Cyanoquinoline-targeting protein degradation molecule, preparation method therefor and use thereof

Abstract

Provided are a cyanoquinoline-targeting protein degradation molecule, a preparation method therefor and a use thereof. Particularly, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising the compound, and a use of the compound as a protein degradation targeting chimera of an androgen receptor in preparation of medicaments for treating related diseases (including prostate cancer, breast cancer, and spinal and bulbar muscular atrophy) controlled by the androgen receptor, wherein the definitions of the substituents in general formula (I) are the same as those in the description.

Description

Cyanoquinoline targeted protein degradation molecules, preparation methods and applications thereof

[0001] This application claims priority to Chinese Patent Application No. 2023108479013, filed on July 12, 2023, and Chinese Patent Application No. 2024105278854, filed on April 29, 2024. The entire text of the above-mentioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to cyanoquinoline targeted protein degradation molecules, and a preparation method and application thereof. Background Art

[0003] Prostate cancer is a common male malignancy, second only to lung cancer in incidence, and the second leading cause of death among adult men worldwide. Currently, androgen deprivation therapy (ADT) is the main treatment for early-stage prostate cancer and includes both surgical and medical castration. However, ADT cannot cure prostate cancer. After a median treatment duration of 14-30 months, nearly all patients gradually develop castration-resistant prostate cancer (CRPC), becoming insensitive to ADT and with a median survival of less than 20 months. In prostate cancer tissue, proliferation or mutation of the androgen receptor (AR) sensitizes prostate cancer to low serum androgen levels and is the primary cause of prostate cancer progression. Currently, representative androgen receptor inhibitors for the treatment of CRPC include abiraterone and enzalutamide. However, 15-25% of patients do not respond to second-generation hormonal therapies such as abiraterone and enzalutamide, and most patients who do respond eventually develop severe drug resistance, leading to a poor prognosis.

[0004] The ubiquitin-proteasome system (UPS) is the main pathway for protein degradation in cells, and is involved in the degradation of more than 80% of proteins in cells. The UPS is composed of ubiquitin (Ub), ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), ubiquitin-protein ligase (E3), 26S proteasome and its target proteins. The ubiquitin activating enzyme system is responsible for activating ubiquitin and binding it to the protein to be degraded to form a polyubiquitin chain of the target protein, i.e. ubiquitination. The proteasome system can recognize ubiquitinated proteins and degrade them. Protein proteolysis-targeting chimeras (PROTACs) are hybrid bifunctional small molecule compounds, including a small molecule compound that can bind to the target protein, a linker group at its appropriate position, and a small molecule compound that can bind to the E3 ubiquitin ligase. PROTACs work by bringing the target protein and the E3 in the cell closer together to form a target protein-PROTACs-E3 ternary polymer, adding a ubiquitinated protein tag to the target protein through the E3 ubiquitin ligase, and using the ubiquitin-proteasome system (UPS) to specifically degrade the target protein.

[0005] Using the PROTACs strategy, we prepared a protein degradation-targeted chimera that can target and recognize / bind to the androgen receptor. It can regulate the level of androgen receptor through the intracellular ubiquitin-proteasome degradation system and induce androgen receptor degradation, thereby achieving the effect of treating prostate cancer and other related diseases regulated by the androgen receptor.

[0006] Therefore, the development of a bifunctional chimeric molecule that can target and bind to the androgen receptor and effectively degrade the androgen receptor has good application prospects in the treatment of related diseases regulated by the androgen receptor.

[0007] Summary of the Invention

[0008] The present invention provides a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0009] in:

[0010] M1 is selected from N or CR1;

[0011] M2 is selected from N or CR2;

[0012] M3 is selected from N or CR3;

[0013] M4 is selected from N or CR4;

[0014] M5 is selected from N or CR5;

[0015] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, cycloalkyl or heterocyclyl;

[0016] Ring A, Ring B and Ring C are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0017] L1 is selected from a bond, -C(O)NH-, -NH-, -O-, -NHC(O)-, -C(O)-, -S(=O)-, -S(=O)2-, -CH2- or -(CH2)2-;

[0018] L2 is -Ak1-Cy1-Ak2-Cy2-Ak3-,

[0019] Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -、-(CH2) n4 -S-(CH2) n5 、-(CH2) n6 -C(O)NH-(CH2) n7 -、-(CH2) n8 -NH-(CH2) n9 、-(CH2) n10 -NHC(O)-(CH2) n11 、-(CH2) n12 -C(O)-(CH2) n13 、-(CH2) n14 -S(=O)-(CH2) n15 -or-(CH2) n16 -S(=O)2-(CH2) n17 -, the -(CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -、-(CH2) n4 -S-(CH2) n5 、-(CH2) n6 -C(O)NH-(CH2) n7 -、-(CH2) n8 -NH-(CH2) n9 、-(CH2) n10 -NHC(O)-(CH2) n11 、-(CH2) n12-C(O)-(CH2) n13 、-(CH2) n14 -S(=O)-(CH2) n15 - and -(CH2) n16 -S(=O)2-(CH2) n17 -, optionally may be further substituted;

[0020] Cy1 and Cy2 are each independently selected from a bond, a cyclohexylene, a piperidinylene, a piperazinylene, an azetidinylene, an azocyclopentylene, a cyclobutylene or a cyclopentylene group, wherein the cyclohexylene, piperidinylene, piperazinylene, an azetidinylene, an azocyclopentylene, a cyclobutylene or a cyclopentylene group may be further substituted; alternatively, any two atoms of the cyclohexylene, piperidinylene, piperazinylene, an azetidinylene, an azocyclopentylene, a cyclobutylene or a cyclopentylene group may be linked to form a cycloalkyl or heterocyclic group;

[0021] R a 、R b and R c Each is independently selected from hydrogen, deuterium, halogen, oxo, cyano, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0022] Or, any two R c Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0023] Or, R a Linked to L1 to form a cycloalkyl group, a heterocyclic group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group and the heteroaryl group may be further substituted;

[0024] x, y and z are each independently selected from 0, 1, 2 or 3;

[0025] n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, n13, n14, n15, n16 and n17 are each independently selected from 0, 1, 2 or 3.

[0026] In one embodiment of the present invention, the general formula (I) described above is further represented by the general formula (II):

[0027] Where: R d Selected from hydrogen, halogen or C 1-3Alkyl; p1 and p2 are each independently selected from 0, 1, 2, 3 or 4; L4 is selected from a bond, -CH2-, -NH-, -O-, -S- or -C(O)-.

[0028] In one embodiment of the invention, M2, M3, M4 and M5 are not N at the same time.

[0029] In a preferred embodiment of the present invention, the ring A mentioned above is selected from phenyl, 5-6 membered monocyclic heteroaryl or 9-10 membered bicyclic heterocyclyl;

[0030] Preferably, ring A is selected from phenyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, benzopyridazinone, benzopyrazolyl or benzopyrrolidinyl;

[0031] Alternatively, ring B is selected from cyclohexyl or cyclobutane;

[0032] Alternatively, ring C is selected from phenyl, 5-6 membered monocyclic heteroaryl, 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic heteroaryl;

[0033] Preferably, ring C is selected from benzopyridyl, phenyl, benzothiazolyl, benzopyrazinyl, pyridopyrazolyl, pyridotriazolyl, pyridophenyl, benzothiadiazole or benzopyridazinyl.

[0034] In a preferred embodiment of the present invention, the compound described above is further represented by the general formula (II-A):

[0035] in:

[0036] Selected from and,

[0037] when Selected from When ring A is not

[0038] In a preferred embodiment of the present invention, the ring A is selected from phenyl, pyridyl,

[0039] In a preferred embodiment of the present invention, the above-mentioned general formula (I) or general formula (II) Selected from

[0040] In a preferred embodiment of the present invention, the above R a 、R b and R cEach independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, hydroxyl C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3- 4-membered cycloalkyl or 3-4-membered heterocyclic group.

[0041] In a preferred embodiment of the present invention, R1, R2, R3, R4 and R5 are independently selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, hydroxy C 1-3 Alkyl, hydroxyl C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group.

[0042] In a preferred embodiment of the present invention, L1 as described above is selected from a bond, -C(O)NH-, -NH-, -O-, -NHC(O)-, -C(O)-, -CH2- or -(CH2)2-;

[0043] L2 is selected from

[0044] In a preferred embodiment of the present invention, the compound described above is further represented by general formula (II-B):

[0045] in:

[0046] L3 and L4 are each independently selected from a bond, -CH2-, -NH-, -O-, -S- or -C(O)-;

[0047] M6 and M7 are each independently selected from -CR6R7- or -C(O)-;

[0048] M8 is selected from N or CR8;

[0049] R6, R7 and R8 are each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group;

[0050] j, p1 and p2 are each independently selected from 0, 1, 2, 3 or 4.

[0051] In a specific embodiment of the present invention, the compound of general formula (II) described above is further represented by general formula (II-C):

[0052] wherein: M2 is selected from N or CR2; M3 is selected from N or CR3; M4 is selected from N or CR4; M5 is selected from N or CR5; Ring B is selected from cyclohexyl or cyclobutane; Ring C is selected from phenyl, 5-6 membered monocyclic heteroaryl or 10 membered bicyclic heteroaryl; preferably, Ring C is selected from phenyl, pyridyl or benzopyridyl; R a Selected from hydrogen, halogen or C 1-3 Alkyl; R d Selected from hydrogen, halogen or C 1-3 Alkyl; R b are each independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Hydroxyalkyl; R c Each independently selected from hydrogen, cyano, halogen, hydroxyl, C 1-3 Alkyl, C 1- 3 alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 Hydroxyalkoxy; R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 y and z are each independently selected from 0, 1, 2 or 3.

[0053] In a specific embodiment of the present invention, the R a is selected from hydrogen, fluorine, chlorine, methyl or ethyl.

[0054] In a specific embodiment of the present invention, the R b Each is independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxymethyl or hydroxyethyl.

[0055] In a specific embodiment of the present invention, the R c Each is independently selected from hydrogen, cyano, fluorine, chlorine, hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, hydroxymethyl or hydroxyethyl.

[0056] In a specific embodiment of the present invention, the R d is selected from hydrogen, fluorine, chlorine, methyl or ethyl.

[0057] In a specific embodiment of the present invention, R2, R3, R4 and R5 described above are each independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, hydroxymethyl or hydroxyethyl.

[0058] In a preferred embodiment of the present invention, the above-mentioned ring Selected from

[0059] In a preferred embodiment of the present invention, the present invention as described above for

[0060] In a preferred embodiment of the present invention, the compound described above is selected from the following compounds in Table 5:

[0061] Table 5

[0062] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.

[0063] The present invention also relates to a preferred embodiment, involving the use of each compound of the general formula, its stereoisomers or pharmaceutically acceptable salts, or the composition described above, in the preparation of drugs for androgen receptor-regulated related diseases.

[0064] Furthermore, the above-mentioned disease is selected from prostate cancer, breast cancer, and Kennedy's disease.

[0065] The present invention also provides a drug for treating diseases regulated by androgen receptors, wherein the drug is a preparation prepared with the above-mentioned compound, or its isotope compound, or its optical isomer, or its tautomer, or its pharmaceutically acceptable salt, or its prodrug, or its solvate as an active ingredient, and a pharmaceutically acceptable excipient.

[0066] The present invention also provides a compound represented by formula (A-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0067] Where: R 10 Selected from hydrogen or amino protecting group; Ring A, M1, L1, L4, R a , p1, p2 and x are as defined above in the present invention.

[0068] In the present invention, the amino protecting group is preferably SEM, tert-butyloxycarbonyl, -CH2-tert-butyloxycarbonyl, -CH2COOH, -COCH3, ethoxycarbonyl, benzyl, p-methoxybenzyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl or allyloxycarbonyl.

[0069] The present invention also relates to the use of a structural unit of formula (A-1-1) as a structural unit of a protein degradation inhibitor:

[0070] Among them: Ring A, M1, L1, L4, R a , p1, p2 and x are as defined above in the present invention.

[0071] In a preferred embodiment of the present invention, the compound of formula (A-1) is further represented by formula (A-1-a):

[0072] In a preferred embodiment of the present invention, the formula (A-1-1) is further shown as formula (A-1-1-a):

[0073] Experiments have demonstrated that the compound of formula (I) provided herein can target and degrade the androgen receptor in prostate cancer cells and inhibit the proliferation of prostate cancer cells, while also exhibiting good metabolic stability and pharmacokinetic properties. The compound of the present invention has promising application prospects in the preparation of chimeras targeting androgen receptor protein degradation, as well as in the preparation of drugs for treating androgen receptor-regulated diseases (including prostate cancer, breast cancer, and Kennedy's disease).

[0074] Detailed Description of the Invention

[0075] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0076] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and various branched isomers thereof. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl are preferred in the present invention.

[0077] The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc.

[0078] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0079] The term "alkenylene" refers to an alkenyl group in which one of its hydrogen atoms is further substituted. For example, "ethenylene" refers to -(CH)2-.

[0080] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms, and even more preferably 3 to 4 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused ring, and bridged ring cycloalkyls, non-limiting examples of which include The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0081] The term "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is further substituted. Non-limiting examples include: cyclohexylene, The cycloalkylene group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0082] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O), S(O)(=NH) or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 12 ring atoms; most preferably, it contains 3 to 6 ring atoms, and even more preferably, it contains 3 to 4 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetane, azetidine, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetane, thietane, azetidine, tetrahydrofuranyl, tetrahydropyranyl, 1-aminoylidene-1-oxothiopyran, azepanyl, piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged ring heterocyclic groups, non-limiting examples include The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0083] The term "heterocyclylene" refers to a heterocyclyl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include: piperidinylene, piperazinylene, pyrrolopyrrolylene, diazaspiro[5.5]undecylene, azaspiro[5.5]undecylene, benzopiperidinylene, azetidinylene, diazetidinylene, pyrrolidinylene, azaspiro[3.5]nonylene, diazaspiro[3.5]nonylene, azabicyclo[3.1.1]heptanylene, azaspiro[2.5]octanylene, The heterocyclylene group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0084] The term "aryl" refers to a 6- to 14-membered, all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably a 6- to 10-membered, more preferably a phenyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0085] The term "arylene" refers to an aryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include: The arylene group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0086] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5-8 membered monoheteroaryl or an 8-14 membered biheteroaryl group, more preferably a 5-membered monoheteroaryl, a 6-membered monoheteroaryl or a 9-membered biheteroaryl group, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyridoimidazolyl, pyrimidoimidazolyl and the like, preferably pyridoimidazolyl and pyrimidoimidazolyl. The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0087] The term "heteroarylene" refers to a heteroaryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include pyridylene, pyrimidylene, pyrazolylene, pyridazinylene, pyrazinylene,

[0088] Term " alkoxy " refers to-O-(alkyl) and-O-(non-substituted cycloalkyl), and wherein the definition of alkyl is as described above.The limiting examples of alkoxy comprises: methoxyl group, ethoxyl, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally substituted or non-substituted, and when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.Non-limiting examples comprise trifluoromethoxy, trifluoroethoxy, difluoromethoxy.

[0089] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0090] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0091] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. Non-limiting examples include: -C(CH3)2(OH).

[0092] "Hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxy group wherein alkoxy is as defined above.

[0093] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0094] In the present invention Indicates that the key does not exist;

[0095] Unless otherwise specified, the chiral carbon atoms in the compounds of the present invention are in the R or S configuration.

[0096] The hydrogen atoms described in the present invention may be replaced by their isotope deuterium. Any hydrogen atom in the example compounds of the present invention may also be replaced by a deuterium atom.

[0097] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0098] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0099] The substituents in “optionally may be further substituted” are each independently selected from deuterium, halogen, cyano, hydroxy, nitro, amino, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein, halogen, cyano, hydroxy, nitro, amino, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are as defined above.

[0100] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0101] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0102] General synthesis method of compound of formula (II):

[0103] In Scheme 1, PG in the compound of Formula III represents a protecting group, such as tert-butyl or methyl. As shown in Scheme 1, the compound of Formula III undergoes an aromatic nucleophilic substitution reaction with a compound of Formula IV-A or IV-B under basic conditions (e.g., using N,N-diisopropylethylamine as a base) in a suitable solvent such as N,N-dimethylformamide, or undergoes a Buchwald-Hartwig coupling reaction using a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride in a suitable solvent such as toluene and an appropriate base such as cesium carbonate to obtain a compound of Formula VA or VB.

[0104] The deprotected product of the compound of formula VA or VB, the compound of formula VI-A or VI-B, is reacted with the compound of formula VII using conventional methods reported in the literature, such as using N,N-diisopropylethylamine as a base and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other condensation reagents as an activating reagent to obtain the amide compound of formula VIII-A or VIII-B.

[0105] The compound of formula VIII-A is oxidized (e.g., using a Dess-Martin reagent) to obtain a compound of formula IX. The compound of formula VIII-B is hydrolyzed under acidic conditions (e.g., hydrochloric acid) to obtain a compound of formula IX. The compound of formula IX undergoes a reductive amination reaction with a compound of formula X in the presence of a suitable reducing agent (e.g., sodium acetate borohydride) to obtain the final product, the compound of formula II.

[0106] Alternatively, the compound of Formula VIII-A can be converted into the sulfonate compound of Formula XI using conventional methods reported in the literature, such as using triethylamine as a base and methylsulfonyl chloride. The compound of Formula XI undergoes a nucleophilic substitution reaction with the compound of Formula X in a suitable solvent such as N,N-dimethylformamide under alkaline conditions (e.g., using potassium carbonate as a base) to obtain the final product, the compound of Formula II.

[0107] Another route involves oxidizing the compound of Formula VA (e.g., using a Dess-Martin reagent as an oxidant) to obtain the compound of Formula XII. The compound of Formula VB is then hydrolyzed under acidic conditions (e.g., hydrochloric acid) to yield the compound of Formula XII. The compound of Formula XII is then subjected to a reductive amination reaction with the compound of Formula X in the presence of a suitable reducing agent (e.g., sodium acetate borohydride) to yield the compound of Formula XIV. Alternatively, the compound of Formula VA can be converted to the sulfonate compound of Formula XIII using conventional methods reported in the literature, such as triethylamine as a base and methylsulfonyl chloride. The compound of Formula XIII undergoes a nucleophilic substitution reaction with the compound of Formula X in a suitable solvent, such as N,N-dimethylformamide, under alkaline conditions (e.g., using potassium carbonate as a base) to yield the compound of Formula XIV.

[0108] The deprotected product of the compound of formula XIV, the compound of formula XV, is reacted with the compound of formula VII using conventional methods reported in the literature, such as using N,N-diisopropylethylamine as a base, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other condensation reagents to obtain the final product, the compound of formula II. DETAILED DESCRIPTION

[0109] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0110] The starting materials and reagents used in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0111] Preparation of intermediate 1-4

[0112] Step 1: Preparation of compound 1-2

[0113] At room temperature, 6-bromophthalazin-1(2H)-one (1-1) (5.0 g, 22.2 mmol, 1.0 eq.), tert-butylpiperazine-1-carboxylate (8.0 g, 44.4 mmol, 2.0 eq.), NaO tTo a solution of Bu (4.3 g, 44.4 mmol, 2.0 eq.) in toluene (60 mL) were added Pd2(dba)3 (0.8 g, 0.89 mmol, 0.04 eq.) and RuPhos (0.85 g, 1.78 mmol, 0.08 eq.). The reaction mixture was stirred at 110 ° C under N2 atmosphere for 5 hours. Cooled to room temperature, the mixture was quenched with saturated NH4Cl aqueous solution (60 mL), and then extracted with EA (120 mL). The organic layer was concentrated to about 60 mL and a precipitate was formed. The mixture was filtered, and the filter cake was washed with DCM (15 mL) and MeOH (5 mL) and dried to give tert-butyl 4-(1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate (1-2) (5.5 g). MS: m / z=331 [M+H] + .

[0114] Step 2: Preparation of Compound 1-3

[0115] To a solution of tert-butyl 4-(1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate (1-2) (0.2 g, 0.61 mmol, 1.0 eq.) in DMF (5 mL) was added NaH (60% Wt, 60 mg, 1.53 mmol, 2.5 eq.) at room temperature. After stirring at 35°C for 30 minutes, a solution of 3-bromopiperidine-2,6-dione (174 mg, 0.92 mmol, 1.5 eq.) in 2 mL of DMF was added dropwise to the mixture, and stirring was continued at 35°C for 4 hours. The mixture was cooled to room temperature, diluted with H2O (10 mL), and extracted with EA (10 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (HCOOH buffer) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate (1-3) (95 mg). MS: m / z = 442 [M+H] + .

[0116] Step 3: Preparation of Compound 1-4

[0117] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate (1-3) (95 mg, 0.22 mmol) in EA (2 ml) was added HCl (5 mL, 4 M in EA) at room temperature. After stirring for 1 hour, the mixture was concentrated to afford 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione hydrochloride (1-4) (95 mg) as an amber solid. MS: m / z = 342 [M+H] + .

[0118] Preparation of intermediate 2-3

[0119] Step 1: Preparation of compound 9-1

[0120] To a solution of tert-butyl 4-fluorobenzoate (5.0 g, 25.5 mmol, 1.0 eq.) and piperidin-4-ylmethanol (5.9 g, 51.0 mmol, 2.0 eq.) in DMF (40 mL) was added K2CO3 (8.8 g, 51.0 mmol, 2.0 eq.) at room temperature. After stirring at 118°C for 16 hours, the mixture was cooled to room temperature, and H2O (60 mL) and EtOAc (200 mL) were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column with PE / EA (50 / 1 to 1 / 2) to give tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (9-1) (5.9 g). MS: m / z = 292 [M+H] +

[0121] Step 1: Preparation of compound 2-3

[0122] To a solution of compound 9-1 (2.9 g, 10 mmol) and Et3N (3 g, 30 mmol, 3 eq.) in DCM (50 mL) was added MsCl (1.72 g, 15 mmol, 1.5 eq.) in portions at 0°C. The reaction mixture was stirred at room temperature for 2 h, diluted with H2O (100 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA=5:1) to give tert-butyl 4-(4-(((methylsulfonyl)oxy)methyl)piperidin-1-yl)benzoate 2-3 (3.24 g). MS: m / z=370 [M+H] + .

