 8 (0.07 g, 0.083 mmol) in methanol (1 mL). The resulting mixture was stirred for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 100-12 / 88) to obtain compound 9 (0.104 g). LCMS [M+H] + m / z: 835.3.

[0748] Step I: (2S,4R)-N-(2-((3-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)-2-methylpropyl)(cyclopropyl)amino)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0749] To a solution of compound 9 (0.07 g, 0.136 mmol) in N,N-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (0.055 g, 0.426 mmol), VHL-INT-02 (0.095 g, 0.287 mmol), and HATU (0.065 g, 0.171 mmol). The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC (C18, flow rate: 30 mL / min, mobile phase: H2O (0.1% FA) / CH3CN = 30 / 70) to obtain the target compound A52 (6 mg, yield: 6%) as a white solid. LCMS [M+H] + m / z: 1003.5. 1 H NMR (400MHz, MeOD): δ7.79 (d, J=7.7Hz, 1H), 7.51 (s, 1H), 7.46 (dd, J=7.9, 3.9Hz, 1H), 7.36 (d, J=1.8Hz, 1H), 7.23 (ddd, J=11.4, 8.6, 3.5Hz, 3H), 7.0 8(t, J=7.0Hz, 1H), 6.96–6.88(m, 2H), 6.82(t, J=8.2Hz, 2H), 4.75(s, 1H), 4.59 (dd, J) = 14.2, 6.7Hz, 1H), 4.51 (d, J = 13.3Hz, 2H), 4.38 (d, J = 16.1Hz, 1 H), 3.95–3.77(m, 4H), 3.55(d, J=2.4Hz, 2H), 3.27(s, 1H), 3.18(s, 4H), 3. 04 (dd, J=12.3, 5.0Hz, 1H), 2.68 (s, 5H), 2.46 (d, J=2.5Hz, 4H), 2.22 (s, 1H ), 2.10 (dd, J=9.1, 4.4Hz, 1H), 1.37-1.25 (m, 4H), 1.09 (dd, J=6.8, 2.4Hz, 3H), 1.05 (t, J=5.2Hz, 9H), 0.66 (d, J=6.3Hz), 2H), 0.46 (d, J=17.6Hz, 2H).

[0750] Preparation of compound A53

[0751] Step A: 2-(Cyclopentylamino)-4-(4-methylthiazol-5-yl)benzonitrile

[0752] To a solution of compound 1 (5 g, 22.9 mmol) in dimethyl sulfoxide (60 mL) were added cyclopentylamine (2.15 g, 25.2 mmol) and N,N-diisopropylethylamine (8.9 g, 68.7 mmol). The resulting mixed solution was stirred at 100 ° C overnight. After cooling to room temperature, the reaction solution was diluted with water (200 mL) and extracted three times with ethyl acetate. The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography and eluted with petroleum ether / ethyl acetate (100 / 0-85 / 15) to give a yellow solid compound 2 (4.1 g, yield: 64.2%). LCMS [M+H] + m / z: 284.2.

[0753] Step B: 2-((3-((tert-Butyldimethylsilyl)oxy)propyl)(cyclopentyl)amino)-4-(4-methylthiazol-5-yl)benzonitrile

[0754] Under nitroge...

Claims

1. A compound as represented by chemical formula I, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, or hydrates: in, R1 is selected from hydrogen, alkyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; R2 is selected from hydrogen, alkyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; L is a linker selected from any one of the structures shown in chemical formula II: or or or or (II) in, R3, R4, R 10 、R 11 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, halogen, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocyclic ring, aromatic heterocyclic ring, substituted aromatic heterocyclic ring; R3, R4, R 10 、R 11 It can be the same or different; Group A is independently selected from the following structures: In group A, R5 and R6 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, cyano, alkoxy, substituted alkoxy, trifluoromethyl, C 3-8 saturated or unsaturated carbon ring, aryl, substituted aryl, C 3-8 saturated or unsaturated heterocycle, aromatic heterocycle, substituted aromatic heterocycle; In particular, the group A is When the right side of group A is connected to the N atom of R1, a 6-membered ring is formed; POI is a structure represented by the chemical formula III or IV: in, R7 is independently selected from hydroxy, amino, substituted amino, and hydroxymethyl; R8 is independently selected from hydrogen, trifluoromethyl, halogen, cyano, alkyl, alkoxy; R9 is independently selected from the following structures: wherein the right side of R9 is connected to the left side of group A.

2. The compound represented by the general chemical structure I according to claim 1, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, or hydrates thereof, characterized in that: R1 is selected from hydrogen, methyl, isopropyl, saturated C 3-5 Membered ring, cyclopropylmethyl, phenyl; R2 is selected from hydrogen or methyl; R3, R4, R 10 、R 11 are independently selected from hydrogen, methyl, isopropyl; R3, R4, R 10 、R 11 It can be the same or different; R5, R6 are independently selected from hydrogen, fluorine, trifluoromethyl, methoxy; R7 is a hydroxyl group; R8 is hydrogen.

3. The compound represented by the general chemical structure I according to claim 1 or 2, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, and hydrates thereof, characterized in that: When the right side of group A has two substitutions, the right side of group A and the N atom to which R1 is connected form a 6-membered ring.

4. The compound represented by the general chemical structure I according to claim 3, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, and hydrates thereof, characterized in that: Group A is 5. The compound represented by the general chemical structure I according to any one of claims 1 to 4, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, and hydrates thereof, characterized in that: The compound is selected from:

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, its tautomers, enantiomers, diastereomers, and pharmaceutically acceptable salts, solvates, hydrates thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

7. Use of the compound according to any one of claims 1 to 5, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates thereof, or the pharmaceutical composition according to claim 6 in the preparation of a SMARCA2 degrading agent.

8. Use of the compound according to any one of claims 1 to 5, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates thereof, or the pharmaceutical composition according to claim 6 in the preparation of a PROTACS degrader targeting SMARCA2.

9. Use of the compound according to any one of claims 1 to 5, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates, hydrates thereof or the pharmaceutical composition according to claim 6 in the preparation of a medicament for preventing and / or treating acute myeloid leukemia, myelodysplastic syndrome or uveal melanoma.

10. The use according to any one of claims 7 to 9, characterized in that The compound, its tautomers, enantiomers, diastereomers and pharmaceutically acceptable salts, solvates and hydrates thereof are administered to mammals in the form of pharmaceutical compositions by parenteral, transdermal, oral, intranasal, topical, rectal or intratumoral administration.

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