[0123] Preparation of intermediate 5-4

[0124] Step 1: Preparation of compound 5-3

[0125] To a solution of tert-butyl (R)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.50 g, 4.22 mmol, 1.0 eq.) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1.16 g, 4.22 mmol, 1.0 eq.) in DMF (15 mL) were added KCO (1.75 g, 12.66 mmol, 3.0 eq.) and NaI (63 mg, 0.422 mmol, 0.1 eq.) at room temperature. After stirring at 80°C for 3 hours, the mixture was cooled to room temperature, HO (100 mL) and EA (100 mL) were added, and the aqueous layer was extracted with EA (3 x 100 mL). The organic layer was dried and evaporated. The residue was purified by chromatography on silica gel eluting with PE / EA (1:1 to 1:2) to give tert-butyl (3R)-3-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (5-3) (1.16 g). MS: m / z=457 [M+H] +

[0126] Step 2: Preparation of compound 5-4

[0127] To a solution of tert-butyl (3R)-3-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (5-3) (200 mg, 0.437 mmol, 1.0 eq.) in EA was added 4M HCl in ethyl acetate (1 mL, 4 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours and concentrated to give 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-pyrrolidin-3-yl)methoxy)isoindolin-1,3-dione hydrochloride (5-4) (160 mg). MS: m / z = 357 [M+H] +

[0128] Preparation of intermediate 5-5

[0129] Step 1: Preparation of compound 5-5-1

[0130] To a solution of 8-bromo-5-fluoroquinoline (2 g, 8.85 mmol, 1.0 equiv., Zn(CN)2 (2.07 g, 17.7 mmol, 2.0 equiv.) in DMF (20 mL) was added RuPhos Pd G3 (300 mg, 0.35 mmol, 0.04 equiv.) at room temperature. The reaction mixture was stirred at 100°C under a N2 atmosphere for 16 hours. After completion of the reaction, the mixture was diluted with H2O (200 mL) and extracted with EA (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and purified on a silica gel column (PE:EA=2:1) ​​to give 5-fluoroquinoline-8-carbonitrile (5-5-1) (1.4 g). MS: m / z=173 [M+H] +

[0131] Step 2: Preparation of compound 5-5-2

[0132] To a solution of 5-fluoroquinoline-8-carbonitrile (5-5-1) (200 mg, 1.16 mmol, 1.0 eq) and tert-butyl ((1r, 4r)-4-hydroxycyclohexyl)carbamate (274 mg, 1.28 mmol, 1.1 eq) in MeCN (2 ml) was added Cs2CO3 (755 mg, 2.32 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with EA (10 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and purified on a silica gel column (MeCN:H2O / 9:1) to give tert-butyl ((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)carbamate (5-5-2) (220 mg). MS: m / z = 367 [M+H] +

[0133] Step 3: Preparation of Compound 1-7

[0134] To a solution of tert-butyl ((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)carbamate (5-5-2) (3 g, 8.17 mmol, 1.0 eq.) in EA (10 mL) was added a 4M HCl solution in EA (30 mL) at room temperature. After stirring for 16 hours, the reaction mixture was concentrated under vacuum to give 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (2.9 g, crude). MS: m / z = 267 [M+H] +

[0135] Step 4: Preparation of Compound 1-5

[0136] At room temperature, tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (5 g, 17.18 mmol, 1.0 eq.) and IBX (5.75 g, 20.61 mmol, 1.2 eq.) were mixed in DMSO (50 mL). The reaction mixture was stirred at 60°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with H2O (500 mL), and extracted with EA (100 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and purified on a silica gel column (PE:EA = 1:1) to obtain tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (1-5) (4.2 g). MS: m / z = 289 [M+H] +

[0137] Step 5: Preparation of compound 5-5-5

[0138] To a solution of tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (1-5) (2 g, 6.92 mmol, 1.0 eq) in DCM (50 mL) was added TFA (5 mL) at room temperature. After stirring for 16 hours, the reaction mixture was concentrated under vacuum to give tert-butyl 4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzoate (5-5-5) (1.9 g, crude). MS: m / z = 233 [M+H] +

[0139] Step 6: Preparation of compound 5-5-6

[0140] To a solution of tert-butyl 4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzoate (5-5-5) (2 g, 8.58 mmol, 1.0 equiv) and ethylene glycol (800 μL, 12.87 mmol, 1.5 equiv) in toluene (20 mL) was added TsOH (40 mg, 0.25 mmol, 0.03 equiv) at room temperature. The reaction mixture was stirred at 100° C. for 1 hour. After completion of the reaction, the mixture was concentrated under vacuum and purified on a silica gel column (MeCN:H 2 O / 55%:45%) to give 4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzoic acid (5-5-6) (1.29 g). MS: m / z=277 [M+H] +

[0141] Step 7: Preparation of compound 5-5-7

[0142] To a solution of 4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzoic acid (5-5-6) (1.29 g, 4.65 mmol, 1.0 eq.), 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (1.25 g, 4.65 mmol, 1.0 eq.), and HATU (2.13 g, 5.58 mmol, 1.2 eq.) in DMF (25 mL) was added DIEA (4 mL, 23.2 mmol, 5.0 eq.) at room temperature. The reaction mixture was stirred at 80° C. for 6 hours, cooled to room temperature, filtered, and the filter cake washed with DCM (5 mL). The filtrate was concentrated under vacuum to give 4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)benzamide (5-5-7) (2.0 g). MS: m / z=526 [M+H] +

[0143] Step 8: Preparation of compound 5-5

[0144] To a solution of 4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)benzamide (5-5-7) (2 g, 3.8 mmol, 1.0 eq.) in MeCN (10 mL) and H₂O (50 mL) was added 12N HCl (5 mL, 28.5 mmol, 7.5 eq.) at room temperature. The reaction mixture was stirred at 60° C. for 16 hours and then purified by column chromatography (MeCN:H₂O=75%) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (1.8 g). MS: m / z=482 [M+H] +

[0145] Preparation of Intermediate 21-6

[0146] Step 1: Preparation of compound 21-2

[0147] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (21-1) (100 mg, 0.2 mmol, 1.0 eq.) was added a solution of B2Pin2 (60 mg, 0.24 mmol, 1.2 eq.) in 1,4-dioxane (5 mL) at room temperature. KOAc (40 mg, 0.4 mmol, 2.0 eq.) and Pd(dppf)Cl2 (10 mg, 0.01 mmol, 0.05 eq.) were added. After stirring at 85°C for 16 hours, the mixture was cooled to room temperature, H2O (20 mL) was added, and the mixture was extracted with EA (5 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA=50:1) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (21-2) (100 mg). MS: m / z=547 [M+H] +

[0148] Step 2: Preparation of compound 21-3

[0149] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (21-2) (100 mg, 0.18 mmol, 1.0 eq.) in THF (3 mL) was added 30% H₂O₂ (100 μL, 0.9 mmol, 10.0 eq.) at room temperature. After stirring for 6 hours, the mixture was concentrated to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-ol (21-3) (100 mg). MS: m / z = 437 [M+H] +

[0150] Step 3: Preparation of compound 21-4

[0151] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-ol (21-3) (50 mg, 0.23 mmol, 1.0 eq.) and tert-butyl (R)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (97 mg, 0.27 mmol, 1.2 eq.) in DMF (2 mL) was added Cs2CO3 (150 mg, 0.46 mmol, 2.0 eq.) at room temperature. The mixture was stirred at 80°C for 1 hour, cooled to room temperature, concentrated, and purified on a silica gel column (PE:EA=2:1) ​​to give ((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (21-4) (100 mg). MS: m / z=620 [M+H] +

[0152] Step 4: Preparation of compound 21-5

[0153] A mixture of tert-butyl ((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (21-4) (100 mg, 0.16 mmol, 1.0 eq.) and 10% Pd / C (20 mg, 20% wt) in EA (5 mL) was stirred at room temperature under a H atmosphere for 16 hours. The mixture was filtered, concentrated under vacuum, and purified on a silica gel column (PE:EA=1:1) to give (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (21-5) (40 mg). MS: m / z=442 [M+H] +

[0154] Step 5: Preparation of compound 21-6

[0155] To a solution of tert-butyl ((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (21-5) (40 mg, 0.09 mmol, 1.0 eq.) in EA (2 mL) was added HCl / EA (1 mL). After stirring at room temperature for 16 hours, the mixture was concentrated to give 3-(1-methyl-7-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione (21-6) (40 mg). MS: m / z = 342 [M+H] +

[0156] Preparation of Intermediate 58-1

[0157] To a solution of tert-butyl 4-bromobenzoate (200 mg, 0.77 mmol, 1.0 eq.), methyl (2R, 4R)-2-methylpiperidine-4-carboxylate (120 mg, 0.77 mmol, 1.0 eq.), and CsCO (750 mg, 2.31 mmol, 3.0 eq.) in toluene (10 mL) was added RuPhosPdG (100 mg, 0.15 mmol, 0.2 eq.) and RuPhos (70 mg, 0.15 mmol, 0.2 eq.). The reaction mixture was stirred at 110 ° C. under an N atmosphere for 16 hours. After the reaction was complete, the mixture was diluted with H O (100 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using PE:EA = 10:1 as eluent to give methyl (2R,4R)-1-(4-(tert-butoxycarbonyl)phenyl)-2-methylpiperidine-4-carboxylate (58-1-1) (230 mg, 88%) as a yellow solid. MS: m / z = 277 [M+H-56] + .

[0158] To a solution of methyl (2R, 4R)-1-(4-(tert-butoxycarbonyl)phenyl)-2-methylpiperidine-4-carboxylate (58-1-1) (230 mg, 0.69 mmol, 1.0 eq.) in DCM (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated in vacuo to give 4-((2R, 4R)-4-(methoxycarbonyl)-2-methylpiperidin-1-yl)benzoic acid (58-1) (250 mg, crude material) as a yellow oil. MS: m / z=277[M+H] + .

[0159] Preparation of intermediate 67-6

[0160] To a solution of 4-((2R,4R)-4-(methoxycarbonyl)-2-methylpiperidin-1-yl)benzoic acid (58-1) (100 mg, 0.36 mmol, 1.0 eq.), 5-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyloxy)quinoline-8-carbonitrile (67-3) (106 mg, 0.36 mmol, 1.0 eq.), and HATU (164 mg, 0.43 mmol, 1.2 eq.) in DMF (2 mL) was added DIEA (200 μL, 1.08 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was purified by chromatography using MeCN:H2O=90% to give (2R,4R)-1-(4-(((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)-2-methylpiperidine-4-carboxylic acid methyl ester (67-4) (150 mg, 75%) as a yellow solid. MS: m / z=554 [M+H] + .

[0161] To a solution of methyl (2R,4R)-1-(4-(((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)-2-methylpiperidine-4-carboxylate (67-4) (140 mg, 0.25 mmol, 1.0 eq.) and LiBH4 (55 mg, 2.5 mmol, 10 eq.) in THF (10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was purified by chromatography using MeCN:H2O = 90% to give N-((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-((2R,4R)-4-(hydroxymethyl)-2-methylpiperidin-1-yl)benzamide (67-5) (130 mg, 98%) as a white solid. MS: m / z = 526 [M+H] + .

[0162] To a solution of N-((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-((2R,4R)-4-(hydroxymethyl)-2-methylpiperidin-1-yl)benzamide (67-5) (130 mg, 0.24 mmol, 1.0 eq.) in DCM (5 mL) was added DMP (135 mg, 0.32 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with saturated NaSO (50 mL) and washed with saturated NaHCO (50 mL) and H0 (50 mL), respectively, and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford N-((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-((2R,4R)-4-formyl-2-methylpiperidin-1-yl)benzamide (67-6) (120 mg, crude) as a yellow solid. MS: m / z = 524 [M+H] + .

[0163] Example 1 Preparation of Compound 1

[0164] Step 1: Preparation of Compound 1-6

[0165] To a solution of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (1-4) (180 mg, 0.48 mmol, 1.0 eq.) in DCM / MeOH (6 mL / 4 mL) at room temperature were added tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (1-5) (132 mg, 0.46 mmol, 0.96 eq.) and TEA (18 drops). After stirring for 3 hours, NaBH(OAc)3 (270 mg, 1.30 mmol, 2.7 eq.) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness under reduced pressure. EA / H2O (20 mL + 20 mL) was added to the residue and extracted with EA (20 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude tert-butyl 4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (1-6) (280 mg, crude), which was used directly in the next reaction. MS: m / z = 615 [M+H] +

[0166] Step 2: Preparation of compound 1

[0167] To a solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (1-6) (90 mg, 0.15 mmol, 1.0 eq.) in DCM (4 mL) was added TFA (2 mL) at room temperature. The mixture was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in DMF (4.5 mL), and 5-(((1r, 4r)-4-aminocyclohexyloxy)quinoline-8-carbonitrile (1-7) (56 mg, 0.19 mmol, 1.25 eq.), HATU (62 mg, 0.17 mmol, 1.1 eq.) and DIPEA (193 mg, 1.5 mmol, 10.0 eq.) were added. The reaction mixture was stirred at room temperature for 1 h, then diluted with H2O (20 mL) and extracted with EA (20 mL * 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (HCOOH buffer) to give N N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalic acid-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (1) (11 mg). MS: m / z = 808.4 [M+H] +

[0168] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.06(d,J=1.6Hz,1H),8.64(dd,J=8.5,1.6Hz,1H),8.28(d,J=8.5Hz,1H),8.24(s,1H),8.04(d,J=9 .2Hz,1H),7.98(d,J=7.5Hz,1H),7.74(d,J=8.8Hz,2H),7.68(dd,J=8.5,4.3Hz,1H),7.49(dd,J=9.3,1.6Hz,1H),7.35(d,J=8.5Hz,1H),7 .27–7.22(m,1H),6.93(d,J=8.8Hz,2H),5.77–5.72(m,1H),4.77–4.68(m,1H),3.93–3.78(m,3H),3.42(br,3H),2.98–2.85(m,1H),2.78( t,J=11.6Hz,2H),2.54–2.52(m,3H),2.29–2.19(m,4H),1.98–1.92(m,2H),1.81(d,J=10.3Hz,3H),1.72–1.51(m,5H),1.29–1.20(m,5H).

[0169] Example 2 Preparation of Compound 2

[0170] Step 1: Preparation of compound 2-1

[0171] A mixture of methyl 4-fluorobenzoate (2.1 g, 13.6 mmol), tert-butyl piperazine-1-carboxylate (5.06 g, 27.2 mmol, 2.0 eq.), and KCO (3.75 g, 27.2 mmol, 2.0 eq.) in DMSO (20 mL) was stirred at 120°C for 24 h. After cooling to room temperature, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (PE:EA = 1:1) to give tert-butyl 4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2-1) (1.74 g). MS: m / z = 321 [M+H] +

[0172] Step 2: Preparation of compound 2-2

[0173] To a solution of tert-butyl 4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2-1) (1.74 g, 5.4 mmol) in dioxane (20 mL) was added HCl (5 mL, 4 M in dioxane) at room temperature. After stirring at room temperature for 6 h, the solution was concentrated to afford methyl 4-(piperazin-1-yl)benzoate (2-2) (1.1 g) as an amber solid. MS: m / z = 221 [M+H] +

[0174] Step 3: Preparation of Compound 2-4

[0175] A mixture of methyl 4-(piperazin-1-yl)benzoate (2-2) (1.0 g, 4.5 mmol), tert-butyl 4-(4-((((methylsulfonyl)oxy)methyl)piperidin-1-yl)benzoate (2-3) (1.66 g, 4.5 mmol, 1.0 eq.), and Et3N (1.36 g, 13.5 mmol, 3.0 eq.) in acetonitrile (20 ml) was stirred at 80°C for 12 h at room temperature. The mixture was cooled to room temperature, diluted with H2O (50 mL), and extracted with EA (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=1:1) to give tert-butyl 4-(4-((4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (2-4) (500 mg). MS: m / z = 494 [M+H] +

[0176] Step 4: Preparation of compound 2-5

[0177] To a solution of tert-butyl 4-(4-(4-((4-(4-((methoxycarbonyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (2-4) (500 mg 1.0 mmol) in 20 mL of methanol:THF:H2O (3:1:1) was added LiOH (96 mg 4.0 mmol 4.0 eq.) at room temperature. The mixture was stirred at 45°C for 12 h, cooled to room temperature, and washed with 4N The mixture was neutralized with HCl (2 mL) and extracted with EA (20 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product of 4-(4-((4-(tert-butyloxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)benzoic acid. The crude product was then dissolved in DMF (10 mL), and 3-aminopiperidine-2,6-dione (140 mg, 1.1 mmol, 1.1 eq.), HATU (761 mg, 2.0 mmol, 2.0 eq.), and DIPE were added. A (516 mg, 4.0 mmol, 4.0 eq.). After stirring at room temperature for 4 h, H2O (100 mL) was added and extracted with EA (100 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=1:5) to obtain tert-butyl 4-(4-(4-[4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (2-5) (220 mg) as a white solid. MS: m / z=590 [M+H] +

[0178] Step 5: Preparation of compound 2

[0179] To a solution of tert-butyl 4-((4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (2-5) (170 mg, 0.29 mmol) in DCM (10 mL) was added TFA (5 mL) at room temperature. After stirring at room temperature for 4 h, the mixture was concentrated. The residue was dissolved in DMF (20 mL) and 5-(((1r,4r)-4-aminocyclohexyloxy)quinoline-8-carbonitrile (1-7) (310 mg, 1.16 mmol, 4.0 eq.), HATU (221 mg, 0.58 mmol, 2.0 eq.) and DIPEA (150 mg, 1.16 mmol, 4.0 eq.) were added. After stirring at room temperature for 4 h, H2O (50 mL) was added and the mixture was dried with EA( The product was extracted with 50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give N-((1r, 4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (2) (2.8 mg). MS: m / z=783[M+H] +

[0180] Example 3 Preparation of Compound 3

[0181] Step 1: Preparation of compound 3-2

[0182] To a solution of 2-bromo-4,5-difluorobenzoic acid (11.4 g, 48.3 mmol, 1.0 eq.) in SOCl₂ (45 mL) was added 0.38 mL of DMF at room temperature. After stirring at 80°C for 2 hours, the mixture was cooled to room temperature and concentrated to dryness. Then, 150 mL of DCM and DEA (17.6 g, 242 mmol, 5.0 eq.) were added sequentially. After stirring at room temperature for 6 hours, the mixture was washed with 45 mL of saturated aqueous NaHCO₃ and 45 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield crude 2-bromo-N,N-diethyl-4,5-difluorobenzamide (3-2) (13.7 g, crude), which was used directly in the next step. MS: m / z = 292 [M+H] +

[0183] Step 2: Preparation of compound 3-3

[0184] To a solution of 2-bromo-N,N-diethyl-4,5-difluorobenzamide (3-2) (13.7 g, crude product, 1.0 eq.) in 1,4-dioxane (120 mL) and H₂O (30 mL) were added potassium vinyl trifluoroborate (7.5 g, 56 mmol, 1.2 eq.), Pd(dppf)Cl₂ (1.6 g, 2.3 mmol, 0.05 eq.), and K₂CO₃ (15.2 g, 116 mmol, 2.5 eq.) at room temperature. After stirring at 95° C. for 16 hours, the mixture was cooled to room temperature, the solid was filtered off, and the mixture was concentrated under reduced pressure. The residue was then added to 150 mL of EtOAc and 45 mL of H₂O. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude N,N-diethyl-4,5-difluoro-2-vinylbenzamide (3-3) (10.5 g, crude product), which was used directly in the next step. MS: m / z = 240 [M+H] +

[0185] Step 3: Preparation of compound 3-4

[0186] To 1,4-dioxane (100 mL) and H₂O (40 mL) were added N,N-diethyl-4,5-difluoro-2-vinylbenzamide (3-3) (10.5 g, 44 mmol, 1.0 eq.), K₂OsO₄·2H₂O (0.83 g, 1.7 mmol, 0.04 eq.), and NaIO₄ (18.2 g, 110 mmol, 2.5 eq.) in that order at room temperature. After stirring at room temperature for 2 hours, the mixture was filtered and concentrated under reduced pressure. The residue was then added to 150 mL of EtOAc and 45 mL of H₂O. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (50 / 1 to 1 / 1) to yield N,N-diethyl-4,5-difluoro-2-formylbenzamide (3-4) (3.9 g). MS: m / z = 242 [M+H] +

[0187] Step 4: Preparation of compound 3-5

[0188] To a solution of N,N-diethyl-4,5-difluoro-2-formylbenzamide (3-4) (3.9 g, 21.4 mmol, 1.0 eq.) in AcOH (11 mL) was added 85% hydrazine hydrate (1.1 mL, 27.8 mmol, 1.3 eq.) at room temperature. After stirring at 145°C for 1 hour, the mixture was cooled to room temperature and filtered to obtain crude 6,7-difluorophthalazin-1(2H)-one (3-5) (2.3 g, crude), which was used directly in the next reaction. MS: m / z = 183 [M+H]+

[0189] Step 5: Preparation of compound 3-6

[0190] To a solution of 6,7-difluorophthalazin-1(2H)-one (3-5) (1.2 g, 6.6 mmol, 1.0 eq.) in DMF (20 mL) was added NaH (60% Wt, 712 mg, 17.8 mmol, 2.7 eq.) at room temperature. After stirring at 38°C for 1 hour, a solution of 3-bromopiperidine-2,6-dione (1.9 g, 9.9 mmol, 1.5 eq.) in DMF (4 mL) was added dropwise to the mixture. After stirring at 38°C for 3 hours, the mixture was cooled to room temperature, H2O (140 mL) was added, and extraction was performed with EA (400 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 3-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (3-6) (1.3 g, crude), which was used directly in the next reaction. MS: m / z = 294 [M+H] +

[0191] Step 6: Preparation of compound 3-7

[0192] To a solution of 3-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (3-6) (1.3 g crude product, 4.4 mmol, 1.0 eq.) in DMSO (19 mL) at room temperature were added tert-butyl piperazine-1-carboxylate (1.65 g, 8.8 mmol, 2.0 eq.) and DIPEA (2 mL). After stirring at 138°C for 2 hours, the mixture was cooled to room temperature, and 450 mL of EtOAc and 130 mL of water were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (100 / 1 to 1 / 2) to give tert-butyl 4-(2-(2,6-dioxopiperidinyl)-7-fluoro-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate (3-7) (0.8 g). MS: m / z = 460 [M+H] +

[0193] Step 7: Preparation of compound 3-8

[0194] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidinyl)-7-fluoro-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate (3-7) (350 mg, 0.76 mmol) in EA (2 mL) was added hydrochloric acid (5 mL, 4 M in EA) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated to give 3-(7-fluoro-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H-yl)piperidine-2,6-dione hydrochloride (3-8) (0.30 g). MS: m / z = 360 [M+H] +

[0195] Step 8: Preparation of compound 3-9

[0196] To a solution of 3-(7-fluoro-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H-yl)piperidine-2,6-dione (3-8) (160 mg, 0.4 mmol, 1.0 eq.) in DCM / MeOH (6 mL / 4 mL) at room temperature were added tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (1-5) (110 mg, 0.38 mmol, 0.95 eq.) and TEA (16 drops). After stirring at room temperature for 3 hours, NaHB(OAc)3 (270 mg, 1.08 mmol, 2.7 eq.) was added. After stirring at room temperature for 2 hours, the mixture was concentrated to dryness. EA / H2O (20 mL / 20 mL) was added to the residue, followed by extraction with EA (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (3-9) (230 mg, crude), which was used in the next step without purification. MS: m / z = 633 [M+H] +

[0197] Step 9: Preparation of compound 3

[0198] To a solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate (3-9) (110 mg, 0.17 mmol, 1.0 eq.) in DCM (4 mL) was added TFA (2 mL) at room temperature. The mixture was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in DMF (5 mL), and 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (56 mg, 0.19 mmol, 1.1 eq.), HATU (73 mg, 0.19 mmol, 1.1 eq.), and DIPEA (219 mg, 1.7 mmol, 10.0 eq.) were added. After stirring at room temperature for 1 h, the mixture was diluted with H2O (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCOOH buffer) to give N-((1r,4r)-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((4-(2-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxo-1,2-dihydrophthalic acid-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (3) (11 mg). MS: m / z = 826.3 [M+H] +

[0199] 1 H NMR(400MHz,dmso)δ11.02(s,1H),9.07(d,J=4.2Hz,1H),8.64(dd,J=8.6,0.9Hz,1H),8.36(s,1H),8.28(d,J=8.5Hz,1H),7.98(d,J= 7.7Hz,1H),7.84(d,J=13.3Hz,1H),7.74(d,J=8.6Hz,2H),7.68(dd,J=8.7,4.2Hz,1H),7.51(d,J=8.1Hz,1H),7.35(d,J=8.3Hz,1H),6 .93(d,J=8.5Hz,2H),5.77(dd,J=11.6,7.0Hz,1H),4.79–4.66(m,1H),3.85(d,J=13.5Hz,3H),3.26–3.22(m,4H),2.98–2.86(m,1H), 2.77(t,J=10.9Hz,2H),2.57(br,4H),2.30–2.19(m,4H),1.98–1.92(m,2H),1.86–1.76(m,3H),1.70–1.55(m,4H),1.28–1.20(m,5H).

[0200] Example 4 Preparation of Compound 4

[0201] Step 1: Preparation of compound 4-2

[0202] To a solution of (1R,5S,6r)-3-(tert-butyloxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (4-1) (2.0 g, 8.8 mmol, 1.0 eq.) in tetrahydrofuran (20 mL) was added dropwise BH3·THF (1M THF, 44 mL, 44 mmol, 5.0 eq.) at 0°C. Stirring was continued at 0°C for 2 hours, the reaction was quenched with methanol (15.0 mL) and concentrated. The residue was diluted with saturated sodium carbonate (5.0 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4-2) (1.6 g). MS: m / z=213 [M+H] +

[0203] Step 2: Preparation of compound 4-3

[0204] To a solution of tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4-2) (1.5 g, 7.5 mmol, 1.0 eq.) in DCM (15 mL) was added 4 M HCl in dioxane (8 mL, 2 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give ((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methanol hydrochloride (1.5 g).

[0205] To a solution of ((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methanol hydrochloride (1.5 g, 13.2 mmol, 1.0 eq.) in DMF (15 mL) was added tert-butyl 4-fluorobenzoate (1.02 g, 14.5 mmol, 1.1 eq) followed by KCO (7.2 g, 52.8 mmol, 4.0 eq). After stirring at 140° C. for 4 h, the mixture was cooled to room temperature and partitioned into H O (100 mL) and EA (100 mL), and extracted with EA (3 x 100 mL). The organic layer was dried and evaporated. The residue was purified on a silica gel column with PE / EA (10:1 to 3:1) to give tert-butyl 4-((1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (4-3) (1.1 g). MS: m / z = 289 [M+H] +

[0206] Step 3: Preparation of compound 4-4

[0207] To a solution of tert-butyl 4-((1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (4-3) (1.1 g, 3.8 mmol, 1.0 eq.) in DMSO (15 mL) at room temperature was added IBX (1.1 g, 4.18 mmol, 1.1 eq.). After stirring at room temperature for 12 h, water (10 mL) was added to form a white precipitate. The mixture was then filtered and the filter cake was dried to give tert-butyl 4-((1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (4-4) (1.0 g). MS: m / z = 287 [M+H] +

[0208] Step 4: Preparation of Compound 4-6

[0209] To a solution of tert-butyl 4-(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (4-4) (300 mg, 1.04 mmol, 1.0 eq.) in DCM (3 mL) at room temperature were added 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (4-5) (354 mg, 1.04 mmol, 1.0 eq.) and AcOH (6.0 mg, 0.1 mmol, 0.1 eq.). The mixture was stirred at room temperature for 4 hours, and then NaBH(OAc) (219 mg, 1.04 mmol, 1.0 eq.) was added. Stirring was continued at room temperature for 4 hours, and the mixture was then concentrated to dryness under reduced pressure. H O (20 mL) was added to the residue, and the mixture was extracted with EA (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was washed with DCM:EA (1:1, 3 mL) to give tert-butyl 4-((1R,5S,6S)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (4-6) (280 mg), which was used directly in the next reaction. MS: m / z = 612 [M+H] +

[0210] Step 5: Preparation of Compound 4-7

[0211] To a solution of tert-butyl 4-((1R,5S,6S)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoate (4-6) (280 mg, 0.5 mmol, 1.0 eq.) in DCM (4 mL) was added 4M HCl in dioxane (2 mL) at room temperature. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure to give 4-((1R,5S,6S)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoic acid (4-7) (270 mg).

[0212] Step 6: Preparation of compound 4

[0213] To a solution of 4-((1R,5S,6S)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoic acid (4-7) (120 mg, 0.2 mmol, 1.0 eq.) and 5-(1r,4R)-4-aminocyclohexyloxy)quinoline-8-carbonitrile (1-7) (53.4 mg, 0.2 mmol, 1.0 eq.) in DMF (2 ml) were added DIEA (56 mg, 0.4 mmol, 2.0 eq.) and HATU (91.2 mg, 0.24 mmol, 1.2 eq.) at room temperature. After stirring at room temperature for 2 h, H2O (20 mL) was added and extracted with EA (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (HCOOH buffer) to give N-((1r, 4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(((1R, 5S, 6S)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)benzamide (4) (8.2 mg). MS: m / z=806[M+H] +

[0214] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.07(dd,J=4.4,1.7Hz,1H),8.64(dd,J=8.4,1.7Hz,1H),8.28(d,J=8.4Hz,1H),8.26(s,1H),8.13 –8.07(m,1H),7.92(d,J=7.6Hz,1H),7.73(d,J=8.5Hz,1H),7.68(dd,J=8.5,4.3Hz,1H),7.56(d,J=9.0Hz,1H),7.34(d,J=9.0Hz,2H),6.5 5(d,J=8.5Hz,2H),5.79–5.72(m,1H),4.72(br,1H),3.86(br,1H),3.63(d,J=9.8Hz,2H),2.97–2.86(m,3H),2.64–2.50(m,6H),2.36–2.1 4(m,3H),2.12–2.05(m,1H),2.03–1.88(m,3H),1.80(s,1H),1.69–1.52(m,4H),1.47–1.38(m,1H),1.24–1.21(m,1H),1.02–0.93(m,1H).

[0215] Example 5 Preparation of Compound 5

[0216] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-pyrrolidin-3-yl)methoxy)isoindoline-1,3-dione hydrochloride (5-4) (160 mg, 0.406 mmol, 1.0 eq.) in DCM (3 mL) at room temperature were added N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (1-7) (196 mg, 0.406 mmol, 1.0 eq.) and TEA (62 mg, 0.609 mmol, 1.5 eq.). After stirring at room temperature for 4 hours, NaBH(OAc)3 (86 mg, 0.406 mmol, 1.0 eq.) was added. Stirring was continued at room temperature for 4 hours, and the mixture was concentrated to dryness under reduced pressure. The residue was added with H2O (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with saturated brine, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r, 4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3S)-(((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)methyl)pyrrolidin-1-yl)methylpiperidin-1-yl)benzamide (5) (50 mg, 85% purity). MS: m / z=824[M+H] +

[0217] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),9.07–9.01(m,1H),8.60(d,J=1.5Hz,1H),8.26(dd,J=8.4,1.4Hz,1H),7.98(d,J=7.6Hz,1H),7.86(dd,J=8 .2,1.7Hz,1H),7.73(d,J=8.4Hz,2H),7.67(ddd,J=8.5,4.2,1.3Hz,1H) ,7.49–7.43(m,1H),7.38–7.29(m,2H),7.01–6.90(m,2H),5.11(dd,J=12 .6,5.4Hz,1H),4.71(br,1H),4.28–4.16(m,2H),3.86(d,J=12.6Hz,3H),3.67(br,4H),3.12(d,J=6.7Hz,3H),2.95(t,J=11.3Hz,1H),2.87–2.73 (m,3H),2.60(d,J=3.7Hz,1H),2.48(d,J=1.8Hz,2H),2.23(d,J=10.9Hz,2H),1.94(br,3H),1.82(br,2H),1.66–1.52(m,4H),1.31–1.21(m,2H).

[0218] Example 6 Preparation of Compound 6

[0219] Step 1: Preparation of compound 6-1

[0220] A mixture of methyl 4-fluorobenzoate (5.00 g, 32.4 mmol, 1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (6.97 g, 48.7 mmol, 1.5 eq.) and K2CO3 (8.97 g, 64.9 mmol, 2.0 eq.) in DMSO (20 mL) was stirred at 120°C for 16 hours. The mixture was cooled to room temperature and EA (100 ml) was added. The mixture was filtered. The filtrate was washed with water (100 mL). The organic layer was concentrated. The residue was purified by column chromatography (PE / EA 2:1) to give methyl 4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)benzoate (6-1) (4.90 g).

[0221] Step 2: Preparation of compound 6-2

[0222] A solution of methyl 4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)benzoate (6-1) (4.00 g, 14.4 mmol, 1.0 eq) and 2N HCl (7.2 mL, 14.4 mmol, 1.0 eq.) in EtOH (30 mL) was stirred at 75° C. for 16 hours. The mixture was cooled to room temperature and EA (100 mL) and water (100 mL) were added. The organic layer was concentrated. The residue was purified by preparative-TLC (pure EA) to give methyl 4-(4-oxopiperidin-1-yl)benzoate (6-2) (1.33 g).

[0223] Step 3: Preparation of compound 6-3

[0224] To a solution of methyl 4-(4-oxopiperidin-1-yl)benzoate (6-2) (550 mg, 2.36 mmol, 1.0 eq.) in THF (5 ml) and water (5 ml) was added LiOH·H2O (300 mg, 7.07 mmol, 3.0 eq.) at room temperature. After stirring for 16 hours, EA (50 ml) and water (50 ml) were added. The aqueous layer was acidified to pH = 2 with HCl and extracted with EA (50 mL x 2). The combined organic layers were concentrated to give 4-(4-oxopiperidin-1-yl)benzoic acid (6-3) (427 mg).

[0225] Step 4: Preparation of compound 6-4

[0226] To a solution of 4-(4-oxopiperidin-1-yl)benzoic acid (6-3) (105 mg, 0.48 mmol, 1.0 eq.) in DMF (1 mL) was added DIEA (248 mg, 1.92 mmol, 4.0 eq.) and HATU (200 mg, 0.53 mmol, 1.1 eq.) at room temperature. After 10 minutes, 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (145 mg, 0.48 mmol, 1.0 eq.) was added. After stirring for 16 hours, EA (20 mL) and water (20 mL) were added. The organic layer was concentrated. The residue was purified by preparative PC-TLC (neat EA) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-oxopiperidin-1-yl)benzamide (6-4) (57 mg).

[0227] Step 5: Preparation of compound 6

[0228] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-oxopiperidin-1-yl)benzamide (6-4) (47 mg, 0.10 mmol, 1.0 eq.) and 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-pyrrolidin-3-yl)methoxy)isoindoline-1,3-dione (5-4) (40 mg, 0.10 mmol, 1.0 eq.) in DCM (1 ml) at room temperature were added TEA (51 mg, 0.50 mmol, 5.0 eq.) and MgSO4 (120 mg, 1.00 mmol, 10 eq.). The mixture was stirred at 25°C for 1 hour. NaBH3CN (16 mg, 0.25 mmol, 2.5 eq.) was added. After stirring at 25° C. for 16 hours, DCM (20 ml) and water (20 ml) were added. The organic layer was concentrated. The residue was purified by preparative-TLC (DCM / MeOH 10:1) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)piperidin-1-yl)benzamide (6) (2 mg). MS: m / z=810 [M+H] +

[0229] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.07(dd,J=4.4,2.0Hz,1H),8.64(dd,J=8.4,1.6Hz,1H),8.28 (d,J=8.4Hz,1H),8.01(d,J=7.6Hz,1H),7.85(d,J=8.4Hz,1H),7.76-7.67(m,3H),7.46(s,1H),7.38- 7.34(m,2H),6.97(d,J=8.4Hz,2H),5.14-5.09(m,1H),4.73(bs,1H),4.23-4.17(m,3H),3.93-3.84( m,3H),2.93-2.77(m,5H),2.67-2.57(m,2H),2.32-2.23(m,3H),2.06-1.90(m,6H),170-1.58(m,6H).

[0230] Example 7 Preparation of Compound 7

[0231] Step 1: Preparation of compound 7-1

[0232] To a solution of tert-butyl (3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (5-3) (100 mg, 0.22 mmol, 1.0 eq.) in AcOH (15 ml) was added zinc powder (257 mg, 4.39 mmol, 20 eq.) at room temperature. After stirring at 80°C for 16 hours, the mixture was cooled to room temperature and concentrated. The residue was purified by reverse phase chromatography (TFA buffer) to give tert-butyl (3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxoisoindolin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (7-1) (15 mg). MS: m / z = 385 [M+H] +

[0233] Step 2: Preparation of compound 7-2

[0234] To a solution of tert-butyl (3R)-3-((((2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxoisoindolin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (7-1) (15 mg, 0.032 mmol, 1.0 eq.) and triethylsilane (15 mg, 0.13 mmol, 4.0 eq.) in DCM (2 ml) was added TFA (1 ml) at room temperature. After stirring at room temperature for 3 hours, the mixture was concentrated to give 3-(1-oxo-5-(((R)-pyrrolidin-3-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione (7-2b) (15 mg, crude). MS: m / z=343 [M+H] +

[0235] Step 3: Preparation of compound 7

[0236] To a solution of 3-(1-oxo-5-(((R)-pyrrolidin-3-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione (7-2) (15 mg, 0.043 mmol, 1.0 eq.) in DMF (1 mL) was added N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (20 mg, 0.043 mmol, 1.0 eq.) and TEA (43 mg, 0.43 mmol, 10 eq.) at room temperature. After stirring at room temperature for 4 hours, NaBH(OAc) (86 mg, 0.406 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature for 4 hours, concentrated, and H O (20 mL) was added, followed by extraction with EA (20 mL*3). The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)methyl)pyrrolidin-1-yl)methyl (7) (16.3 mg). MS: m / z = 810 [M+H] +

[0237] 1H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 9.08 (dd, J=4.2, 1.8Hz, 1H), 8.64 (dd, J= 8.5,1.7Hz,1H),8.29(d,J=8.3Hz,1H),8.01(d,J=7.6Hz,1H),7.76(d,J=8.4Hz ,2H),7.72–7.63(m,2H),7.36(d,J=8.5Hz,1H),7.20(d,J=2.5Hz,1H),7.09(dt ,J=8.5,2.5Hz,1H),7.00–6.93(m,2H),5.08(dd,J=13.3,5.0Hz,1H),4.74(brs ,1H),4.43–4.35(m,1H),4.33–4.24(m,1H),4.22–4.06(m,2H),3.94–3.78(m,4 H),3.42–3.32(m,1H),3.23–3.12(m,3H),3.05–2.86(m,3H),2.85–2.76(m,3H) ,2.68–2.57(m,1H),2.44–2.31(m,1H),2.26(d,J=11.1Hz,2H),2.19–2.08(m,1 H),2.04–1.91(m,4H),1.88–1.78(m,2H),1.72–1.54(m,4H),1.35–1.23(m,2H)

[0238] Example 8 Preparation of Compound 8

[0239] Step 1: Preparation of compound 8-1

[0240] To a solution of tert-butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.0 g, 14.9 mmol, 1.0 eq.) and TEA (3.01 g, 29.8 mmol, 2.0 eq.) in DCM (30 mL) was added MsCl (3.1 g, 26.8 mmol, 1.8 eq. 0) at zero degrees Celsius. After stirring at room temperature for 4 hours, the mixture was washed with 30 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude tert-butyl (R)-3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (8-1) (3.0 g, crude), which was used in the next step without purification. MS: m / z = 280 [M+H] +

[0241] Step 2: Preparation of compound 8-2

[0242] To a solution of tert-butyl (R)-3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (8-1) (3.0 g, crude product, 1.4 eq.) and methyl 4-hydroxybenzoate (SM02) (1.61 g, 10.7 mmol, 1.0 eq.) in DMF (20 mL) were added KCO (2.9 g, 21.4 mmol, 2.0 eq.) and NaI (0.8 g, 5.4 mmol, 0.5 eq.) at room temperature. After stirring at 80°C for 16 hours, the mixture was cooled to room temperature, and EtOAc (200 mL) and saturated aqueous NaHCO (60 mL) were added. The organic layer was washed with saturated aqueous NaHCO and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. PE / EA (100 / 1 to 2 / 1) was purified by silica gel column chromatography to give (R)-tert-butyl 3-((4-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate (8-2) (0.8 g). MS: m / z = 336 [M+H] +

[0243] Step 3: Preparation of compound 8-3

[0244] To a solution of tert-butyl (R)-3-((4-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate (8-2) (1.8 g, 5.4 mmol, 1.0 eq.) in DCM (14 mL) was added TFA (3 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated to give methyl (R)-4-(pyrrolidin-3-ylmethoxy)benzoate trifluoroacetate (8-3) (2.0 g). MS: m / z = 236 [M+H] +

[0245] Step 4: Preparation of compound 8-5

[0246] To a solution of (R)-methyl 4-(pyrrolidin-3-ylmethoxy)benzoate trifluoroacetate (8-3) (2.0 g, crude, 1.0 eq.) and tert-butyl 4-(4-(((((methylsulfonyl)oxy)methyl)piperidin-1-yl)benzoate (2-3) (2.2 g, 6.0 mmol, 1.1 eq.) in DMF (8 ml) at room temperature were added K2CO3 (2.25 g, 16.4 mmol, 3.0 eq.) and NaI (0.56 g, 2.7 mmol, 0.5 eq.). After stirring at 80°C for 1 hour, the mixture was cooled to room temperature and EtOAc (150 mL) and H2O (45 mL) were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column purification using DCM / MeOH (200 / 1 to 20 / 1) to give methyl 4-(3R)-1-((1-(4-(tert-butoxycarbonyl)cyclohexa-2,4-dien-1-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methoxy)benzoate (8-5) (1.7 g) as a colorless oil. MS: m / z = 511 [M+H] +

[0247] Step 5: Preparation of compound 8-6

[0248] To a solution of methyl 4-(((3R)-1-((1-(4-(tert-butoxycarbonyl)cyclohexa-2,4-dien-1-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methoxy)benzoate (8-5) (2.0 g, 3.9 mmol, 1.0 eq.) in THF / H2O (18 mL / 12 mL) was added LiOH·H2O (1.0 g, 23.4 mmol, 6.0 eq.) at room temperature. After stirring at 45°C for 40 hours, the mixture was cooled to room temperature, acidified to pH = 5 with 1N HCl, and extracted with EA (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 4-(((3R)-1-((1-(4-(tert-butoxycarbonyl)cyclohexa-2,4-dien-1-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methoxy)benzoic acid (8-6) (1.8 g, crude), which was used in the next step without purification. MS: m / z = 497 [M+H] +

[0249] Step 6: Preparation of compound 8-7

[0250] To a solution of 4-(((3R)-1-((1-(4-((tert-butoxycarbonyl)cyclohexa-2,4-dien-1-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)methoxy)benzoic acid (8-6) (1.8 g, crude product, 1.0 eq.) and 3-aminopiperidine-2,6-dione (0.64 g, 3.8 mmol, 1.05 eq.) in DMF (12 ml) at room temperature were added HATU (1.48 g, 3.8 mmol, 1.05 eq.) and DIEA (2.4 g, 18.1 mmol, 5.0 eq.). After stirring at room temperature for 3 hours, H2O (100 mL) was added and extracted with EA (100 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a column chromatography (pH = 9 to 10). Purification by column chromatography using (DCM:MeOH = 100 / 1 to 30 / 1) as the eluent gave 4-(4-(3R)-3-((4-(2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoate (8-7) (0.32 g). MS: m / z = 605 [M+H] +

[0251] Step 7: Preparation of compound 8

[0252] To a solution of tert-butyl 4-(4-(3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoate (8-7) (90 mg, 0.15 mmol, 1.0 eq.) in DCM (4 mL) was added TFA (2 mL) at room temperature. The mixture was stirred at room temperature for 1 h and concentrated. The residue was dissolved in DMF (4.5 mL), and the resulting mixture was added with 5-(((1r, 4r)-4-aminocyclohexyloxy)quinoline-8-carbonitrile (1-7) (50 mg, 0.17 mmol, 1.1 eq.), HATU (61 mg, 0.17 mmol, 1.1 eq.) and DIPEA (193 mg, 1.5 mmol, 10.0 eq.). After stirring at room temperature for 2 hours, H2O (20 mL) was added and extracted with EA (20 mL*3). The combined organic layers were washed with water and lysine. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCOOH buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3R)-3-((4-(2,6-dioxopyrimidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl]piperidin-1-yl)benzamide (8) (6 mg). MS: m / z = 798.4 [M+H] +

[0253] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.52–9.33(br,1H),7.99(d,J=7.6Hz,1H),7.86(d,J=8.8Hz,1H),7.74(d,J=8.8Hz,2H),7.38(d,J=2.4H z,1H),7.14(dd,J=8.8,2.4Hz,1H),6.95(d,J=8.8Hz,2H),6.89(t,J=9.3Hz,1H),6.54(dd,J=15.1,2.0Hz,1H),6.45(dd,J=8.5,2.4Hz,1H),4.5 8–4.47(m,1H),4.28(dd,J=11.5,4.8Hz,1H),3.87(d,J=12.6Hz,3H),3.58(d,J=11.5Hz,3H),3.32–3.12(m,4H),3.13–2.99(m,4H),2.79(t,J= 12.1Hz,2H),2.76–2.64(m,1H),2.57(dt,J=17.2,3.7Hz,1H),2.13–2.0 0(m,3H),1.90–1.79(m,3H),1.50(q,J=11.5Hz,4H),1.33–1.23(m,3H).

[0254] Example 9 Preparation of Compound 9

[0255] Step 1: Preparation of compound 9-1

[0256] To a solution of tert-butyl 4-fluorobenzoate (5.0 g, 25.5 mmol, 1.0 eq.) and piperidin-4-ylmethanol (5.9 g, 51.0 mmol, 2.0 eq.) in DMF (40 mL) was added K2CO3 (8.8 g, 51.0 mmol, 2.0 eq.) at room temperature. After stirring at 118°C for 16 hours, the mixture was cooled to room temperature, and H2O (60 mL) and EtOAc (200 mL) were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column with PE / EA (50 / 1 to 1 / 2) to give tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (9-1) (5.9 g). MS: m / z = 292 [M+H] +

[0257] Step 2: Preparation of compound 9-2

[0258] To a solution of tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (9-1) (4.5 g, 15.5 mmol, 1.0 eq.) in dioxane (64 mL) was added HCl (84 mL, 4 M in dioxane) at room temperature. After stirring at 75°C for 16 hours, the mixture was cooled to room temperature and concentrated to dryness. The residue was stirred in EA (40 mL) at room temperature for 30 minutes. The resulting mixture was filtered, and the filter cake was washed with acetonitrile (40 mL) and dried to give 4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid (9-2) (3.6 g). MS: m / z = 236 [M+H] +

[0259] Step 3: Preparation of compound 9-4

[0260] To a solution of 4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid (9-2) (1.5 g, 6.4 mmol, 1.0 eq.) and 4-((((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (9-3) (1.6 g, 5.8 mmol, 0.9 eq.) in DMF (36 mL) were added HOAt (1.7 g, 12.8 mmol, 2.0 eq.), EDCI·hydrochloric acid (2.5 g, 12.8 mmol, 2.0 eq.) and DIPEA (4.2 mL, 25.6 mmol, 4.0 eq.). After stirring at room temperature for 3 hours, H2O (80 mL) was added and extracted with EA (80 mL*3). The combined organic layers were washed with saturated brine, dried, and concentrated. The residue was stirred in n-heptane / EA (50 mL / 10 mL) at room temperature for 30 minutes. The resulting mixture was filtered and dried to give N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide (9-4) (2.2 g). MS: m / z=468[M+H] +

[0261] Step 4: Preparation of compound 9-5

[0262] To a solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide (9-4) (1.1 g, 2.4 mmol, 1.0 eq.) in DCM (120 mL) was added Dess-Martin reagent (1.2 g, 2.9 mmol, 1.2 eq.) at room temperature. After stirring at 25°C for 16 hours, the mixture was diluted with saturated aqueous Na2S2O3 (60 mL) and extracted with DCM (40 mL*2). The combined organic layers were washed with saturated aqueous Na2S2O3 solution (50 mL), saturated aqueous NaHCO3 solution (50 mL), and water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (9-5) (1.02 g). MS: m / z = 466 [M+H] +

[0263] Step 5: Preparation of compound 9-6

[0264] To a solution of 1,2-difluoro-4-nitrobenzene (2.5 g, 15.7 mmol, 1.0 eq.) and tert-butylpiperazine-1-carboxylate (3.2 g, 17.3 mmol, 1.1 eq.) in DMF (12 mL) was added K2CO3 (4.4 g, 31.4 mmol, 2.0 eq.) at room temperature. After stirring at 60°C for 3 hours, the mixture was cooled to room temperature and poured into ice water (38 mL) and stirred for 20 minutes. The solid was filtered and washed with water (15 mL*2), and dried to give tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (9-6) (4.8 g). MS: m / z=326 [M+H] +

[0265] Step 6: Preparation of compound 9-7

[0266] To tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (9-6) (2.0 g, 6.2 mmol, 1.0 eq.) in EA (30 mL) was added Pd / C (5% Wt, 0.26 g, 0.69 mmol, 0.02 eq.) at room temperature. The reaction mixture was stirred at 25°C under an H2 atmosphere for 16 hours. After the reaction was complete, the mixture was filtered through a celite pad and washed with EA (10 mL). The filtrate was concentrated in vacuo to give tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (9-7) (1.80 g). MS: m / z = 296 [M+H] +

[0267] Step 7: Preparation of compound 9-8

[0268] To a solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (9-7) (0.9 g, 3.1 mmol, 1.0 eq.) and 3-bromopiperidine-2,6-dione (1.76 g, 9.3 mmol, 3.0 eq.) in DMF (6 mL) was added CsCO (2.5 g, 31 mmol, 10.0 eq.) at room temperature. After stirring at 85°C for 24 hours, the mixture was cooled to room temperature, diluted with ice water (50 mL), and extracted with MTBE (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (50 / 1 to 1 / 2) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (9-8) (0.24 g). MS: m / z = 407 [M+H] +

[0269] Step 8: Preparation of compound 9-9

[0270] To a solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-ylamino)-2-fluorophenyl)piperazine-1-carboxylate (9-8) (120 mg, 0.30 mmol, 1.0 eq.) in dioxane (3 mL) was added HCl (15 mL, 4 M in dioxane) at room temperature. After stirring at 50°C for 16 hours, the mixture was cooled to room temperature and concentrated to give 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (9-9) (130 mg). MS: m / z = 307 [M+H] +

[0271] Step 9: Preparation of compound 9

[0272] To 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (9-9) (90 mg, 0.26 mmol, 1.0 eq.) in DCM / MeOH (10 mL / 5 mL) at room temperature were added N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (9-5) (108 mg, 0.24 mmol, 0.9 eq.) and TEA (6 drops). After stirring at room temperature for 16 hours, NaBH(OAc) (132 mg, 0.65 mmol, 2.5 eq.) was added. Stirring was continued at room temperature for 1 hour, and the mixture was concentrated to dryness under reduced pressure. EA / H2O (20 mL + 20 mL) was added, and the mixture was extracted with EA (20 mL * 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (9) (75 mg). MS: m / z = 756.3 [M+H] +

[0273] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.52–9.33(br,1H),7.99(d,J=7.6Hz,1H),7.86(d,J=8.8Hz,1H),7.74(d,J=8.8Hz,2H),7.38(d,J=2.4H z,1H),7.14(dd,J=8.8,2.4Hz,1H),6.95(d,J=8.8Hz,2H),6.89(t,J=9.3Hz,1H),6.54(dd,J=15.1,2.0Hz,1H),6.45(dd,J=8.5,2.4Hz,1H),4.5 8–4.47(m,1H),4.28(dd,J=11.5,4.8Hz,1H),3.87(d,J=12.6Hz,3H),3.58(d,J=11.5Hz,3H),3.32–3.12(m,4H),3.13–2.99(m,4H),2.79(t,J= 12.1Hz,2H),2.76–2.64(m,1H),2.57(dt,J=17.2,3.7Hz,1H),2.13–2.0 0(m,3H),1.90–1.79(m,3H),1.50(q,J=11.5Hz,4H),1.33–1.23(m,3H).

[0274] Example 10 Preparation of Compound 10

[0275] Step 1: Preparation of compound 10-1

[0276] To a solution of 5-bromoindoline (120 mg, 0.6 mmol, 1.0 eq.) in DCM (2 mL) at room temperature were added DIEA (234 mg, 1.8 mmol, 3.0 eq.) and CbzCl (124 mg, 0.7 mmol, 1.2 eq.). After stirring at room temperature for 4 hours, the mixture was concentrated. The residue was purified by flash chromatography on silica gel eluted with hexane / ethyl acetate (8:1) to give 5-bromoindoline-1-carboxylic acid benzyl ester (10-1) (195 mg). MS: m / z = 332 [M+H] +

[0277] Step 2: Preparation of compound 10-2

[0278] To a solution of benzyl 5-bromoindoline-1-carboxylate (10-1) (195 mg, 0.61 mmol, 1.0 eq.) in toluene were added tert-butyl piperazine-1-carboxylate (136.4 mg, 0.73 mmol, 1.2 eq.), NaOtBu (82 mg, 0.85 mmol, 1.4 eq.), XantPhos (28 mg, 0.05 mmol, 0.08 eq.), and Pd2(dba)3 (22 mg, 0.02 mmol, 0.04 eq.) at room temperature. The reaction vessel was evacuated and backfilled with nitrogen (three times). After stirring at 90°C for 4 hours, the mixture was cooled to room temperature, H2O (20 mL) was added, and the mixture was extracted with EA (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate (8:1) to give benzyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)indoline-1-carboxylate (100 mg). MS: m / z = 438 [M+H] +

[0279] To 5-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)indoline-1-carboxylate (100 mg, 0.3 mmol, 1.0 eq.) in MeOH (2 mL) was added Pd / C (10.0 mg, 0.1 eq.). After stirring under H2 atmosphere for 6 hours, the mixture was filtered and washed with MeOH (5 mL). The filtrate was concentrated to give tert-butyl 4-(indolin-5-yl)piperazine-1-carboxylate (10-2) (60 mg) as a white solid. MS: m / z = 304 [M+H] +

[0280] Step 3: Preparation of compound 10-3

[0281] To a solution of tert-butyl 4-(indolin-5-yl)piperazine-1-carboxylate (10-2) (60.0 mg, 0.19 mmol, 1.0 eq.) in MeCN (1 mL) at room temperature were added 3-bromopiperidine-2,6-dione (75 mg, 0.39 mmol, 2.0 eq.) and NaHCO 3 (49 mg, 0.59 mmol, 3 eq.). After stirring at 95° C. for 2 hours, the reaction mixture was purified by reverse phase chromatography (TFA buffer) to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)indolin-5-yl)piperazine-1-carboxylate (10-3) (70 mg).

[0282] MS: m / z = 415 [M+H] +

[0283] Step 4: Preparation of compound 10-4

[0284] To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)indolin-5-yl)piperazine-1-carboxylate (10-3) (70 mg, 0.2 mmol, 1.0 eq.) in DCM (3 mL) was added 4M HCl in EA (3 mL) at room temperature. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give 3-(5-(5-(piperazin-1-yl)indolin-1-yl)piperidine-2,6-dione hydrochloride (10-4) (50 mg). MS: m / z = 314 [M+H] +

[0285] Step 5: Preparation of compound 10

[0286] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (52 mg, 0.1 mmol, 1 eq.) in DCM (1 mL) was added 3-(5-((piperazin-1-yl)indolin-1-yl)- Piperidine-2,6-dione (10-4) (34 mg, 0.1 mmol, 1.0 eq.), TEA (one drop), and MgSO4 (129 mg, 1.0 mmol, 10.0 eq.) were added. After stirring at room temperature for 30 minutes, NaHB(OAc)3 (68 mg, 0.3 mmol, 3.0 eq.) was added. After stirring at room temperature for another hour, the reaction mixture was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)indolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (10) (9.5 mg). MS: m / z = 782 [M+H] +

[0287] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),9.05(dd,J=4.0,1.8Hz,1H),8.62(dd,J=8.6,1.4Hz,1H),8.27(d,J=8.2Hz,1H),7.97(d, J=7.6Hz,1H),7.72(s,1H),7.67(dd,J=8.4,4.2Hz,1H),7.34(d,J=8.4Hz,1H),6.91(d,J=8.6Hz,2H),6.73(s,1H),6.54(d,J=7. 4Hz,1H),6.35(d,J=8.4Hz,1H),4.74–4.68(m,1H),4.50(dd,J=12.8,4.8Hz,1H),3.94–3.75(m,4H),2.97–2.89(m,3H),2.87–2 .83(m,1H),2.80–2.69(m,3H),2.25–2.13(m,4H),2.00–1.88(m,4H),1.80–1.74(m,2H),1.66–1.50(m,5H),1.24–1.16(m,10H).

[0288] Example 11 Preparation of Compound 11

[0289] Step 1: Preparation of compound 11-2

[0290] To a solution of 4-bromo-2-fluorobenzonitrile (11-1) (15.0 g, 75.0 mmol, 1.0 eq.) in DMA (75 mL) was added MeNHNH2·H2SO4 (13.0 g, 90.0 mmol, 1.2 eq.) and DIEA (33.9 g, 262.5 mmol, 3.5 eq.) at room temperature. After stirring at 150°C for 24 hours, the mixture was cooled to room temperature, and EA (750 mL) and water (750 mL) were added. Extraction was performed with EA (500 mL). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EA (1:1) to yield 6-bromo-1-methyl-1H-indazol-3-amine (11-2) (13.4 g).

[0291] Step 2: Preparation of compound 11-3

[0292] A mixture of lactic acid (420 mg, 85%, 3.97 mmol, 1.3 eq.) and DBU (604 mg, 3.97 mmol, 1.3 eq.) was stirred at 25°C for 16 h, followed by the addition of 6-bromo-1-methyl-1H-indazol-3-amine (11-2) (670 mg, 2.96 mmol, 1.0 eq.) and methyl acrylate (1.84 g, 21.4 mmol, 7.0 eq.). After stirring at 85°C for 16 h, the mixture was cooled to room temperature and EA (20 mL) and water (20 mL) were added. The organic layer was concentrated, and the residue was purified by chromatography on silica gel eluting with PE / EA (1:1) to give methyl 3-((6-bromo-1-methyl-1H-indazol-3-amino)propanoate (11-3) (650 mg).

[0293] Step 3: Preparation of compound 11-4

[0294] To a solution of 3-((6-bromo-1-methyl-1H-indazole-3-amino)propanoate (11-3) (650 mg, 2.08 mmol, 1.0 eq.) in AcOH (6.5 mL) was added KCNO (338 mg, 4.16 mmol, 2.0 eq.) at room temperature. After stirring at 25°C for 16 s, EA (50 mL) and water (50 mL) were added. The organic layer was concentrated, and the residue was purified on a silica gel column with EA / MeOH (10:1) to give methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propanoate (11-4) (518 mg) as a colorless oil.

[0295] Step 4: Preparation of compound 11-5

[0296] To a solution of 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propanoate (11-4) (485 mg, 1.37 mmol, 1.0 eq.) in MeCN (5 mL) was added Triton-B (400 mg, 40%, 0.96 mmol, 0.7 eq.) at room temperature. After stirring at 25°C for 16 h, EA (50 mL) and water (50 mL) were added. The organic layer was concentrated to give 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (11-5) (364 mg).

[0297] Step 5: Preparation of compound 11-6

[0298] To a solution of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (11-5) (1.00 g, 3.09 mmol, 1.0 eq.) in toluene was added tert-butyl piperazine-1-carboxylate (690 mg, 3.71 mmol, 1.2 eq.), Pd2(dba)3 (140 mg, 0.15 mmol, 0.05 eq.), XantPhos (180 mg, 0.31 mmol, 0.1 eq.), and t-BuONa (890 mg, 9.28 mmol, 3.0 eq.) at room temperature. After stirring at 85°C for 4 hours, the reaction was cooled to room temperature, quenched with aqueous NH4Cl (20%, 30 mL), and extracted with EA (30 mL). The organic layer was concentrated. The residue was purified by preparative TLC (pure EA) to give tert-butyl piperazine-1-carboxylate, 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (11-6) (440 mg). MS: m / z = 429 [M+H] +

[0299] Step 6: Preparation of compound 11-7

[0300] To a solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (10-6) (170 mg, 0.397 mmol, 1.0 eq.) in EA (5 mL) was added 4M HCl in dioxane (2.5 mL) at room temperature. Stirring was continued for 16 hours, and LCMS showed that the reaction was complete. EA (20 mL) was added to the mixture and stirred for 5 minutes before filtration. The filter cake was dried to give 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (11-7) (100 mg). MS: m / z=329[M+H]+

[0301] Step 7: Preparation of compound 11

[0302] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (103 mg, 0.21 mmol, 1.0 eq.) and 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (11-7) (70 mg, 0.21 mmol, 1.0 eq.) in DCM (5 ml) was added TEA (216 mg, 2.13 mmol, 10.0 eq.) and MgSO4 (256 mg, 2.13 mmol, 10.0 eq.) at room temperature. After stirring at 25°C for 2 hours, NaBH(OAc)3 (113 mg, 0.53 mmol, 2.5 eq.) was added. The mixture was stirred at 25° C. for 16 hours, and DCM (20 mL) and water (20 mL) were added. The mixture was filtered to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (11) (60 mg, 35% yield). MS: m / z=795 [M+H] +

[0303] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),9.04(d,J=3.2Hz,1H),8.62(d,J=7.6Hz,1H),8.26(d,J= 8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.73-7.65(m,2H),7.43(d,J=9.2Hz,1H),7.33(d,J=8.8Hz, 1H),6.92-6.89(m,2H),6.80(s,1H),4.73-4.68(m,1H),3.89-3.81(m,5H),3.30(s,10H),3.21(bs,3H),2.83-2.69( m,3H),2.51(bs,3H),2.24-2.19(m,3H),1.96-1.92(m,2H),1.81-1.77(m,2H),1.68-1.55(m,3H),1.23-1.13(m,2H).

[0304] Example 12 Preparation of Compound 12

[0305] Step 1: Preparation of compound 12-1

[0306] To a solution of 1-bromo-3-chloro-5-nitrobenzene (100 mg, 0.42 mmol, 1 eq.) in toluene (2 mL) were added tert-butyl piperazine-1-carboxylate (94.5 mg, 0.51 mmol, 1.2 eq.), Pd2(dba)3 (19.3 mg, 0.02 mmol, 0.05 eq.), BINAP (26.3 mg, 0.042 mmol, 0.10 eq.), and NaOtBu (56.9 mg, 0.59 mmol, 1.4 eq.) at room temperature. The mixture was stirred at 100°C for 4 hours. After cooling, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated. Purification by flash chromatography (hexane / ethyl acetate = 18:1) gave tert-butyl 4-(3-chloro-5-nitrophenyl)piperazine-1-carboxylate (12-1) (195 mg). MS: m / z = 267 [M+H] +

[0307] Step 2: Preparation of compound 12-2

[0308] To a solution of tert-butyl 4-(3-chloro-5-nitrophenyl)piperazine-1-carboxylate (12-1) (190 mg, 0.55 mmol, 1.0 eq.) in MeOH (40 mL) was added PtO2 (20 mg, 0.1 w.) at room temperature. After stirring under a H2 atmosphere for 4 hours, the mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(3-amino-5-chlorophenyl)piperazine-1-carboxylate (12-2) (150 mg). MS: m / z = 312 [M+H] +

[0309] Step 3: Preparation of compound 12-3

[0310] To a solution of tert-butyl 4-(3-amino-5-chlorophenyl)piperazine-1-carboxylate (12-2) (150 mg, 0.48 mmol, 1.0 eq.) in DMF (2 mL) was added 3-bromopiperidine-2,6-dione (183 mg, 0.96 mmol, 2.0 eq.) and NaHCO₃ (121 mg, 1.44 mmol, 3.0 eq.) at room temperature. After stirring at 70°C and cooling to room temperature, the reaction mixture was purified by reverse phase chromatography (TFA buffer) to give tert-butyl 4-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (12-3) (100 mg). MS: m / z = 423 [M+H] +

[0311] Step 4: Preparation of compound 12-4

[0312] To a solution of tert-butyl 4-(3-chloro-5-((2,6-dioxopiperidin-3-ylamino)phenyl)piperazine-1-carboxylate (12-3) (100 mg, 0.23 mmol, 1.0 eq.) in DCM (3 mL) was added 4M HCl in EA (3 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and concentrated to give 3-((3-chloro-5-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (12-4) (70 mg, crude). MS: m / z=323 [M+H] +

[0313] Step 5: Preparation of compound 12

[0314] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (37 mg, 0.077 mmol, 1 eq.) in DCM (1 mL) was added 3-((3-chloro-5-(piperazin-1-ylphenyl)amino)piperidine-2,6-dione (12-4) (25.0 mg, 0.077 mmol, 1.0 eq.), TEA (3 drops) and MgSO4 (93 mg, 0.077 mmol, 1 eq.) at room temperature. 0.07 mmol, 10.0 eq.). After stirring at room temperature for 30 minutes, NaBH(OAc)3 (16 mg, 0.077 mmol, 1.0 eq.) was added. After stirring at room temperature for 1 hour, the reaction mixture was purified by reverse phase chromatography (TFA buffer) to give 4-(4-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)benzamide (12) (17.6 mg). MS: m / z = 789 [M+H] +

[0315] 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.37(s,1H),9.05(dd,J=4.4,1.7Hz,1H),8.62(dd,J=8.4,1.8Hz,1H),8.27(d,J=8.4Hz,1H),7.99(d,J=7.6Hz,1 H),7.74(d,J=8.6Hz,2H),7.67(dd,J=8.4,4.2Hz,1H),7.33(d,J=8.4Hz,1H ),6.94(d,J=8.8Hz,2H),6.27–6.19(m,3H),4.76–4.69(m,2H),4.37(dd,J=1 1.8,4.9Hz,2H),3.86(d,J=10.2Hz,4H),3.74(d,J=12.2Hz,3H),3.57(d,J= 11.0Hz,3H),3.05–2.99(m,2H),2.85–2.74(m,2H),2.58(d,J=4.2Hz,1H),2 .55–2.51(m,1H),2.25–2.19(m,2H),2.07–2.02(m,2H),1.97–1.89(m,2H), 1.85–1.78(m,3H),1.68–1.62(m,2H),1.58–1.53(m,1H),1.31–1.24(m,2H).

[0316] Example 13 Preparation of Compound 13

[0317] Step 1: Preparation of compound 13-1

[0318] To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (3.0 g, 21.1 mmol, 1 eq.) in THF (30 mL) at room temperature were added 4-nitro-1H-pyrazole (2.39 g, 21.1 mmol, 1.0 eq.), DIAD (5.13 g, 25.4 mmol, 1.2 eq.), and PPh3 (6.6 g, 25.4 mmol, 1.2 eq.). The mixture was stirred at room temperature for 12 h, then water (30 mL) was added and extracted with EA (3 x 30 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel eluting with PE / EA (10:1 to 3:1) to give benzyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-1) (3.3 g). MS: m / z = 331 [M+H] +

[0319] Step 2: Preparation of compound 13-2

[0320] To a solution of benzyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-1) (3.3 g, 16.4 mmol, 1.0 eq.) in methanol (40 ml) was added PtO2 (330 mg, 0.1 mmol) at room temperature. After stirring under a H2 atmosphere for 4 hours, the mixture was filtered and the filtrate was concentrated to give 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-2) (3.0 g). MS: m / z = 301 [M+H] +

[0321] Step 3: Preparation of compound 13-3

[0322] A mixture of lactic acid (5.0 g, 56.3 mmol, 5.0 eq) and DBU (8.5 g, 56.3 mmol, 5.0 eq.) was stirred at 25° C. for 16 h, followed by the addition of 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-2) (3.0 g, 11.27 mmol, 1.0 eq) and methyl acrylate (30 mL). After stirring at room temperature for 16 h, EA (50 mL) and water (50 mL) were added. The organic layer was concentrated, and the reaction mixture was purified by reverse phase chromatography (TFA buffer) to give benzyl 4-(4-(3-methoxy-3-oxopropyl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-3) (2.28 g). MS: m / z=387 [M+H] +

[0323] Step 4: Preparation of compound 13-4

[0324] To a solution of benzyl 4-(4-(3-methoxy-3-oxopropyl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-3) (620 mg, 1.6 mmol, 1.0 eq.) in ACOH (6.2 mL) was added KCNO (260 mg, 3.2 mmol, 2.0 eq.) at room temperature. After stirring at 25°C for 16 h, EA (20 mL) and water (20 mL) were added. The organic layer was concentrated, and the residue was purified by chromatography on silica gel eluting with EA / MeOH (10:1) to give benzyl 4-(4-(1-(3-methoxy-3-oxopropyl)ureido)-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-4) (470 mg). MS: m / z = 430 [M+H] +

[0325] Step 5: Preparation of compound 13-5

[0326] To a solution of benzyl 4-(4-(1-(3-(3-methoxy-3-oxopropyl)ureido)-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-4) (420 mg, 0.97 mmol, 1.0 eq.) in MeCN (12 mL) was added Triton-B (409 mg, 40%, 2.44 mmol, 2.5 eq.) at room temperature. After stirring at 25° C. for 16 h, EA (50 mL) and water (50 mL) were added. The organic layer was concentrated to give benzyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-5) (450 mg). MS: m / z=398 [M+H] +

[0327] Step 6: Preparation of compound 13-6

[0328] To a solution of benzyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-5) (450 mg, 1.13 mmol, 1.0 eq.) was added PtO2 (45 mg, 0.1 W) in MeOH (40 mL) at room temperature. After stirring under a H2 atmosphere for 4 hours, the mixture was filtered and the filtrate was concentrated to give 1-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (13-6) (300 mg). MS: m / z = 283 [M+H] +

[0329] Step 7: Preparation of compound 13

[0330] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (90 mg, 0.19 mmol, 1.0 eq.) and 1-(1-((piperidin-4-yl)-1H-pyrazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dihydropyrimidine-2,4(1H,3H)-dione (13-6) (50 mg, 0.19 mmol, 1.0 eq.) in DCM (5 mL) was added TEA (4 drops) at room temperature. The mixture was stirred at 25° C. for 2 hours, and then N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (90 mg, 0.19 mmol, 1.0 eq.) was added TEA (4 drops). The mixture was stirred at 25° C. for 2 hours, and then N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (90 mg, 0.19 mmol, 1.0 eq.) was added aBH(OAc)3 (120.1 mg, 0.5 mmol, 3.0 eq.). The reaction mixture was stirred at 25°C for 16 hours, and DCM (20 mL) and water (20 mL) were added. The mixture was filtered to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (13) (21.4 mg). MS: m / z=730 [M+H] +

[0331] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.32(brs,1H),9.08(dd,J=4.2,1.7Hz,1H),8.65(dd,J=8.5,1.7Hz,1H),8.29(d,J=8.3Hz,1H),8.0 2(d,J=7.6Hz,1H),7.99(s,1H),7.76(d,J=8.7Hz,2H),7.69(dd,J=8.5,4.3Hz,1H),7.36(d,J=8.5Hz,1H),6.97(d,J=8.9Hz,2H),4.74(br s,1H),4.47(brs,1H),3.89(d,J=11.1Hz,3H),3.77(t,J=6.8Hz,3H),3.68(d,J=11.1Hz,2H),3.18–3.00(m,4H),2.81(t,J=11.5Hz,2H),2 .70(t,J=6.8Hz,2H),2.30–2.19(m,5H),2.07(brs,1H),2.01–1.89(m,2H),1.86(d,J=12.6Hz,2H),1.69–1.55(m,4H),1.39–1.20(m,2H).

[0332] Example 14 Preparation of Compound 14

[0333] Step 1: Preparation of compound 14-1

[0334] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (300 mg, 1.49 mmol, 1 eq.) in THF (3 mL) at room temperature were added 4-nitro-1H-pyrazole (168 mg, 1.49 mmol, 1.0 eq.), DIAD (361 mg, 1.79 mmol, 1.2 eq.), and PPh3 (469 mg, 1.79 mmol, 1.2 eq.). After stirring at room temperature for 4 h, the mixture was diluted with water (20 mL) and extracted with EA (3 x 20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE / EA (10:1 to 3:1)) to give tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (14-1) (100 mg). MS: m / z = 297 [M+H] +

[0335] Step 2: Preparation of compound 14-2

[0336] To a solution of tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (13-1) (100 mg, 0.55 mmol, 1.0 eq.) in MeOH (40 mL) was added PtO2 (10 mg, 0.1 w.) at room temperature. The resulting mixture was stirred under a H2 atmosphere for 4 hours, filtered, and the filtrate was concentrated to give tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (14-2) (70 mg, crude product). MS: m / z = 267 [M+H] +

[0337] Step 3: Preparation of compound 14-3

[0338] To a solution of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (14-2) (70 mg, 0.48 mmol, 1.0 eq.) in DMF (2 mL) was added 3-bromopiperidine-2,6-dione (183 mg, 0.96 mmol, 2.0 eq.) and NaHCO₃ (121 mg, 1.44 mmol, 3.0 eq.) at room temperature. After stirring at 70°C for 1 hour, the mixture was cooled to room temperature and purified by reverse phase chromatography (TFA buffer) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (14-3) (50 mg). MS: m / z = 378 [M+H] +

[0339] Step 4: Preparation of compound 14-4

[0340] To a solution of tert-butyl 4-(4-(((2,6-dioxopiperidin-3-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (14-3) (50.0 mg, 0.23 mmol, 1.0 eq.) in DCM (3 mL) was added a 4M HCl solution in EA (3 mL) at room temperature. After stirring at room temperature for 2 hours, the mixture was concentrated to give compound 14-4 (25 mg). MS: m / z=278 [M+H] +

[0341] Step 5: Preparation of compound 14

[0342] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (43 mg, 0.09 mmol, 1 eq.) in DCM (1 mL) were added compound 14-4 (25.0 mg, 0.09 mmol, 1.0 eq.), TEA (3 drops) and MgSO4 (108 mg, 0.07 mmol, 10.0 eq.) at room temperature. The mixture was stirred at room temperature for 30 minutes, and then NaBH(OAc)3 (19 mg, 0.09 mmol, 1.0 eq.) was added. After the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-((2,6-dioxopiperidin-3-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide (14) (6.1 mg). MS: m / z=744 [M+H] +

[0343] 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),9.05(dd,J=4.2,1.8Hz,2H),8.62(dd,J=8.4,1.8Hz, 1H),8.27(d,J=8.4Hz,1H),8.02–7.97(m,1H),7.74(d,J=8.4Hz,2H),7.67(dd,J=8.4 ,4.3Hz,1H),7.33(d,J=8.4Hz,1H),6.94(d,J=9.0Hz,2H),4.75–4.68(m,1H),4.32–4 .25(m,1H),3.92–3.77(m,6H),3.15–2.96(m,4H),2.78(t,J=12.2Hz,2H),2.26–2.11 (m,6H),1.97–1.88(m,2H),1.85–1.78(m,2H),1.70–1.49(m,4H),1.31–1.20(m,2H).

[0344] Example 15 Preparation of Compound 15

[0345] Step 1: Preparation of compound 15-1

[0346] To a solution of 6-chloropyridazine-3-carboxylic acid (2 g, 12.6 mmol, 1.0 eq.) and DMAP (776 mg, 6.3 mmol, 0.5 eq.) in THF (50 mL) was added Boc2O (3.6 g, 16.4 mmol, 1.3 eq.) at room temperature. After stirring at 50°C for 6 hours, H2O (400 mL) was added and the mixture was extracted with EA (100 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA (1:1)) to give tert-butyl 6-chloropyridazine-3-carboxylate (15-1) (2.2 g). MS: m / z = 158 [M+H-56] +

[0347] Step 2: Preparation of compound 15-2

[0348] To tert-butyl 6-chloropyridazine-3-carboxylate (15-1) (1 g, 4.66 mmol, 1.0 eq.) and piperidin-4-ylmethanol (1.33 g, 9.31 mmol, 2.0 eq.) in 1,4-dioxane (25 mL) was added DIPEA (1.5 mL, 9.31 mmol, 2.0 eq.) at room temperature. After stirring at 100°C for 16 hours, the mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography using PE:EA = 1:3 to give tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (15-2) (900 mg). MS: m / z = 293 [M+H-56] +

[0349] Step 3: Preparation of compound 15-3

[0350] A mixture of compound 15-2 (100 mg, 0.34 mmol, 1.0 eq.) and DMP (173 mg, 0.41 mmol, 1.2 eq.) in DCM (2 mL) was stirred at room temperature for 2 hours. Saturated Na2S2O3 (50 mL) was added to dilute the mixture and washed with saturated NaHCO3 (50 mL) and H2O (50 mL), respectively. The aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 6-(4-formylpiperidin-1-yl)pyridazine-3-carboxylate (15-3) (80 mg).

[0351] Step 4: Preparation of compound 15-4

[0352] A mixture of compound 15-3 (60 mg, 0.21 mmol, 1.0 eq.), 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione 4-5 (69 mg, 0.21 mmol, 1.0 eq.), TEA (90 μL, 0.62 mmol, 3.0 eq.), and MgSO (20 mg) in DCM (2 mL) was stirred at room temperature for 16 hours. NaBH(OAc) (51 mg, 0.25 mmol, 1.2 eq.) was then added and stirred at room temperature for 2 hours. H O (10 mL) was then added, and the mixture was extracted with DCM (10 mL x 2). The organic layers were combined and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA (1:1)) to give tert-butyl 6-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxylate (15-4) (100 mg). MS: m / z = 616 [M+H] +

[0353] Step 5: Preparation of compound 15-5

[0354] To a solution of compound 15-4 (100 mg, 0.16 mmol, 1.0 eq.) in DCM (1 mL) was added TFA (0.5 mL) at room temperature. After stirring for 3 hours, the mixture was concentrated to give 6-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxylic acid (15-5) (90 mg). MS: m / z=561 [M+H] +

[0355] Step 6: Preparation of compound 15

[0356] To a solution of compound 15-5 (40 mg, 0.071 mmol, 1.0 eq.), HATU (33 mg, 0.082 mmol, 1.2 eq.) and DIEA (27 mg, 0.231 mmol, 3.0 eq.) in DMF (2 mL) was added 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (20 mg, 0.071 mmol, 1.0 eq.) at room temperature. After stirring at room temperature for 16 hours, H2O (10 mL) was added, and the mixture was extracted with DCM (10 mL*2). The organic layers were combined and concentrated in vacuo. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (15) (21 mg). MS: m / z=810 [M+H] +

[0357] 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.08–9.03(m,1H),8.61(m,2H),8.26(m,2H),8.10(d,J=8.9Hz,1H),7.8 3(d,J=9.5Hz,1H),7.67(dd,J=8.5,4.3Hz,1H),7.57(d,J=8.7Hz,1H),7.42–7.27(m,3H),5.78–5.71(m,1H),4 .71(m,1H),4.50(d,J=13.2Hz,2H),4.14(d,J=12.9Hz,2H),3.92(m,2H),3.65(m,2H),3.11(m,6H),2.91(s,2H ),2.59(m,2H),2.23(m,3H),2.07(m,1H),2.01–1.92(m,2H),1.87(d,J=12.4Hz,2H),1.70(m,3H),1.23(m,3H).

[0358] Example 16 Preparation of Compound 16

[0359] Step 1: Preparation of compound 16-1

[0360] To a solution of methyl 5-fluoropicolinate (1.0 g, 6.4 mmol, 1.0 eq.) and piperidin-4-ylmethanol (0.89 g, 7.7 mmol, 1.2 eq.) in DMSO (3.5 mL) was added KCO (1.1 g, 7.7 mmol, 1.2 eq.) at room temperature. After stirring at 110°C for 1 hour, the mixture was cooled to room temperature and DCM (40 mL) and H2O (20 mL) were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 5-(4-(hydroxymethyl)piperidin-1-yl)picolinate (16-1) (1.52 g). MS: m / z = 251 [M+H] +

[0361] Step 2: Preparation of compound 16-2

[0362] To a solution of methyl 5-(4-(hydroxymethyl)piperidin-1-yl)picolinate (16-1) (0.9 g, 3.6 mmol, 1.0 eq.) in THF / H2O (10 mL / 10 mL) was added LiOH·H2O (0.6 g, 14.4 mmol, 4.0 eq.) at room temperature. After stirring at 35°C for 16 hours, the mixture was concentrated to remove THF and then acidified to pH = 5 with 1N HCl. The resulting mixture was purified by reverse phase chromatography (HCOOH buffer) to give 5-(4-(hydroxymethyl)piperidin-1-yl)picolinic acid (16-2) (0.35 g). MS: m / z = 237 [M+H] +

[0363] Step 3: Preparation of compound 16-3

[0364] To a solution of 5-(4-(hydroxymethyl)piperidin-1-yl)picolinic acid (16-2) (120 mg, 0.51 mmol, 1.0 eq.) and 5-((((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (160 mg, 0.54 mmol, 1.05 eq.) in DMF (6 ml) at room temperature were added HBTU (208 mg, 0.54 mmol, 1.05 eq.) and DIPEA (505 uL, 3.06 mmol). After stirring at room temperature for 16 hours, H2O (80 mL) was added and extracted with EA (80 mL*3). The combined organic layers were washed with saturated brine and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r, 4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)picolinamide (16-3) (100 mg). MS: m / z = 486 [M+H] +

[0365] Step 4: Preparation of compound 16-4

[0366] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)picolinamide (16-3) (92 mg, 0.19 mmol, 1.0 eq.) in DCM (14 mL) was added Dess-Martin reagent (104 mg, 0.25 mmol, 1.3 eq.) at room temperature. After stirring at 25° C. for 3 hours, saturated aqueous Na₂S₂O₃ (25 mL) was added, and the mixture was extracted with DCM (25 mL*3). The combined organic layers were washed with saturated aqueous Na2S2O3 solution (15 mL), saturated aqueous NaHCO3 solution (15 mL), and H2O (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)picolinamide (16-4) (140 mg). MS: m / z = 484 [M+H] +

[0367] Step 5: Preparation of compound 16

[0368] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)picolinamide (16-4) (130 mg, crude, 1.0 eq.) and 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (4-5) (90 mg, 0.24 mmol, 0.9 eq.) in DCM (14 mL) was added TEA (13 drops) at room temperature. After stirring at room temperature for 2 hours, NaBH(OAc) (143 mg, 0.67 mmol, 2.5 eq.) was added. Stirring was continued at room temperature for 1 hour, and the mixture was concentrated to dryness. DCM / H2O (20 mL + 20 mL) was added to the residue, and the mixture was extracted with DCM (20 mL * 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r, 4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalic acid-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)picolinamide (16) (31 mg). MS: m / z = 809 [M+H] +

[0369] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.54(br,1H),9.07(dd,J=4.2,1.8Hz,1H),8.64(dd,J=8.4,1.8Hz,1H),8.29(dd,J=1 0.8,2.5Hz,3H),8.19(d,J=8.2Hz,1H),8.12(d,J=9.0Hz,1H),7.86(d,J=8.8Hz,1H),7.69(dd,J=8.4,4.2Hz,1H),7.60(dd,J =9.0,1.4Hz,1H),7.44(dd,J=8.8,2.5Hz,1H),7.38(d,J=1.6Hz,1H),7.32(d,J=8.4Hz,1H),5.77(dd,J=12.0,5.4Hz,1H),4. 79–4.66(br,1H),4.23–4.09(m,2H),3.97(d,J=12.9Hz,2H),3.92–3.84(br,2H),3.33(t,J=12.6Hz,2H),3.24–3.10(m,3H), 2.96–2.85(m,3H),2.64–2.57(m,1H),2.26–2.19(m,2H),2.15–2.05(m,2H),1.98–1.9 2(m,2H),1.90–1.82(m,2H),1.71–1.61(m,4H),1.35–1.27(m,2H),1.25–1.17(m,2H).

[0370] Example 17 Preparation of Compound 17

[0371] Step 1: Preparation of compound 17-1

[0372] To a solution of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.8 mmol, 1.0 eq.) and piperidin-4-ylmethanol (0.89 g, 5.8 mmol, 1.0 eq.) in DMSO (5 mL) was added KCO (0.96 g, 6.9 mmol, 1.2 eq.) at room temperature. After stirring at 110°C for 1 hour, the mixture was cooled to room temperature and DCM (40 mL) and H2O (20 mL) were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylate (17-1) (1.29 g). MS: m / z = 252 [M+H] +

[0373] Step 2: Preparation of compound 17-2

[0374] To a solution of methyl 5-(4-(hydroxymethyl)piperidin-1-yl)picolinate (17-1) (500 mg, 1.9 mmol, 1.0 eq.) in THF / H2O (10 mL / 10 mL) was added LiOH·H2O (316 mg 7.9 mmol, 4.0 eq.) at room temperature. After stirring at 35°C for 16 hours, the mixture was concentrated to remove THF and then acidified to pH = 5 with 1N HCl. The resulting mixture was purified by reverse phase chromatography (TFA buffer) to give 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylic acid (17-2) (146 mg). MS: m / z = 238 [M+H] +

[0375] Step 3: Preparation of compound 17-3

[0376] To a solution of 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylic acid (17-2) (120 mg, 0.51 mmol, 1.0 eq.) and 5-((((1r,4R)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (160 mg, 0.54 mmol, 1.05 eq.) in DMF (6 ml) at room temperature were added HBTU (208 mg, 0.54 mmol, 1.05 eq.) and DIPEA (505 uL, 3.06 mmol). , 6.0 eq.). After stirring at room temperature for 16 hours, H2O (80 mL) was added and extracted with EA (80 mL*3). The combined organic layers were washed with saturated brine and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r, 4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (17-3) (100 mg). MS: m / z=487 [M+H] +

[0377] Step 4: Preparation of compound 17-4

[0378] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (17-3) (100 mg, 0.2 mmol, 1.0 eq.) in DCM (3 mL) was added Dess-Martin reagent (104 mg, 0.26 mmol, 1.3 eq.) at room temperature. After stirring at 25° C. for 3 hours, the mixture was diluted with saturated aqueous Na2S2O3 solution (25 mL) and extracted with DCM (25 mL*3). The combined organic layers were washed with saturated aqueous Na2S2O3 solution (15 mL), saturated aqueous NaHCO3 solution (15 mL), and H2O (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (17-4) (72 mg). MS: m / z = 485 [M+H] +

[0379] Step 5: Preparation of compound 17

[0380] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (17-4) (50 mg, crude, 1.0 eq.) and 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (4-5) (30 mg, 0.09 mmol, 0.9 eq.) in DCM (4 mL) was added TEA (4 drops) at room temperature. After stirring at room temperature for 2 h, NaBH(OAc) (63 mg, 0.3 mmol, 3.0 eq.) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure. DCM / H2O (20 mL + 20 mL) was added to the residue and extracted with DCM (20 mL * 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalic acid-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide (17) (9.6 mg). MS: m / z=810 [M+H] +

[0381] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.58(s,1H),9.08(dd,J=4.2,1.8Hz,1H),8.67–8.60(m,2H),8.30(s,1H),8.28(d,J=2. 8Hz,1H),8.16–8.08(m,2H),7.70(dd,J=8.4,4.2Hz,1H),7.59(d,J=8.8Hz,1H),7.37(s,1H),7.32(d,J=8.4Hz,1H),5.79–5.7 4(m,1H),4.72(s,2H),4.51(d,J=13.0Hz,2H),4.15(s,2H),3.91(s,1H),3.67(s,2H),3.07–3.01(m,2H),2.94–2.89(m,1H),2 .68–2.65(m,1H),2.35–2.31(m,1H),2.24(s,2H),2.12–2.08(m,1H),1.98–1.86(m,4H),1.73–1.63(m,4H),1.30–1.15(m,4H).

[0382] Example 18 Preparation of Compound 18

[0383] Step 1: Preparation of compound 18-1

[0384] To a solution of 2-(4-(hydroxymethyl)piperidin-1-yl (1.0 g, 4.1 mmol, 1.0 eq.) and piperidin-4-ylmethanol (668 mg, 5.8 mmol, 1.0 eq.) in THF (10 mL) was added DIEA (1.5 g, 11.6 mmol, 1.5 eq.) at room temperature. The mixture was stirred at room temperature for 3 hours, and H2O (100 mL) and DCM (100 mL) were added, followed by extraction with EA (3 x 100 mL). The combined organic layers were washed with 1N HCl (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylate (18-1). MS: m / z = 265 [M+H] +

[0385] Step 2: Preparation of compound 18-2

[0386] To a solution of ethyl 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylate (18-1) (1.1 g, 7.5 mmol, 1.0 eq.) in THF (10 mL) was added LiOH·H2O (945 mg, 22.5 mmol, 3.0 eq.) in H2O (3 mL) at room temperature. After stirring at room temperature for 16 hours, 2N HCl was added to acidify to pH <4, and a white precipitate formed. The mixture was then filtered and dried to give 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (18-2) (400 mg). MS: m / z = 237 [M+H] +

[0387] Step 3: Preparation of compound 18-3

[0388] To a solution of 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (18-2) (100 mg, 0.42 mmol, 1.0 eq.) in DMF (15 mL) at room temperature were added DIEA (218 mg, 1.68 mmol, 4.0 eq.) and HATU (160 mg, 0.42 mmol, 1.0 eq.). After stirring at room temperature for 20 minutes, 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile hydrochloride (128 mg, 0.42 mmol, 1.0 eq.) was added. The reaction was stirred at room temperature for 2 hours, H2O (20 mL) and EA (20 mL) were added, and the aqueous layer was extracted with EA (3 x 20 mL). The organic layer was dried and evaporated. The residue was purified by silica gel chromatography (DCM / MeOH (20:1)) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (18-3) (50 mg). MS: m / z = 486 [M+H] +

[0389] Step 4: Preparation of compound 18-4

[0390] A solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (18-3) (50 mg, 0.102 mmol, 1.0 eq.) and Dess-Martin reagent (49 mg, 0.113 mmol, 1.1 eq.) in DCM (4 mL) was stirred at room temperature for 12 hours. HO (50 mL) and DCM (50 mL) were added, and the aqueous layer was extracted with DCM (3 x 50 mL). The organic layer was dried and evaporated. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (18-4) (20 mg). MS: m / z = 484 [M+H] +

[0391] Step 5: Preparation of compound 18

[0392] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (18-4) (20 mg, 0.04 mmol, 1.0 eq.) and 3-(1-oxo-6-((piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione hydrochloride (4-5) (15.6 mg, 0.04 mmol, 1.0 eq.) in DCM (2 ml) at room temperature were added TEA (41 mg, 0.41 mmol, 10.0 eq.) and MgSO4 (49 mg, 0.41 mmol, 10.0 eq.). q.). After stirring for 2 hours, NaBH(OAc)3 (26 mg, 0.12 mmol, 3.0 eq.) was added. Stirring was continued at 25°C for 16 hours, and DCM (20 ml) and water (20 ml) were added. The organic layer was concentrated. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (18) (9 mg). MS: m / z=810 [M+H] +

[0393] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.08(dd,J=4.2,1.7Hz,1H),8.79(s,2H),8.64(dd,J=8.5,1.8Hz,1H),8.35–8.26(m,2H),8.18(d,J=7.4 Hz,1H),8.12(d,J=8.9Hz,1H),7.69(dd,J=8.5,4.3Hz,1H),7.63–7.54(m,1H),7.43–7.32(m,2H),5.77(dd,J=12.0,5.5Hz,1H),4.75(d,J=12.5 Hz,3H),4.16(d,J=13.5Hz,2H),3.87(brs,1H),3.75–3.61(m,2H),3.38 –3.27(m,2H),3.26–3.09(m,4H),3.08–2.98(m,2H),2.97–2.88(m,1H), 2.68–2.55(m,2H),2.31–2.16(m,3H),2.15–2.06(m,1H),1.99(d,J=11. 5Hz,2H),1.88(d,J=12.6Hz,2H),1.73–1.53(m,4H),1.26–1.13(m,2H).

[0394] Example 19 Preparation of Compound 19

[0395] Step 1: Preparation of compound 19-1

[0396] To a solution of methyl 6-chloronicotinate (1.0 g, 5.8 mmol, 1.0 eq.) and piperidine-4-methanol (671 mg, 5.8 mmol, 1.0 eq.) in DMSO (10 mL) was added DIEA (2.2 g, 17.5 mmol, 3.0 eq.) at room temperature. The mixture was stirred at 120°C for 3 hours, cooled to room temperature, and H2O (50 mL) and DCM (50 mL) were added. The aqueous layer was extracted with EA (3 x 50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 1.2 g of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (19-1). MS: m / z = 251 [M+H] +

[0397] Step 2: Preparation of compound 19-2

[0398] To a solution of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (19-1) (1.2 g, 4.8 mmol, 1.0 eq.) in THF (10 mL) was added a solution of LiOH·H2O (604 mg, 14.3 mmol, 3.0 eq.) in H2O (3 mL) at room temperature. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was neutralized with 2N hydrochloric acid to pH = 7. The residue was purified by reverse phase chromatography (TFA buffer) to give 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinic acid (19-2) (500 mg). MS: m / z = 237 [M+H] +

[0399] Step 3: Preparation of compound 19-3

[0400] To 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinic acid (19-2) (120 mg, 0.5 mmol, 1.0 eq.) in DMF (15 mL) was added DIEA (258 mg, 2.0 mmol, 4.0 eq.) and HBTU (285 mg, 0.75 mmol, 1.5 eq.) at room temperature. After stirring at room temperature for 20 minutes, 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile hydrochloride (1-7 hydrochloride) (152 mg, 0.5 mmol, 1.0 eq.) was added. After stirring at room temperature for 2 hours, H2O (20 mL) and EA (20 mL) were added, and the aqueous layer was extracted with EA (3 x 20 mL). The organic layer was dried and evaporated. The residue was purified by silica gel chromatography (DCM / MeOH (20:1)) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (19-3) (50 mg). MS: m / z = 486 [M+H] +

[0401] Step 4: Preparation of compound 19-4

[0402] A solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (19-3) (50 mg, 0.102 mmol, 1.0 eq.) and Dess-Martin reagent (49 mg, 0.113 mmol, 1.1 eq.) in DCM (4 mL) was stirred at room temperature for 12 hours. HO (50 mL) and DCM (50 mL) were added for dilution, and the aqueous layer was extracted with DCM (3 x 50 mL). The organic layer was dried and evaporated. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)nicotinamide (19-4) (30 mg). MS: m / z = 484 [M+H] +

[0403] Step 5: Preparation of compound 19

[0404] To a solution of N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)nicotinamide (19-4) (30 mg, 0.06 mmol, 1.0 eq.) and 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione hydrochloride (4-5 hydrochloride) (23 mg, 0.06 mmol, 1.0 eq.) in DCM (2 mL) at room temperature were added TEA (61 mg, 0.6 mmol, 10.0 eq.) and MgSO4 (73 mg, 0.6 mmol, 10.0 eq.). After stirring for 2 hours, NaBH(OAc)3 (26 mg, 0.12 mmol, 3.0 eq.) was added. After stirring for 16 hours, DCM (20 ml) and water (20 ml) were added. The organic layer was concentrated. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide (19) (16.0 mg). MS: m / z = 809 [M+H] +

[0405] 1H NMR(400MHz, DMSO-d6)δ11.00(s,1H),9.05(dd,J=4.3,1.8Hz,1H),8.65–8.54(m,2H),8.29–8.20(m,2H),8.08(dd,J=9.5,2.6Hz,2H) ,7.96(dd,J=9.0,2.5Hz,1H),7.67(dd,J=8.5,4.3Hz,1H),7.57(d,J=9.1Hz,1H),7.39–7.30(m,2H),6.87(d,J=9.1Hz,1H),5.75(dd,J =9.0,5.2Hz,1H),4.80–4.65(m,1H),4.48–4.42(m,1H),4.13–4.09(m,1H),3.90–3.78(m,1H),3.70–3.33(m,8H),3.20–3.11(m,3H), 2.95–2.85(m,2H),2.65–2.50(m,1H),2.24–2.04(m,3H),2.24–2.20(m,4H),1.95–1.78(m,3H),1.65–1.50(m,4H),1.23–1.10(m,1H).

[0406] Example 20 Preparation of Compound 20

[0407] Step 1: Preparation of compound 20-1

[0408] To a solution of tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.47 mmol, 1.0 eq.) in EA (0.5 mL) was added HCl / EA (4 M, 0.5 mL) at room temperature. After stirring for 6 hours, the mixture was concentrated to give ((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (20-1) (100 mg). MS: m / z = 113 [M+H] +

[0409] Step 2: Preparation of compound 20-2

[0410] To a solution of 6-chloropyridazine-3-carboxylic acid (142 mg, 0.89 mmol, 1.2 eq.), 5-((((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (200 mg, 0.74 mmol, 1.0 eq.) in DMF (4 mL) were added HATU (313 mg, 1.0 mmol, 1.1 eq.) and DIEA (400 μL, 2.67 mmol, 3.0 eq.) at room temperature. After stirring for 6 h, H O (40 mL) was added and the mixture was washed with EA (10 mL). *2) extraction. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with PE:EA = 3:1 to give 6-chloro-N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)pyridazine-3-carboxamide (20-2) (250 mg). MS: m / z = 407 [M+H] +

[0411] Step 3: Preparation of compound 20-3

[0412] To a solution of 6-chloro-N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)pyridazine-3-carboxamide (20-2) (50 mg, 0.12 mmol, 1.0 eq.) and ((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (20-1) (27 mg, 0.24 mmol, 2.0 eq.) in 1,4-dioxane (1 mL) was added DIEA (32 mg, 0.24 mmol, 2.0 eq.) at room temperature. After stirring at 100°C for 16 hours, the mixture was cooled to room temperature, concentrated, and purified on a silica gel column (PE:EA=1:1) to give N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide (20-3) (45 mg). MS: m / z=484 [M+H] +

[0413] Step 4: Preparation of compound 20-4

[0414] A solution of N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide (20-3) (40 mg, 0.08 mmol, 1.0 eq.) and Dess-Martin periodate (40 mg, 0.1 mmol, 1.2 eq.) in DCM (2 mL) was stirred at room temperature for 2 hours. Saturated Na2S2O3 (10 mL) was added to dilute the mixture, and the mixture was washed with saturated NaHCO3 (10 mL) and H2O (10 mL), respectively. The aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-((1R,5S,6R)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide (20-4) (40 mg). MS: m / z = 482 [M+H] +

[0415] Step 5: Preparation of compound 20

[0416] To a solution of N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(((1R,5S,6R)-6-formyl-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide (20-4) (100 mg, 0.21 mmol, 1.0 eq.), 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (4-5) (70 mg, 0.21 mmol, 1.0 eq.) in DCM (4 ml) were added TEA (0.1 ml) and MgSO4 (50 mg). The reaction mixture was stirred at room temperature for 16 h, and then NaBH(OAc)3( 53 mg, 0.25 mmol, 1.2 eq.). H2O (10 mL) was added to dilute the mixture and extracted with DCM (10 mL*2). The organic layers were combined and concentrated in vacuo. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r, 4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-((1R, 5S, 6S)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyridazine-3-carboxamide (20) (11 mg). MS: m / z=808[M+H] +

[0417] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.08–9.02(m,1H),8.64–8.55(m,2H),8.26(m,2H),8.09(d,J=9.0Hz, 1H),7.84(d,J=9.4Hz,1H),7.67(dd,J=8.5,4.3Hz,1H),7.57(d,J=9.0Hz,1H),7.38–7.28(m,2H),6.97(d,J =9.4Hz,1H),5.74(m,1H),4.71(m,1H),4.17(m,2H),3.90(m,2H),3.67(m,2H),3.55(m,2H),3.24–3.11(m,4 H),2.88(m,2H),2.59(m,3H),2.22(m,2H),2.07(m,2H),1.92(m,3H),1.70(m,3H),1.21(m,2H),1.05(m,1H).

[0418] Example 21 Preparation of Compound 21

[0419] To a solution of 3-(1-methyl-7-(((R)-pyrrolidin-3-ylmethoxy)-1H-indazol-3-yl)piperidine-2,6-dione (21-6) (30 mg, 0.09 mmol, 1.0 eq.), N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (42 mg, 0.09 mmol, 1.0 eq.) in DCM (2 ml) was added TEA (0.5 ml) at room temperature. The mixture was stirred for 16 hours. After 1 hour, NaBH(OAc)3 (23 mg, 0.10 mmol, 1.2 eq.) was added. After the reaction was complete, it was concentrated and purified by reverse phase column, MeCN:H2O=55% to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(3R)-3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (21) (25 mg). MS: m / z=809 [M+H] +

[0420] 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.04(dd,J=4.2,1.7Hz,1H),8.61(dd,J=8.6,1.8Hz,1H),8.26(d,J=8.3Hz,1H),7.99(d,J=7.6H z,1H),7.73(d,J=8.5Hz,2H),7.66(dd,J=8.5,4.3Hz,1H),7.32(d,J=8.4Hz,1H),7.23(d,J=8.1Hz,1H),7.04-6.90(m,3H),6.83(d,J= 7.2Hz,1H),4.76-4.64(m,2H),4.31(dd,J=9.7,5.1Hz,1H),4.16(s,3H),3.92-3.78(m,4H),3.74-3.66(m,1H),3.20-3.10(m,4H),2.7 6(t,J=12.1Hz,2H),2.70–2.53(m,3H),2.40–2.10(m,5H),2.04-1.90(m,4H),1.88-1.76(m,3H),1.70-1.50(m,4H),1.34-1.19(m,2H).

[0421] Example 22 Preparation of Compound 22

[0422] Step 1: Preparation of compound 22-1

[0423] To a solution of 6-bromophthalazin-1(2H)-one (50 mg, 0.22 mmol, 1.0 eq.) and B2Pin2 (68 mg, 0.26 mmol, 1.2 eq.) in dioxane (2 mL) was added Pd(dppf)Cl2·CH2Cl2 (15 mg, 0.02 mmol, 0.08 eq.) and KOAc (44 mg, 0.44 mmol, 2.0 eq.) at room temperature. After stirring at 100°C for 16 hours, the mixture was cooled to room temperature and concentrated. The residue was purified by reverse phase column chromatography to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-1(2H)-one (22-1) (60 mg). MS: m / z = 273 [M+H] +

[0424] Step 2: Preparation of compound 22-2

[0425] To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-1(2H)-one (22-1) (60 mg, 0.22 mmol, 1.0 eq.) in THF (3 mL) was added 30% H2O2 (125 μL, 1.1 mmol, 5.0 eq.) at room temperature. After stirring at room temperature for 16 hours, the mixture was concentrated to give 6-hydroxyphthalazin-1(2H)-one (22-2) (60 mg), which was used in the next step without purification. MS: m / z = 163 [M+H] +

[0426] Step 3: Preparation of compound 22-3

[0427] To a solution of 6-hydroxyphthalazin-1(2H)-one (22-2) (60 mg, 0.22 mmol, 1.0 eq.) and tert-butyl (S)-3-((p-toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylate (118 mg, 0.33 mmol, 1.5 eq.) in DMF (2 ml) was added KCO (76 mg, 0.55 mmol, 2.5 eq.) at room temperature. After stirring at 80°C for 16 hours, the mixture was cooled to room temperature and purified by reverse phase chromatography (TFA buffer) to give (S)-3-(((1-oxo-1,2-dihydrophthalazin-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (22-3) (40 mg). MS: m / z = 346 [M+H] +

[0428] Step 4: Preparation of compound 22-4

[0429] To a solution of tert-butyl (S)-3-(((1-oxo-1,2-dihydrophthalazin-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (22-3) (40 mg, 0.12 mmol, 1.0 eq.) in DMF was added NaH (60% by weight, 10 mg, 0.36 mmol, 3.0 eq.) at room temperature. After stirring at 40°C for 1 hour, a solution of 3-bromopiperidine-2,6-dione (34 mg, 0.18 mmol, 1.5 eq.) in 0.3 mL of DMF was added, and the mixture was stirred at 40°C for 16 hours. The mixture was cooled to room temperature, and saturated aqueous NH4Cl solution (10 mL) was added, followed by extraction with EA (10 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give tert-butyl (3S)-3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (22-4) (52 mg). MS: m / z=457 [M+H] +

[0430] Step 5: Preparation of compound 22-5

[0431] To a solution of tert-butyl (3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (22-4) (52 mg, 0.12 mmol, 1.0 eq.) in EA (1 mL) was added HCl (5 mL, 4 M in EA) at room temperature. After stirring for 16 hours, the mixture was concentrated to give 3-(1-oxo-6-((S)-pyrrolidin-3-ylmethoxy)phthalazin-2(1H)-yl)piperidine-2,6-dione hydrochloride (22-5) (35 mg). MS: m / z = 357 [M+H] +

[0432] Step 6: Preparation of compound 22

[0433] To a solution of 3-(1-oxo-6-(((S)-pyrrolidin-3-methoxy)phthalazin-2(1H)-yl)piperidine-2,6-dione hydrochloride (22-5) (35 mg, 0.12 mmol, 1.0 eq.) and N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (43 mg, 0.12 mmol, 1.0 eq.) in DCM (7 mL) was added TEA (4 drops) and MgSO4 (107 mg, 1.2 mmol, 10.0 eq.) at room temperature. After stirring for 16 h, NaBH(OAc)3 (48 mg, 0.30 mmol, 2.5eq.). After stirring at room temperature for another 1 hour, it was concentrated to dryness. EA / H2O (20mL+20mL) was added and extracted with EA (20mL*2). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3S)-3-((2-(2,6-dioxoopioside-3-yl)-1-oxo-1,2-dihydrophthalic acid-6-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (22) (9 mg). MS: m / z=823.0[M+H] +

[0434] Example 23 Preparation of Compound 23

[0435] Synthesis of 23-1:

[0436] To a solution of 2-fluoro-3-nitrobenzonitrile (23-1-1) (8.60 g, 51.8 mmol, 1.0 eq.) in DMF (86 mL) was added methylhydrazine (22.4 g, 155 mmol, 3.0 eq.) and DIEA (50.2 g, 388 mmol, 7.5 eq.). The reactant was stirred at 25 ° C for 1 hour. TLC (PE / EA 1: 1) showed that the reaction was complete. EA (800 mL) and water (850 mL) were added. The organic layer was concentrated to 100 mL. The mixture was cooled to room temperature and filtered. The residue was dried to give 1-methyl-7-nitro-1H-indazole-3-amine (23-1-2) (7.71 g, 77% yield) as a red solid.

[0437] A mixture of lactic acid (2.15 g, 85%, 20.3 mmol, 1.3 eq.) and DBU (3.09 g, 20.3 mmol, 1.3 eq.) was stirred at 25 ° C for 16 hours. 1-methyl-7-nitro-1H-indazole-3-amine (23-1-2) (3.00 g, 15.6 mmol, 1.0 eq.) and methyl acrylate (9.40 g, 109 mmol, 7.0 eq.) were added. The reactants were stirred at 85 ° C for 40 hours. TLC (PE / EA 1: 1) showed that the reaction was not completed. EA (100 mL) and water (100 mL) were added. The organic layer was concentrated. The residue was purified by column (PE / EA 3:1) to give methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate (23-1-3) (2.08 g, 54% yield) as a red solid.

[0438] To a solution of methyl 3-((1-methyl-7-nitro-1H-indazole-3-yl)amino)propanoate (23-1-3) (1.98 g, 7.13 mmol, 1.0 eq.) in AcOH (20 mL) was added KCNO (1.73 g, 21.4 mmol, 3.0 eq.). The reactant was stirred at 25 ° C for 16 hours. TLC (pure EA) showed that the reaction was almost complete. Water (100 mL) and EA (100 mL) were added. The organic layer was concentrated. The residue was purified by column (PE / EA 1: 1 to pure EA) to give methyl 3-(1-(1-methyl-7-nitro-1H-indazole-3-yl)urea-to)propanoate (23-1-4) (1.26 g, 61% yield) as a yellow solid.

[0439] To a solution of methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate (23-1-4) (1.26 g, 3.92 mmol, 1.0 eq.) in MeCN (13 mL) was added Triton-B (492 mg, 40% in water, 1.18 mmol, 0.3 eq.). The reactants were stirred at 15 ° C for 72 hours. TLC showed that the reaction was complete. Water (100 mL) and EA (100 mL) were added. The organic layer was concentrated to give 1-(1-methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (23-1-5) (1.04 g, 92% yield) as a yellow solid.

[0440] To a solution of 1-(1-methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (23-1-5) (1.00 g, 3.11 mmol, 1.0 eq.) in MeOH (10 mL) and THF (10 mL) was added Fe (520 mg, 9.34 mmol, 1.0 eq.) and NH4Cl aqueous solution (10%, 10 mL). The reactants were stirred at 70 ° C for 4 hours. TLC showed that the reaction was complete. The mixture was filtered and the filter cake was washed with THF (50 mL). The filtrate was concentrated. Water (100 mL) and EA (100 mL) were added. The aqueous layer was extracted with EA (5×100 mL). The combined organic layers were concentrated to give 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (23-1) (820 mg, 92% yield) as a red solid.

[0441] Synthesis of 23-3:

[0442] To a solution of tert-butyl (1R,5S,6r)-6-((benzyloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2-1) (1.2 g, 3.7 mmol, 1.0 eq.) in THF / H2O / MeOH (8 mL / 2 mL / 2 mL) was added LiOH·H2O (333 mg, 9.3 mmol, 2.5 eq.) at room temperature. The reaction mixture was stirred at 40°C for 16 hours, then diluted with H2O (30 mL) and EA (15 mL) and concentrated under reduced pressure. The resulting mixture was neutralized to pH = 5 with 1N HCl and extracted with EA (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (23-3-1) (1.03 g). MS: m / z = 307 [M+H] +

[0443] To a solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (23-3-1) (120 mg, 0.39 mmol, 1.0 eq) in DMF (5 mL) at room temperature were added HBTU (180 g, 46.8 mmol, 1.2 eq) and DIEA (435 μL, 2.34 mmol, 6.0 eq). After stirring at 30°C for 1 hour, 5-(((1r,4r)-4-aminocyclohexyloxy)quinoline-8-carbonitrile hydrochloride (1-7) (230 mg, 0.74 mmol, 1.9 equivalents) was added. The reaction mixture was stirred at 30°C for another 3 hours, diluted with H2O (50 mL), and extracted with EA (50 mL*3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (TFA buffer) to give tert-butyl 4-(4-(1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)carbamoyl)phenyl)piperazine-1-carboxylate (23-3-2) (210 mg). MS: m / z=556 [M+H] +

[0444] To a solution of tert-butyl 4-(4-(1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)carbamoyl)phenyl)piperazine-1-carboxylate (23-3-2) (210 mg, 0.38 mmol, 1.0 eq) in EA (2 mL) was added HCl (5 mL, 4 M in EA) at room temperature. After stirring at room temperature for 16 hours, the mixture was concentrated to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(piperazin-1-yl)benzamide (23-3) (205 mg). MS: m / z = 456 [M+H] +

[0445] Preparation of Compound 23

[0446] To a solution of 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (23-1) (50 mg, 0.19 mmol, 1.0 eq.) in DCM (1 mL) and H₂O (0.5 mL) at room temperature were added bromoacetyl chloride (18 μL, 0.21 mmol, 1.1 eq.) and K₂CO₃ (30 mg, 0.21 mmol, 1.1 eq.) in sequence. After stirring for 6 hours, H₂O (20 mL) was added, and the mixture was extracted with EA (5 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 2-bromo-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (23-2) (80 mg). MS: m / z = 379 [M+H] +

[0447] Step 2: Preparation of compound 23

[0448] To a solution of 2-bromo-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (23-2) (55 mg, 0.15 mmol, 1.5 eq.), N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(piperazin-1-yl)benzamide 23-3 (48 mg, 0.1 mmol, 1.0 eq.) in DMF (1 mL) was added K2CO3 (28 mg, 0.2 mmol, 2.0 eq.) at room temperature. The mixture was stirred at 80° C. for 2 hours, cooled to room temperature, concentrated, and purified by HPLC (MeCN:H 2 O=55%) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)piperazin-1-yl)benzamide (23) (18 mg). MS: m / z=755 [M+H] +

[0449] 1H NMR (400MHz, DMSO-d6) δ10.56(s,1H),9.04(dd,J=4.2,1.7Hz,1H),8.61(dd,J=8.5,1.7Hz,1H),8.26(d,J=8.3Hz,1H), 8.04(d,J=7.6Hz,1H),7.76(d,J=8.4Hz,2H),7.66(dd,J=8.5,4.2Hz,1H),7.52(d,J=8.2Hz,1H),7.32(d,J=8.4Hz,1H), 7.27(d,J=7.3Hz,1H),7.09(t,J=7.7Hz,1H),6.98(d,J=8.5Hz,2H),4.76-4.64(m,1H),4.08(s,3H),3.92–3.80(m,3H) ,3.48-3.18(m,8H),2.75(t,J=6.7Hz,2H),2.28–2.18(m,2H),1.96–1.88(m,2H),1.70–1.51(m,4H),1.26–1.19(m,2H).

[0450] Example 24 Preparation of Compound 24

[0451] Step 1: Preparation of compound 24-1

[0452] To a solution of tert-butyl 6-(4-formylpiperidin-1-yl)pyridazine-3-carboxylate (15-3) (300 mg, 1.03 mmol, 1.0 eq.) in DCM (3 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-pyrrolidine-3-methoxy)isoindoline-1,3-dione hydrochloride (5-4) (405 mg, 1.03 mmol, 1.0 eq.) and TEA (1.04 g, 10.3 mmol, 10.0 eq.) at room temperature. The mixture was stirred for 2 h, and NaBH(OAc)3 (436 mg, 2.06 mmol, 2.0 eq.) was added. The mixture was stirred at room temperature for 16 h, and then concentrated. The residue was purified by reverse phase chromatography (water (0.05%)). The mixture was purified by TFA (TFA) and MeCN) to give 6-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxylate (24-1) (170 mg). MS: m / z=632 [M+H] +

[0453] Step 2: Preparation of compound 24-2

[0454] To a solution of tert-butyl 6-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)pyridazine-3-carboxylate (24-1) (85 mg, 0.147 mmol, 1.0 eq.) in DCM (2 ml) was added TFA (1 ml) at room temperature. After stirring at room temperature for 2 hours, the mixture was concentrated to give 6-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)pyrididin-1-yl)pyridazine-3-carboxylic acid (24-2) (70 mg). MS: m / z = 576 [M+H] +

[0455] Step 3: Preparation of compound 24

[0456] To a solution of 6-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxylic acid (24-2) (70 mg, 0.12 mmol, 1.0 eq.) and 5-(1r,4R)-4-aminocyclohexyloxy)quinoline-8-carbonitrile (1-7) (33 mg, 0.12 mmol, 1.0 eq.) in DMF (2 ml) at room temperature were added DIEA (31 mg, 0.24 mmol, 2.0 eq.) and HATU (55 mg, 0.14 mmol, 1.2 eq.). After stirring for 2 h, the mixture was purified by reverse phase chromatography eluting with water (0.05% TFA) and MeCN to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxamide (24) (29.4 mg). MS: m / z=826 [M+H] +

[0457] 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.08–9.02(m,1H),8.60(dd,J=10.5,8.2Hz,2H),8.26(d,J=8.2Hz,1H),7.84(dd,J=16.9,8.9Hz,2 H),7.67(dd,J=8.4,4.3Hz,1H),7.47(dd,J=5.2,2.2Hz,1H),7.36(dd,J=8.2,2.5Hz,2H),7.32(d,J=8.3Hz,1H),5.10(dd,J=12.8,5.4Hz, 1H),4.71(brs,1H),4.49(d,J=13.2Hz,2H),4.31–4.13(m,2H),3.97–4.82(m,1H),3.75–3.63(m,1H),3.21–3.11(m,3H),3.08–2.94(m,3 H),2.91–2.78(m,3H),2.62–2.49(m,2H),2.27–2.18(m,2H),2.17–2.00(m,3H),1.97–1.78(m,5H),1.74–1.58(m,4H),1.28–1.14(m,2H).

[0458] Example 25 Preparation of Compound 25

[0459] Step 1: Preparation of compound 25-1

[0460] To a solution of tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate (1 g, 3.46 mmol, 1.0 eq.) and 4-methylbenzenesulfonyl chloride (1 g, 5.2 mmol, 1.5 eq.) in CHCl₃ (8 mL) was added pyridine (3 mL) at room temperature. After stirring at 80°C for 16 hours, the mixture was cooled to room temperature, H₂O (50 mL) was added, and the mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and purified by silica gel chromatography (PE:EA = 2:1) to afford (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl-4-methylbenzenesulfonate (25-1) (1 g).

[0461] MS: m / z = 391 [M+H+23] +

[0462] Step 2: Preparation of compound 25-2

[0463] A reaction mixture of 5,8-dibromoquinoxaline (800 mg, 2.78 mmol, 1.0 eq.), CuI (529 mg, 2.78 mmol, 1.0 eq.), and NaOMe (165 mg, 3.06 mmol, 1.1 eq.) in methanol (0.5 mL) and DMF (20 mL) was stirred at 100°C for 16 hours under an N2 atmosphere. The mixture was cooled to room temperature, H2O (20 mL) was added, and the mixture was extracted with EA (50 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and purified by silica gel chromatography (PE:EA = 1:1) to afford 5-bromo-8-methoxyquinoxaline (25-2) (300 mg). MS: m / z = 239 [M+H] +

[0464] Step 3: Preparation of compound 25-3

[0465] A solution of 5-bromo-8-methoxyquinoxaline (25-2) (200 mg, 0.69 mmol, 1.0 eq.) and CuCN (200 mg, 2.08 mmol, 3.0 eq.) in DMF (5 mL) was stirred at 100°C for 16 hours under a N2 atmosphere. The mixture was cooled to room temperature, H2O (10 mL) was added, and the mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by chromatography using MeCN:H2O = 95% afforded 8-methoxyquinoxaline-5-carbonitrile (25-3) (60 mg). MS: m / z = 185 [M+H] +

[0466] Step 4: Preparation of compound 25-4

[0467] At room temperature, BBr3 (1M in DCM) (0.8 mL, 0.3 mmol, 6.0 eq.) was slowly added to a solution of 8-methoxyquinoxaline-5-carbonitrile (25-3) (45 mg, 0.05 mmol, 1.0 eq.) in DCM (1 mL), and the reaction mixture was stirred at 40 ° C for 1 hour. Cooled to room temperature, the mixture was quenched with H2O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were concentrated under vacuum to give 8-hydroxyquinoxaline-5-carbonitrile (25-4) (70 mg) as a yellow solid (70 mg, crude). MS: m / z = 171 [M + H] +

[0468] Step 5: Preparation of compound 25-5

[0469] To a solution of 8-hydroxyquinoxaline-5-carbonitrile (25-4) (70 mg, 0.41 mmol, 1.0 eq.) and (1s,4s)-4-((tert-butyloxycarbonyl)amino)cyclohexyl-4-methylbenzenesulfonate (25-1) (227 mg, 0.61 mmol, 1.5 eq.) in DMF (2 mL) was added KCO (115 mg, 0.82 mmol, 2.0 eq.) at room temperature. After stirring at 80°C for 16 hours, the mixture was cooled to room temperature, H2O (20 mL) was added, and the mixture was extracted with EA (20 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and purified by HPLC (MeCN:H2O = 80%) to give tert-butyl ((1r,4r)-4-((8-cyanoquinoxalin-5-yl)oxy)cyclohexyl)carbamate (25-5) (11 mg). MS: m / z = 368 [M+H] +

[0470] Step 6: Preparation of compound 25-6

[0471] To a solution of tert-butyl (((1r,4r)-4-((8-cyanoquinoxalin-5-yl)oxy)cyclohexyl)carbamate (25-5) (11 mg, 0.03 mmol, 1.0 eq.) in EA (1 mL) was added 4M HCl / EA (0.5 mL) at room temperature. After stirring for 16 hours, the mixture was concentrated to give 8-(((1r,4r)-4-aminocyclohexyl)oxy)quinoxaline-5-carbonitrile (25-6) (10 mg). MS: m / z = 268 [M+H] +

[0472] Step 7: Preparation of compound 25

[0473] To a solution of 8-(((1r,4r)-4-aminocyclohexyloxy)quinoxaline-5-carbonitrile (25-6) (10 mg, 0.03 mmol, 1.0 eq.) was added 6-(4-(3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxylic acid (24-2) (26 mg, 0.04 mmol, 1.2 eq.), HATU (17 mg, 0.04 mmol, 1.2 eq.) in DMF (1 mL) at room temperature was added DIEA (25 μL, 0.1 mmol, 3.0 eq.). After stirring for 4 hours, the mixture was purified by HPLC (using MeCN:H2O=55%) to give N-((1r,4r)-4-((8-cyanoquinoxalin-5-yl)oxy)cyclohexyl)-6-(4-(3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)pyrididine-3-carboxamide (25) (10 mg). MS: m / z=827 [M+H] +

[0474] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),9.18(d,J=6.2Hz,1H),9.12(d,J=6.1Hz,1H),8.71–8.63( m,1H),8.48–8.41(m,1H),7.93–7.85(m,2H),7.66–7.58(m,1H),7.54–7.49(m,1H),7.47–7.39(m ,2H),5.43–5.35(m,1H),5.24–5.11(m,2H),4.57–4.50(m,2H),4.21–4.14(m,2H),3.13–3.03(m ,4H),2.98–2.91(m,2H),2.35–2.25(m,4H),2.13–1.99(m,8H),1.94–1.87(m,2H),1.78–1.71(m, 4H),1.58–1.49(m,4H).

[0475] Example 26 Preparation of Compound 26

[0476] Step 1: Preparation of compound 26-1

[0477] To a solution of methyl 2-methylisonicotinate (1 mL, 6.6 mmol, 1.0 eq.) in MeOH (10 mL) was added 4 M HCl in EA (5 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated to give a white solid. The white solid was added to MeOH (20 mL) and PtO2 (100 mg), and the reaction mixture was stirred at room temperature under a H2 atmosphere (50 Psi) for 6 hours, filtered, and the filter cake was concentrated under vacuum to give cis-2-methylpiperidine-4-carboxylic acid methyl ester (26-1) (1.0 g). MS: m / z = 157 [M+H] +

[0478] Step 2: Preparation of compound 26-2

[0479] To a solution of cis-2-methylpiperidine-4-carboxylic acid methyl ester (26-1) (1 g, 6.37 mmol, 1.0 eq.) in THF (20 mL) was slowly added LiAlH4 (1 M in THF) (9.5 mL, 9.55 mmol, 1.5 eq.) at room temperature. After stirring for 16 hours, the mixture was quenched by the addition of H2O (0.3 mL), 15% NaOH (0.3 mL), and H2O (0.9 mL). The reaction mixture was filtered and the filtrate was concentrated under vacuum to give cis-2-methylpiperidin-4-ylmethanol (26-2) (1 g). MS: m / z = 129 [M+H] +

[0480] Step 3: Preparation of compound 26-3

[0481] To a solution of tert-butyl 6-chloropyridazine-3-carboxylate (500 mg, 2.33 mmol, 1.0 eq.) and ((2R,4R)-2-methylpiperidin-4-yl)methanol (26-2) (600 mg, 4.66 mmol, 2.0 eq.) was added DIEA (1 ml, 4.66 mmol, 2.0 eq.) at room temperature. After stirring at 100°C for 16 hours, the mixture was cooled to room temperature, concentrated, and purified on a silica gel column (PE:EA = 1:1) to give tert-butyl 6-(cis-4-(hydroxymethyl)-2-methylpiperidin-1-yl)pyridazine-3-carboxylate (26-3) (110 mg). MS: m / z = 307 [M+H] +

[0482] Step 4: Preparation of compound 26-4

[0483] At room temperature, a mixture of tert-butyl 6-(cis-4-(hydroxymethyl)-2-methylpiperidin-1-yl)pyridazine-3-carboxylate (26-3) (110 mg, 0.36 mmol, 1.0 eq.), Dess-Martin periodate (180 mg, 0.43 mmol, 1.2 eq.) in DCM (2 mL) was stirred at room temperature for 2 hours. DCM (10 mL) was added to dilute the mixture and washed with saturated Na2S2O3 (10 mL), saturated NaHCO3 (10 mL) and H2O (10 mL), respectively. The organic layer was concentrated under vacuum to give tert-butyl 6-(cis-4-formyl-2-methylpiperidin-1-yl)pyridazine-3-carboxylate (26-4) (100 mg). MS: m / z=305[M+H] +

[0484] Step 5: Preparation of compound 26-5

[0485] A reaction mixture of tert-butyl 6-(cis-4-methylpiperidin-1-yl)pyridazine-3-carboxylate (26-4) (100 mg, 0.32 mmol, 1.0 eq.), 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-pyrrolidin-3-ylmethoxy)isoindoline-1,3-dione (5-4) (140 mg, 0.39 mmol, 1.2 eq.) and TEA (200 μL, 0.96 mmol, 3.0 eq.) in DCM (2 mL) was stirred at room temperature for 2 hours, and then the reaction mixture was added with NaBH(OAc)3 (8 The mixture was stirred for 16 hours, diluted with H2O (20 mL), and extracted with DCM (10 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and purified by chromatography using MeCN:H2O = 60% to give tert-butyl 6-(cis-4-(((3R)-3-(((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)pyridazine-3-carboxylate (26-5) (100 mg). MS: m / z = 646 [M+H] +

[0486] Step 6: Preparation of compound 26-6

[0487] To a solution of tert-butyl 6-(cis-4-(((3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)pyridazine-3-carboxylate (26-5) (100 mg, 0.15 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (1 mL) at room temperature. After stirring for 6 hours, the mixture was concentrated to give 6-(cis-4-(((3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)pyridazine-3-carboxylic acid (26-6) (100 mg). MS: m / z = 590 [M+H] +

[0488] Step 7: Preparation of compound 26

[0489] To a solution of 6-(cis-4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-oxy)methyl)pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)methyl)-2-methylpyrididine-3-carboxylic acid (26-6) (50 mg, 0.08 mmol, 1.0 eq.), 5-(1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (1-7) (25 mg, 0.09 mmol, 1.1 eq.), HATU (39 mg, 0.10 mmol, 1.2 eq.) in DMF (2 mL) was added DIEA (50 μL, 0.25 mmol, 3.0 eq.) at room temperature. After stirring for 16 hours, the mixture was purified by HPLC (MeCN:H2O=55%) to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(cis-4-(3R)-3-(((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)pyridazine-3-carboxamide (26) (10 mg). MS: m / z=840 [M+H] +

[0490] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.07(dd,J=4.3,1.7Hz,1H),8.64(dd,J=8.5,1.7Hz,1H),8.60(d,J=8.0Hz,1H),8.27(d,J=8. 3Hz,1H),7.91–7.80(m,2H),7.68(dd,J=8.5,4.3Hz,1H),7.48(d,J=6.5Hz,1H),7.42–7.29(m,3H),5.13(dd,J=12.9,5.3Hz,1H),4.9 6–4.86(m,1H),4.76–4.70(m,1H),4.45–4.35(m,1H),4.33–4.16(m,3H),4.00–3.87(m,2H),3.24–3.03(m,4H),2.94–2.83(m,2H),2 .66–2.53(m,2H),2.36–2.17(m,4H),2.10–2.03(m,1H),2.02–1.89(m,4H),1.83–1.63(m,5H),1.48–1.41(m,1H),1.30–1.14(m,5H).

[0491] Example 27 Preparation of Compound 27

[0492] Step 1: Preparation of compound 27-1

[0493] To a solution of 5-bromo-2-chloro-3-(trifluoromethyl)pyridine (1.00 g, 3.84 mmol, 1.0 eq.) in DMSO (6 mL) was added benzylpiperazine-1-carboxylate (0.85 g, 3.84 mmol, 1.0 eq.) and K2CO3 (1.59 g, 11.5 mmol, 3.0 eq.) at room temperature. After stirring at 100°C for 4 hours, the mixture was cooled to room temperature, and water (60 mL) and EA (60 mL) were added. The organic layer was concentrated. The residue was purified by column chromatography (PE / EA 4:1) to give benzyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-1) (1.02 g). MS: m / z = 444, 446 [M+H] +

[0494] Step 2: Preparation of compound 27-2

[0495] Benzyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-1) (900 mg, 2.03 mmol, 1.0 eq.), CuI (77 mg, 0.405 mmol, 0.2 eq.), L-proline (93 mg, 0.810 mmol, 0.4 eq.), KCO (420 mg, 3.04 mmol, 1.5 eq.), and NHOH (380 mg, 28%, 3.04 mmol, 1.5 eq.) were mixed in DMSO (5 mL) at room temperature. After stirring at 90°C for 12 hours, the mixture was cooled to room temperature and EA (50 mL) was added. The mixture was filtered. The filtrate was washed with water (50 mL) and concentrated to give benzyl 4-(5-amino-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-2) (810 mg). MS: m / z = 381 [M+H] +

[0496] Step 3: Preparation of compound 27-3

[0497] A mixture of lactic acid (221 mg, 85%, 2.08 mmol, 1.3 eq) and DBU (317 mg, 2.08 mmol, 1.3 eq) was stirred at room temperature for 1 h. Benzyl 4-(5-amino-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-2) (610 mg, 1.52 mmol, 1.0 eq) and methyl acrylate (3 mL) were added. After stirring at 85° C. for 16 h, the mixture was cooled to room temperature, and EA (40 mL) and water (40 mL) were added. The organic layer was concentrated. The residue was purified by column chromatography (PE / EA 2:1 to 1:1) to give benzyl 4-(5-(((3-methoxy-3-oxopropyl)amino)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-3) (445 mg). MS: m / z = 467 [M+H] +

[0498] Step 4: Preparation of compound 27-4

[0499] To a solution of benzyl 4-(5-(3-methoxy-3-oxopropyl)amino)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-3) (445 mg, 0.95 mmol, 1.0 eq.) in AcOH (4.5 mL) was added KCNO (155 mg, 1.91 mmol, 2.0 eq.) at room temperature. After stirring for 16 hours, EA (50 mL) and water (50 mL) were added. The organic layer was concentrated. The residue was purified by column chromatography (EA / MeOH 10:1) to give benzyl 4-(5-(1-(3-methoxy-3-oxopropyl)ureido)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-4) (300 mg). MS: m / z = 510 [M+H] +

[0500] Step 5: Preparation of compound 27-5

[0501] To a solution of benzyl 4-(5-(1-(3-(3-methoxy-3-oxopropyl)ureido)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-4) (300 mg, 0.59 mmol, 1.0 eq.) in MeCN (3 mL) was added Triton-B (246 mg, 0.59 mmol, 1.0 eq.) at room temperature. After stirring for 16 hours, EA (30 mL) and water (30 mL) were added. The organic layer was concentrated. The residue was purified by preparative TLC (pure EA) to give benzyl 4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-5) (84 mg). MS: m / z=478 [M+H] +

[0502] Step 6: Preparation of compound 27-6

[0503] To a solution of benzyl 4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (27-5) (84 mg, 0.176 mmol, 1.0 eq.) in EA (1 mL) was added Pd / C (10 mg, 5%) at room temperature. The mixture was stirred under H2 (1 atm) for 16 hours, filtered, and the filtrate was concentrated to afford 1-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (27-6) (67 mg). MS: m / z = 344 [M+H] +

[0504] Step 7: Preparation of compound 27-7

[0505] To a solution of 1-(6-((piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (27-6) (67 mg, 0.176 mmol, 1.0 eq.) and tert-butyl 6-(4-formylpiperidin-1-yl)pyridazine-3-carboxylate (51 mg, 0.176 mmol, 1.0 eq.) in DCM (2 mL) and DMF (1 mL) was added TEA (178 mg, 1.76 mmol, 10 eq.) and MgSO4 (212 mg, 1.76 mmol) at room temperature. After stirring for 2 h, the mixture was added. NaBH(OAc)3(93 mg, 0.44 mmol, 2.5 eq.). After stirring for 1 hour, DCM(20 mL) was added. The mixture was filtered and the filtrate was concentrated. EA(40 ml) and water(40 ml) were added. The organic layer was concentrated. The residue was purified by preparative TLC (pure MeCN) to give tert-butyl 6-((4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-yl)methyl)pyridazine-3-carboxylate (27-7) (30 mg) as a white solid. MS:m / z=344[M+H] +

[0506] Step 8: Preparation of compound 27-8

[0507] To a solution of tert-butyl 6-((4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)pyridazine-3-carboxylate (27-7) (212 mg, 1.76 mmol, 10 eq.) in DCM (1 ml) was added TFA (1 ml) at room temperature. After stirring for 1 hour, the mixture was concentrated to give 6-(4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxylic acid (27-8) (47 mg). MS: m / z = 563 [M+H] +

[0508] Step 9: Preparation of compound 27

[0509] To a solution of 6-(4-((4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxylic acid (27-8) (47 mg, 0.048 mmol, 1.0 eq.) in DMF (1 mL) were added DIEA (25 mg, 0.192 mmol, 4.0 eq.) and 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile (15 mg, 0.048 mmol, 1.0 eq.) at room temperature. HATU (20 mg, 0.053 mmol, 1.1 eq.) was slowly added. After stirring for 16 hours, EA (20 mL) and water (20 mL) were added. The organic layer was concentrated. The residue was purified by reverse phase chromatography eluting with water (0.05% TFA) and MeCN to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)pyridin-1-yl)pyridazine-3-carboxamide (27) (14 mg). MS: m / z=812 [M+H] +

[0510] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),9.65(s,1H),9.08(dd,J=4.2,1.7Hz,1H),8.67–8.60(m,2H),8.29(d,J=8.4Hz,1H),8.17(d,J =2.5Hz,1H),7.85(d,J=9.5Hz,1H),7.70(dd,J=8.5,4.2Hz,1H),7.41(d,J=9.7Hz,1H),7.35(d,J=8.5Hz,1H),4.76-4.72(m,1H),4. 53(d,J=13.3Hz,2H),3.98-3.93(m,1H),3.86(t,J=6.6Hz,2H),3.68-3.63(m,2H),3.55-3.49(m,2H),3.36(t,J=12.4Hz,2H),3.19– 3.04(m,6H),2.75(t,J=6.6Hz,2H),2.26-2.24(m,3H),1.99-1.97(m,2H),1.91-1.86(m,2H),1.73-1.68(m,3H),1.31-1.22(m,3H).

[0511] Example 28 Preparation of Compound 28

[0512] Step 1: Preparation of compound 28-1

[0513] To a solution of tert-butyl ((1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate (350 mg, 1.44 mmol, 1.00 eq.) in DMF (5 mL) at 0°C was added sodium hydride (115 mg, 2.88 mmol, 60% by weight, 2.00 eq.), followed by the dropwise addition of a solution of 4-fluoro-2-methoxybenzene toluene (239 mg, 1.58 mmol, 1.10 eq.) in DMF (10 mL). The mixture was stirred at room temperature for 3.5 hours, quenched by the addition of saturated aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (30 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=20:1) to give tert-butyl ((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (28-1) (258 mg).

[0514] MS: m / z = 374 [M+H] +

[0515] Step 2: Preparation of compound 28-2

[0516] To a solution of tert-butyl ((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (258 mg, 1.44 mmol, 1.00 eq.) in DCM (5 mL) was added 4M HCl in dioxane (3 mL) dropwise at room temperature. After stirring for 6 hours, the mixture was concentrated to afford 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile (28-2) (240 mg). MS: m / z = 274 [M+H] +

[0517] Step 1: Preparation of compound 28-3

[0518] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(((R)-pyrrolidin-3-yl)methoxy)isoindoline-1,3-dione (5-4) (100 mg, 0.28 mmol, 1.0 eq.) and tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (81 mg, 0.28 mmol, 1.0 eq.) in DCM (2 ml) was added TEA (0.2 ml) at room temperature. After stirring for 1 hour, NaBH(OAc) (71 mg, 0.33 mmol, 1.2 eq.) was added. Stirring was continued for 16 hours, and the mixture was concentrated. HPLC purification (MeCN:H2O=70%) gave tert-butyl 4-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoate (28-3) (80 mg). MS: m / z=630 [M+H] +

[0519] Step 2: Preparation of compound 28-4

[0520] To a solution of tert-butyl 4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoate (28-3) (80 mg, 0.12 mmol, 1.0 eq.) in DCM (2 ml) was added TFA (1 ml) at room temperature. After stirring for 16 hours, the mixture was concentrated to give 4-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoic acid (28-4) (80 mg). MS: m / z = 574 [M+H] +

[0521] Step 3: Preparation of compound 28

[0522] To a solution of 4-(4-(3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoic acid (28-4) (80 mg, 0.14 mmol, 1.0 eq.), 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile (38 mg, 0.14 mmol, 1.0 eq.), HATU (63 mg, 0.16 mmol, 1.2 eq.) in DMF (2 ml) was added DIEA (0.1 ml, 0.42 mmol, 3.0 eq.) at room temperature. After stirring for 16 hours, the mixture was concentrated and purified by HPLC (MeCN:H2O=55%) to give N-((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (28) (22 mg). MS: m / z=831 [M+H] +

[0523] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.81(d,J=8.3Hz,1H),7.70(d,J=8.5Hz,2H),7.62(d,J=8.6Hz,1H),7.49–7.41( m,2H),7.34(dd,J=8.3,2.2Hz,1H),6.92(d,J=8.6Hz,2H),6.61(d,J=2.2Hz,1H),6.51(dd,J=8.7,2.2Hz,1H),5.09(dd, J=13.0,5.4Hz,1H),4.24(s,1H),4.09–3.99(m,3H),3.88(s,3H),3.85–3.77(m,2H),3.48(s,1H),2.93–2.81(m,2H),2. 78–2.68(m,2H),2.63–2.52(m,4H),2.41–2.22(m,4H),2.04–1.89(m,3H),1.83–1.74(m,2H),1.20(s,6H),1.12(s,6H).

[0524] Example 29 Preparation of Compound 29

[0525] To a solution of methyl 4-hydroxybenzoate (3.33 g, 21.8 mmol, 1.10 eq.) and tert-butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (4.00 g, 19.8 mmol, 1.00 eq.) in THF (30 mL) was added PPh3 (6.26 g, 23.8 mmol, 1.20 eq.) at room temperature. The mixture was then cooled to 0°C and DIAD (5.02 g, 24.8 mmol, 1.25 eq.) was added. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give tert-butyl (R)-3-((4-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate (29-3) (7.00 g) as a white solid. MS: m / z = 335 [M+H] +

[0526] Sodium hydroxide (2.98 g, 74.5 mmol, 5.00 eq.) was added to a solution of tert-butyl (R)-3-((4-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate (5.00 g, 14.1 mmol, 1.00 eq.) in MeOH (10 mL) and H₂O (10 mL). The mixture was stirred at room temperature for 6 hours. The aqueous phase was washed with EtOAc (50 mL x 3) and then acidified to pH = 3 with 1N HCl. The resulting solution was extracted with EtOAc (50 mL x 3). The separated organic layer was dried over Na₂SO₄ and evaporated to dryness to give (R)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methoxy)benzoic acid (29-4) (1.00 g). MS: m / z = 321 [M+H] +

[0527] To a solution of (R)-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methoxy)benzoic acid (1.00 g, 3.11 mmol, 1.00 eq.) in acetonitrile (20 mL) were added NMI (1.28 g, 15.1 mmol, 5.00 eq.), TCFH (1.75 g, 6.22 mmol, 2.00 eq.), and 3-aminopiperidine-2,6-dione (438 mg, 3.42 mmol, 1.10 eq.) at room temperature. The mixture was stirred for 16 hours. Ethyl acetate (50 mL) and aqueous NaHCO₃ solution (50 mL) were added, and the separated organic layer was washed with water, dried over Na₂SO₄, and evaporated to dryness to give tert-butyl (3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate (29-5) (400 mg). MS: m / z=431 [M+H] +

[0528] To a solution of tert-butyl (3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate 29-5 (260 mg, 402 μmol, 1.00 eq.) in DCM (3 mL) was added dropwise 4M HCl in dioxane (3 mL) at room temperature. After stirring for 6 hours, the mixture was concentrated to afford N-(2,6-dioxopiperidin-3-yl)-4-((R)-pyrrolidin-3-yl)methoxy)benzamide (29-6) (200 mg). MS: m / z = 331 [M+H] +

[0529] To a solution of N-(2,6-dioxopiperidin-3-yl)-4-(((R)-pyrrolidin-3-yl)methoxy)benzamide 29-6 (200 mg, 543 μmol, 1.00 eq.) and tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (157 mg, 543 μmol, 1.00 eq.) in DCM (10 mL) was added TEA (275 mg, 2.72 mmol, 5.00 eq.) at room temperature. After stirring for 2 hours, NaBH(OAc)3 (345 mg, 1.63 mmol, 3.00 eq.) was added. After stirring for 16 hours, the mixture was concentrated and the residue was purified by reverse phase chromatography (TFA buffer) to give 4-(4-(3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoate (29-7) (278 mg). MS: m / z = 604 [M+H] +

[0530] To a solution of tert-butyl 4-(4-(3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoate 29-7 (270 mg, 446 μmol, 1.00 eq.) in DCM (4 mL) was added TFA (2 mL) at room temperature. The mixture was stirred for 6 hours and concentrated to give 4-(4-(3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoic acid (29-8) (232 mg). MS: m / z = 548 [M+H] +

[0531] To a solution of 4-(4-(3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzoic acid 29-8 (100 mg, 182 μmol, 1.00 eq.) in acetonitrile were added TCFH (102 mg, 364 μmol, 2.00 eq.) and NMI (74.8 mg, 911 μmol, 5.00 eq.) at room temperature. After stirring for 1 hour, 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile (28-2, 57.2 mg, 184 μmol, 1.01 eq.) was added. Stirring was continued for 16 hours, and the mixture was concentrated to dryness to give a crude product. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3R)-3-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenoxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (29) (43.0 mg). MS: m / z=805 [M+H] +

[0532] 1 H NMR (400MHz, DMSO) δ10.84(s,1H),9.61(br,1H),7.88(d,J=8.6Hz,2H),7.76(d,J=8.5Hz,2H),7.65(d,J=8.8Hz,1H),7.50(d, J=9.3Hz,1H),7.05(d,J=8.6Hz,2H),6.98(d,J=8.8Hz,2H),6.63(s,1H),6.54(d,J=10.4Hz,1H),4.79–4.72(m,1H),4.27(s,1H ),4.12–4.01(m,4H),3.91(s,3H),3.88–3.84(m,3H),3.77–3.65(m,2H),3.57–3.51(m,1H),3.39–3.31(m,1H),3.04–2.91(m, 2H),2.85–2.75(m,4H),2.20–2.09(m,2H),2.00–1.94(m,2H),1.86–1.79(m,2H),1.36–1.27(m,2H),1.22(s,6H),1.15(s,6H).

[0533] Example 30 Preparation of Compound 40

[0534] At 0 ° C, to a suspension of 1-methyl-1H-indazole-5-amine (3 g, 20.3 mmol, 1.0 eq.) in H2O / 98% H2SO4=1:1 (40 mL) was slowly added NaNO2 (1.4 g, 20.3 mmol, 1.0 eq.). The reaction mixture was stirred at 120 ° C for 2 hours. After the reaction was completed, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=20:1) to give 1-methyl-1H-indazole-5-ol (40-2) (752 mg, yield: 25%) as a yellow oil. MS: m / z=149[M+H] +

[0535] To a solution of 1-methyl-1H-indazol-5-ol (40-2) (752 mg, 5.07 mmol, 1.0 eq.) and (R)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.8 g, 5.07 mmol, 1.0 eq.) in DMF (10 mL) was added KCO (2.1 g, 15.21 mmol, 3.0 eq.). The reaction mixture was stirred at 80 ° C. for 16 hours. After the reaction was complete, the mixture was diluted with H O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na SO and concentrated. The residue was purified by silica gel column chromatography (PE / EA=4:1) to give (R)-tert-butyl 3-(((1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-3) (1.5 g, yield: 89%) as a yellow oil. MS: m / z=332 [M+H] + .

[0536] To a solution of (R)-tert-butyl 3-(((1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-3) (1.5 g, 4.52 mmol, 1.0 eq.) in DMF (10 mL) was added NIS (2.5 g, 11.3 mmol, 2.5 eq.). The reaction mixture was stirred at 50° C. for 4 hours. After the reaction was complete, the mixture was purified by reverse phase chromatography eluting with neat acetonitrile to afford (R)-tert-butyl 3-(((3-iodo-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-4) (1.98 g, 96% yield) as a brown oil. MS: m / z=402 [M+H-56] + .

[0537] To a solution of (R)-tert-butyl 3-(((3-iodo-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-4) (1.2 g, 2.62 mmol, 1.0 eq.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.42 g, 3.41 mmol, 1.3 eq.), and CsCO (2.56 g, 7.86 mmol, 3.0 eq.) in dioxane (12 mL) and H0 (3 mL) was added Pd(dppf)Cl (213 mg, 0.262 mmol, 0.1 eq.), and the reaction mixture was stirred at 100° C. for 16 h. After completion of the reaction, the reaction was cooled, filtered through a bed of celite, and washed with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography eluting with PE / EA (10:1) to give (R)-tert-butyl 3-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-5) (1.4 g, yield: 86%) as a brown oil. MS: m / z = 621 [M+H] + .

[0538] To a solution of (R)-tert-butyl 3-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-5) (500 mg, 0.805 mmol, 1.0 eq.) and 10% Pd / C (100 mg, 20 wt%) in EtOH (5 mL) was added (Boc)O (175 mg, 0.805 mmol, 1.0 eq.) and the reaction mixture was stirred at room temperature under H (50 Psi) for 16 hours. After the reaction was complete, the mixture was filtered and concentrated in vacuo to afford tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-6) (351 mg, crude) as a brown oil. MS: m / z = 343 [M+H-100] + .

[0539] To a solution of tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (40-6) (305 mg, 0.8 mmol, 1.0 eq.) in EA (2 mL) was added 4M HCl / EA (3 mL), and the reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was concentrated in vacuo to give 3-(1-methyl-5-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (40-7) (252 mg, crude) as a black solid. MS: m / z=343 [M+H] + .

[0540] To a solution of 3-(1-methyl-5-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (40-7) (80 mg, 0.21 mmol, 1.0 eq.) and N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (101 mg, 0.21 mmol, 1.0 eq.) in DMF (2 mL) was added TEA (85 mg, 0.84 mmol, 4.0 eq.), and the reaction mixture was stirred at room temperature for 4 hours, and then NaBH(OAc)3 (69 mg, 0.31 mmol, 1.5 eq.) was added to the mixture and stirred at room temperature for 4 hours. After the reaction was completed, the mixture was purified by reverse phase chromatography eluting with MeCN:H2O=50% to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (40) (29.2 mg, yield: 17%) as a white solid. MS: m / z=810 [M+H] +

[0541] 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),9.48(brs,1H),9.05(dd,J=4.2,1.7Hz,1H), 8.62(dd,J=8.6,1.6Hz,1H),8.27(d,J=8.3Hz,1H),7.97(d,J=7.2Hz,1H),7.73(d, J=8.0Hz,2H),7.67(dd,J=8.5,4.3Hz,1H),7.52(d,J=9.1Hz,1H),7.33(d,J=8.4Hz ,1H),7.15(s,1H),7.12–7.02(m,1H),6.94(d,J=7.1Hz,2H),4.71(brs,1H),4.30( dd,J=9.6,4.9Hz,1H),4.17–4.04(m,1H),4.03–3.91(m,4H),3.86(d,J=11.0Hz,3H ),3.73–3.59(m,2H),3.19–3.09(m,2H),3.03–2.88(m,2H),2.77(t,J=10.6Hz,2H) ,2.71–2.57(m,2H),2.41–2.30(m,1H),2.29–2.21(m,2H),2.21–2.12(m,1H),1.99 –1.88(m,3H),1.88–1.71(m,2H),1.71–1.51(m,4H),1.26(dd,J=20.6,11.1Hz,2H).

[0542] Example 31 Preparation of Compound 43

[0543] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (43-1) (800 mg, 2.72 mmol, 1.0 eq.) and CsCO (2.06 g, 5.44 mmol, 2.0 eq.) in acetonitrile (8 mL) was added (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (950 mg, 5.0 mmol, 1.0 eq.). The reaction mixture was stirred at 100 ° C for 16 hours. After the reaction was complete, the mixture was diluted with H O (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with PE / EA (1:1) to give tert-butyl (3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (43-2) (41 mg, 3.1% yield) as a white solid. MS: m / z = 420 [M+H-56] + .

[0544] To a solution of tert-butyl (3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (43-2) (41 mg, 0.086 mmol, 1.0 eq.) in DCM (1 mL) was added 4M HCl (2 mL) in dioxane. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(((R)-pyrrolidin-3-yl)methoxy)isoindolin-1,3-dione hydrochloride (43-3) (31 mg, crude material) as a white solid. MS: m / z=376[M+H] + .

[0545] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(((R)-pyrrolidin-3-yl)methoxy)isoindoline-1,3-dione hydrochloride (43-3) (31 mg, 0.07 mmol, 1.0 eq.) in DMF (1 mL) was added N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (37 mg, 0.07 mmol, 1.0 eq.) and TEA (30 mg, 0.3 mmol, 4.0 eq.). The reaction mixture was stirred at room temperature for 4 hours, then NaBH(OAc)3 (16 mg, 0.07 mmol, 1.0 eq.) was added. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed the reaction was complete, MS 842. The residue was purified by reverse phase chromatography eluting with water (0.05% TFA) and MeCN to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3R)-3-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (43) (10.8 mg, 17.1% yield) as a white solid. MS: m / z = 842 [M+H] + .

[0546] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),9.52(s,1H),9.05(dd,J=4.4,1.7Hz,1H),8.62(dd,J=8.6,1.7Hz,1H),8.26(d,J=8.3Hz,1 H),7.98(d,J=7.6Hz,1H),7.89(d,J=9.2Hz,1H),7.73(dd,J=8.0,3.3Hz,2H),7.67(dd,J=8.5,4.3Hz,1H),7.32(d,J=8.4Hz,1H) ,6.93(d,J=8.5Hz,2H),5.11(dd,J=12.8,5.4Hz,1H),4.71(m,1H),4.33(br,2H),3.86(m,3H),3.67(s,1H),3.50(m,1H),3.12(m ,4H),3.02–2.72(m,5H),2.63–2.50(m,2H),2.23(m,2H),2.16–2.00(m,2H),1.93(m,3H),1.81(m,2H),1.59(m,4H),1.26(m,2H).

[0547] Example 32 Preparation of Compound 56

[0548] To a solution of 3-bromo-2,4-difluorobenzaldehyde (56-1) (2 g, 9.0 mmol, 1.0 eq.) in DMSO (20 mL) was added 80% N2H4·H2O (2.2 mL, 36.0 mmol, 4.0 eq.). The reaction mixture was stirred at 120°C for 5 hours, allowed to cool to room temperature, poured into H2O (80 mL), and then filtered. The filter cake was washed with H2O (20 mL) and dried under vacuum to give 7-bromo-6-fluoro-1H-indazole (56-2) (1.1 g, yield: 56.8%) as a white solid. MS: m / z = 216 [M+H] + .

[0549] To a solution of 7-bromo-6-fluoro-1H-indazole (56-2) (1.1 g, 5.1 mmol, 1.0 eq.) and KOH (1.0 g, 17.8 mmol, 3.5 eq.) in DMF (11 mL) was added I2 (1.9 g, 7.6 mmol, 1.5 eq.) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 7-bromo-6-fluoro-3-iodo-1H-indazole (56-3) (1.2 g, crude material) as a brown oil. The crude material was used in the next step without purification. MS: m / z=341[M+H] + .

[0550] To a solution of 7-bromo-6-fluoro-3-iodo-1H-indazole (56-3) (1.2 g, 3.5 mmol, 1.0 eq.) and iodomethane (749 mg, 5.2 mmol, 1.5 eq.) in DMF (12 mL) was added t-BuOK (796 mg, 7.1 mmol, 2.0 eq.) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography eluting with PE / EA (10: 1) to give 7-bromo-6-fluoro-3-iodo-1-methyl-1H-indazole (56-4) (651 mg, yield: 52.2%) as a white solid. MS: m / z=355[M+H] + .

[0551] To a solution of 7-bromo-6-fluoro-3-iodo-1-methyl-1H-indazole (56-4) (651 mg, 1.8 mmol, 1.0 eq.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.03 g, 2.4 mmol, 1.3 eq.), and CsCO (1.8 g, 5.5 mmol, 3.0 eq.) in dioxane (8 mL) and H0 (2 mL) was added Pd(dppf)Cl (155 mg, 0.19 mmol, 0.1 eq.) and the reaction mixture was stirred at 100° C. under N for 16 hours. After the reaction was complete, the reaction was cooled, filtered through a celite bed, and washed with EA. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography eluting with PE / EA (10:1) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-6-fluoro-1-methyl-1H-indazole (56-5) (510 mg, yield: 53.7%) as a white solid. MS: m / z = 519 [M+H] + .

[0552] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-6-fluoro-1-methyl-1H-indazole (56-5) (510 mg, 0.98 mmol, 1.0 eq.), t-BuXphos (83 mg, 0.2 mmol, 0.2 eq.) and KOH (112 mg, mmol, 2.0 eq.) in dioxane (8 mL) and H2O (2 mL) was added Pd2(dba)3 (92 g, 0.1 mmol, 0.1 eq.) and the reaction mixture was stirred at 100 ° C. under N2 for 16 hours. After the reaction was complete, the reaction was cooled, filtered through a celite bed, and washed with EA. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography eluting with PE / EA (4:1) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-1-methyl-1H-indazol-7-ol (56-6) (101 mg, yield: 22%) as a white solid. MS: m / z = 457 [M+H] + .

[0553] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-1-methyl-1H-indazol-7-ol (56-6) (101 mg, 0.22 mmol, 1.0 eq.) and (R)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (79 mg, 0.22 mmol, 1.0 eq.) in DMF (2 mL) was added KCO (91 mg, 0.66 mmol, 3.0 eq.). The reaction mixture was stirred at 80 ° C for 16 hours. After the reaction was complete, the mixture was diluted with H O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na SO and concentrated. The residue was purified by silica gel column chromatography (PE / EA=10:1) to give (R)-tert-butyl 3-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (56-7) (121 mg, 85.7% yield) as a white solid. MS: m / z=639 [M+H] + .

[0554] To a solution of (R)-tert-butyl 3-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (56-7) (121 mg, 0.18 mmol, 1.0 eq.) and 10% Pd / C (24 mg, 20 wt%) in EtOH (3 mL) was added (Boc)O (41 mg, 0.18 mmol, 1.0 eq.) and the reaction mixture was stirred at room temperature under H atmosphere (50 Psi) for 16 h. After the reaction was complete, the mixture was filtered and concentrated in vacuo to afford tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (56-8) (81 mg, crude) as a brown solid. The crude material was used in the next step without purification. MS: m / z = 361 [M+H-100] + .

[0555] To a solution of tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (56-8) (81 mg, 0.17 mmol, 1.0 eq.) in EA (2 mL) was added 4M HCl / EA (2 mL), and the reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was concentrated in vacuo to give 3-(6-fluoro-1-methyl-7-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (56-9) (55 mg, crude) as a green solid. The crude material was used in the next step without purification. MS: m / z=361 [M+H] + .

[0556] To a solution of 3-(6-fluoro-1-methyl-7-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (56-9) (55 mg, 0.15 mmol, 1.0 eq.) and N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (72 mg, 0.15 mmol, 1.0 eq.) in DMF (2 mL) was added TEA (61 mg, 0.61 mmol, 4.0 eq.), and the reaction mixture was stirred at room temperature for 2 hours. Then, NaBH(OAc)3 (48 mg, 0.225 mmol, 1.5 eq.) was added to the mixture and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was purified by reverse phase chromatography eluting with MeCN:H2O=56% to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (56) (31.9 mg, yield: 25.5%) as a white solid. MS: m / z=827 [M+H] + .

[0557] 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.07(dd,J=4.2,1.8Hz,1H),8.64(dd,J=8.5,1.8Hz,1H),8.29(d,J=8.3Hz,1H),7. 89(d,J=8.3Hz,1H),7.75–7.67(m,2H),7.52–7.46(m,2H),7.39(d,J=8.2Hz,1H),7.34(d,J=8.4Hz,1H),6.84–6.75(m,2H ),5.13(dd,J=12.8,5.4Hz,1H),4.79–4.70(m,1H),4.24–4.17(m,1H),3.94–3.84(m,4H),3.19–3.09(m,4H),3.03–2.92( m,2H),2.89–2.76(m,4H),2.69–2.58(m,2H),2.25–2.19(m,2H),2.08–1.92(m,7H),1.85–1.78(m,3H),1.71–1.54(m,4H).

[0558] Example 33 Preparation of Compound 57

[0559] To a solution of 2,4-difluorophenol (3 g, 23.0 mmol, 1.0 eq.) and (R)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (8.2 g, 23.0 mmol, 1.0 eq.) in DMF (30 mL) was added KCO (9.5 g, 69.1 mmol, 3.0 eq.). The reaction mixture was stirred at 80 ° C for 16 hours. After the reaction was completed, the mixture was diluted with H O (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over Na SO and concentrated. The residue was purified by silica gel column chromatography (PE / EA=10:1) to give (R)-tert-butyl 3-((2,4-difluorophenoxy)methyl)pyrrolidine-1-carboxylate (57-1) (4.8 g, yield: 66%) as a colorless oil. MS: m / z = 314 [M+H] + .

[0560] To a solution of (R)-tert-butyl 3-((2,4-difluorophenoxy)methyl)pyrrolidine-1-carboxylate (57-1) (4.8 g, 15.3 mmol, 1.0 eq.) in THF (50 mL) was added n-BuLi (6.7 mL, 2.5 M) at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour. DMF (1.7 g, 22.9 mmol, 1.5 eq.) was added dropwise and the mixture was stirred at -78 ° C for 1 hour. After the reaction was complete, H2O (50 mL) was slowly added at the same temperature. The mixture was allowed to warm to room temperature and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to give (R)-tert-butyl 3-((2,4-difluoro-3-formylphenoxy)methyl)pyrrolidine-1-carboxylate (57-2) (4.8 g, crude material) as a colorless oil. MS: m / z = 342 [M+H] + .

[0561] To a solution of (R)-tert-butyl 3-((2,4-difluoro-3-formylphenoxy)methyl)pyrrolidine-1-carboxylate (57-2) (2 g, 5.8 mmol, 1.0 eq.) in DMSO (20 mL) was added hydrazine hydrate 80% (1.5 g, 23.4 mmol, 4.0 eq.). The reaction mixture was stirred at 120 ° C. for 16 hours. After the reaction was completed, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE / EA=10:1) to give (R)-tert-butyl 3-(((4-fluoro-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-3) (705 mg, yield: 36%) as a colorless oil. MS: m / z=336 [M+H] + .

[0562] To a solution of (R)-tert-butyl 3-(((4-fluoro-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-3) (705 mg, 2.1 mmol, 1.0 eq.) and KOH (412 mg, 7.3 mmol, 3.5 eq.) in DMF (7 mL) was added I (800 mg, 3.1 mmol, 1.5 eq.) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(((4-fluoro-3-iodo-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-4) (951 mg, crude) as a brown oil. The crude material was used in the next step without purification. MS: m / z = 462 [M+H] + .

[0563] To a solution of (R)-tert-butyl 3-(((4-fluoro-3-iodo-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-4) (951 mg, 2.06 mmol, 1.0 eq.) and iodomethane (438 mg, 3.09 mmol, 1.5 eq.) in DMF (10 mL) was added t-BuOK (462 mg, 4.12 mmol, 2.0 eq.) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(((4-fluoro-3-iodo-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-5) (902 mg, crude) as a brown oil. The crude material was used in the next step without purification. MS: m / z = 476 [M+H] + .

[0564] To a solution of (R)-tert-butyl 3-(((4-fluoro-3-iodo-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-5) (902 mg, 1.9 mmol, 1.0 eq.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (57-3) (1.03 g, 2.46 mmol, 1.3 eq.), and CsCO (1.8 g, 5.7 mmol, 3.0 eq.) in dioxane (12 mL) and H0 (3 mL) was added Pd(dppf)Cl (155 mg, 0.19 mmol, 0.1 eq.), and the reaction mixture was stirred at 100° C. under N for 16 h. After completion of the reaction, the reaction was cooled, filtered through a celite bed, and washed with EA. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography eluting with PE / EA (10:1) to give (R)-tert-butyl 3-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-6) (851 mg, yield: 70%) as a brown oil. MS: m / z = 639 [M+H] + .

[0565] To a solution of (R)-tert-butyl 3-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-6) (851 mg, 1.3 mmol, 1.0 eq.) and 10% Pd / C (170 mg, 20 wt%) in EtOH (8 mL) was added (Boc)O (291 mg, 1.3 mmol, 1.0 eq.) and the reaction mixture was stirred at room temperature under H atmosphere (50 Psi) for 16 h. After the reaction was complete, the mixture was filtered and concentrated in vacuo to afford tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-7) (604 mg, crude) as a brown oil. The crude material was used in the next step without purification. MS: m / z = 361 [M+H-100] + .

[0566] To a solution of tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (57-7) (604 mg, 1.3 mmol, 1.0 eq.) in EA (2 mL) was added 4M HCl / EA (3 mL), and the reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was concentrated in vacuo to give 3-(4-fluoro-1-methyl-5-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (57-8) (352 mg, crude) as a green solid. The crude material was used in the next step without purification. MS: m / z=361 [M+H] + .

[0567] To a solution of 3-(4-fluoro-1-methyl-5-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (57-8) (100 mg, 0.25 mmol, 1.0 eq.) and N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-formylpiperidin-1-yl)benzamide (5-5) (121 mg, 0.25 mmol, 1.0 eq.) in DMF (2 mL) was added TEA (106 mg, 1.05 mmol, 4.0 eq.), and the reaction mixture was stirred at room temperature for 4 hours, and then NaBH(OAc)3 (79 mg, 0.37 mmol, 1.5 eq.) was added to the mixture and stirred at room temperature for 4 hours. After the reaction was completed, the mixture was purified by reverse phase chromatography eluting with MeCN:H2O=56% to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-methyl-1H-indazol-5-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)benzamide (57) (47.9 mg, yield: 23%) as a white solid. MS: m / z=827 [M+H] + .

[0568] 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.05(dd,J=4.3,1.7Hz,1H),8.61(dd,J=8.5,1.7Hz,1H),8.26(d,J=8.3Hz,1H),7.98(d,J=7.6Hz,1H),7.73(d,J =8.4Hz,2H),7.66(dd,J=8.5,4.2Hz,1H),7.32(d,J=8.4Hz,1H),6.98–6.89 (m,2H),6.80–6.70(m,2H),4.71(brs,1H),4.28(dd,J=11.4,5.2Hz,1H),4.2 3–4.04(m,5H),3.85(d,J=12.7Hz,4H),3.71(brs,1H),3.61–3.51(m,1H),3 .45–3.32(m,1H),3.23–3.17(m,3H),3.08–2.95(m,1H),2.93–2.83(m,1H),2 .82–2.68(m,3H),2.61–2.51(m,1H),2.32–2.18(m,3H),2.17–2.05(m,1H), 2.03–1.87(m,3H),1.86–1.77(m,2H),1.71–1.52(m,4H),1.35–1.18(m,2H).

[0569] Example 34 Preparation of Compounds 58 and 58A

[0570] To a solution of 4-((2R,4R)-4-(methoxycarbonyl)-2-methylpiperidin-1-yl)benzoic acid (80 mg, 0.28 mmol, 1.0 eq.) in DMF (1 mL) and DIEA (149 mg, 1.15 mmol, 4.0 eq.) was added HATU (164 mg, 0.43 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for 20 minutes. 5-(((1r,4r)-4-aminocyclohexyl)oxy)quinoline-8-carbonitrile hydrochloride (87 mg, 0.31 mmol, 1.0 eq.) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was partitioned between HO (20 mL) and EA (20 mL), and the aqueous layer was extracted with EA (3 x 20 mL). The organic layer was dried and evaporated. The residue was purified by silica gel chromatography eluting with pure EA to give methyl (2R,4R)-1-(4-(((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)carbamoyl)phenyl)-2-methylpiperidine-4-carboxylate (58-2) (51 mg, 33% yield) as a yellow solid. MS: m / z = 527 [M+H] + .

[0571] To a solution of methyl (2R,4R)-1-(4-(((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)carbamoyl)phenyl)-2-methylpiperidine-4-carboxylate (58-2) (51 mg, 0.09 mmol, 1.0 eq.) in THF (1 mL) was added LiBH (21 mg, 0.96 mmol, 10.0 eq.). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was partitioned between H O (20 mL) and EA (20 mL), and the aqueous layer was extracted with EA (3×20 mL). The organic layer was dried and evaporated to give N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4R)-4-(hydroxymethyl)-2-methylpiperidin-1-yl)benzamide (58-3) (31 mg, crude) as a yellow solid. MS: m / z = 499 [M+H] + .

[0572] To a solution of N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4R)-4-(hydroxymethyl)-2-methylpiperidin-1-yl)benzamide (58-3) (31 mg, 0.06 mmol, 1.0 eq.) and Dess-Martin reagent (29 mg, 0.06 mmol, 1.1 eq.) in DCM (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was partitioned between HO (20 mL) and DCM (20 mL), and the aqueous layer was extracted with DCM (3×20 mL). The organic layer was dried and evaporated. The residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4R)-4-formyl-2-methylpiperidin-1-yl)benzamide (58-4) (19 mg, 61% yield) as a white solid. MS: m / z = 497 [M+H] + .

[0573] N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4S)-4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)benzamide (58)

[0574] N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4R)-4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)benzamide (58A)

[0575] To a solution of N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4R)-4-formyl-2-methylpiperidin-1-yl)benzamide (58-4) (19 mg, 0.038 mmol, 1.0 eq.) and 3-(1-methyl-7-(((R)-pyrrolidin-3-yl)methoxy)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (15 mg, 0.1 mmol, 1.0 eq.) in DMF (1 mL) was added TEA (19 mg, 0.19 mmol, 5.0 eq.). The reaction was stirred at room temperature for 2 hours, then NaBH(OAc) (12 mg, 0.057 mmol, 1.5 eq.) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the residue was purified by reverse phase chromatography (TFA buffer) to give N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4S)-4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)benzamide (58) (3.6 mg, 11.5% yield, Rf = 0. 6, DCM:MeOH=10:1) and N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((2R,4R)-4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)oxy)methyl)pyrrolidin-1-yl)methyl)-2-methylpiperidin-1-yl)benzamide (58A) (4 mg, 12% yield, Rf=0.5, DCM:MeOH=10:1) as a white solid. MS: m / z=823 [M+H] + .

[0576] Compound 58: 11H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.08 (dd, J = 4.3, 1.8 Hz, 1H), 8.64 (dd, J = 8.5, 1.7 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.71–7.68 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 7.6 Hz, 1H), 4.73 (brs, 1H), 4.43–4.25 (m, 3H), 4.22–4.13 (m, 4H), 3.94–3.83 (m, 2H), 3.78–3.67 (m, 1H), 3.63–3.57 (m, 2H), 3.21–3.04 (m, 4H), 2.99–2.86 (m, 2H), 2.73–2.60 (m, 2H), 2.35–2.31 (m, 2H), 2.28–2.23 (m, 2H), 2.21–2.14 (m, 2H), 1.98–1.91 (m, 2H), 1.90–1.80 (m, 1H), 1.79–1.73 (m, 1H), 1.69–1.56 (m, 4H), 1.27–1.18 (m, 2H), 1.04 (d, J = 6.5 Hz, 3H).

[0577] Compound 58A: 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.07(d,J=2.8Hz,1H),8.65(d,J=8.3Hz,1H),8.29(d,J=8.3Hz,1H),8.11(d,J=7.6Hz,1H),7 .76(d,J=8.5Hz,2H),7.69(dd,J=8.5,4.2Hz,1H),7.36(d,J=8.6Hz,1H),7.22(d,J=8.0Hz,1H),7.04–6.95(m,3H),6.84(d,J=7.4Hz ,1H),4.77–4.72(m,1H),4.32(dd,J=9.9,5.1Hz,1H),4.19(s,3H),4.16–4.11(m,2H),4.07–4.02(m,2H),3.95–3.81(m,3H),2.97– 2.90(m,1H),2.40–2.22(m,6H),2.21–2.08(m,2H),2.07–1.84(m,6H),1.70–1.57(m,6H),1.31–1.19(m,4H),0.96(d,J=5.9Hz,3H).

[0578] Example 35 Compounds 67 and 67A were synthesized by referring to the preparation of compounds 58 and 58A.

[0579] Example 36 Preparation of Compound 86

[0580] To a solution of 1-(3-bromo-2-hydroxyphenyl)ethan-1-one (5 g, 25.0 mmol, 1.0 eq.) and diethyl carbonate (11.8 g, 100.0 mmol, 4.0 eq.) in toluene (50 mL) was added 60% NaH (4 g, 100.0 mmol, 4.0 eq.) at 0 ° C. The reaction mixture was stirred at 120 ° C for 16 hours. After the reaction was completed, the residue was mixed with ice-water (200 mL), acidified to pH 2-3 with aqueous HCl solution (3 M) and extracted with EA (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give ethyl 3-(3-bromo-2-hydroxyphenyl)-3-oxopropanoate (86-1) (5 g, crude material) as a yellow solid. MS: m / z=288[M+H] + .

[0581] To a solution of ethyl 3-(3-bromo-2-hydroxyphenyl)-3-oxopropanoate (86-1) (5 g, crude material) in DMF (50 mL) was added KCO (7.2 g, 52.2 mmol, 3.0 eq.). The reaction mixture was stirred at 120 ° C for 4 hours. After the reaction was complete, the residue was mixed with ice-water (200 mL), acidified to pH 2-3 with aqueous HCl solution (3 M) and extracted with EA (100 mL × 3). The combined organic layers were dried over NaSO and concentrated. The residue was purified by reverse phase to give 8- bromo-4-hydroxy-2H-chromen-2-one (86-2) (2.6 g, 43% two-step yield) as a yellow solid. MS: m / z = 242 [M + H] + .

[0582] To a solution of 8-bromo-4-hydroxy-2H-chromen-2-one (86-2) (2.6 g, 10.7 mmol, 1.0 eq.) and sodium acetate (4.4 g, 53.9 mmol, 5.0 eq) in EtOH (21 mL) was added hydroxylamine hydrochloride (3.7 g, 53.9 mmol, 5.0 eq). The reaction mixture was stirred at 90 ° C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 3N hydrochloric acid was added to adjust the pH = 5, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give 2- (7-bromobenzo [d] isoxazol-3-yl) acetic acid (86-3) (2.1 g, crude material) as a white solid. MS: m / z = 257 [M + H] + .

[0583] To a solution of 2-(7-bromobenzo[d]isoxazol-3-yl)acetic acid (86-3) (2.1 g, crude material) in EtOH (20 mL) was added 5 drops of sulfuric acid, and the reaction mixture was stirred at 80° C. for 3 hours. After the reaction was complete, it was concentrated and the residue was purified by silica gel chromatography (PE / EA=4:1) to give ethyl 2-(7-bromobenzo[d]isoxazol-3-yl)acetate (86-4) (1.1 g, two-step yield: 53.7%) as a colorless oil. MS: m / z=284 [M+H] + .

[0584] To a solution of ethyl 2-(7-bromobenzo[d]isoxazol-3-yl)acetate (86-4) (1.1 g, 3.8 mmol, 1.0 eq.), bis(pinacolato)diboron (1.27 g, 5.0 mmol, 1.3 eq.) and KOAc (1.14 g, 11.6 mmol, 3.0 eq.) in dioxane (11 mL) was added Pd(dppf)Cl2 (288 mg, 0.38 mmol, 0.1 eq.) and the reaction mixture was stirred at 100° C. under N2 for 16 h. After the reaction was complete, the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL×3). The organic layer was separated, dried over Na2SO4 and concentrated to give ethyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazol-3-yl)acetate (86-5) (1.01 g, crude) as a yellow oil. MS: m / z = 332 [M+H] + .

[0585] To a solution of ethyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazol-3-yl)acetate (86-5) (1.01 g, crude) in THF (10 mL) and H2O (5 mL) at 0°C were added NaHCO3 (63 mg, 7.6 mmol, 2.0 eq.) and 30% H2O2 (1.72 g, 15.2 mmol, 4.0 eq.), and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the pH was adjusted to 5-6 with aqueous HCl (1 N), the mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3), concentrated, and the residue was purified by reverse phase and silica gel column (PE / EA = 4:1) to give ethyl 2-(7-hydroxybenzo[d]isoxazol-3-yl)acetate (86-6) (702 mg, two-step yield: 82%) as a colorless oil. MS: m / z = 222 [M+H] + .

[0586] To a solution of ethyl 2-(7-hydroxybenzo[d]isoxazol-3-yl)acetate (86-6) (702 mg, 3.17 mmol, 1.0 eq.) and tert-butyl (R)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.12 g, 3.17 mmol, 1.0 eq.) in DMF (7 mL) was added KCO (1.3 g, 9.51 mmol, 3.0 eq.). The reaction mixture was stirred at 80° C. for 16 hours. After the reaction was complete, the mixture was diluted with H O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na SO and concentrated. The residue was purified by silica gel column chromatography (PE / EA=4:1) to give (R)-tert-butyl 3-(((3-(2-ethoxy-2-oxoethyl)benzo[d]isoxazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (86-7) (621 mg, yield: 48%) as a white solid. MS: m / z=405 [M+H] + .

[0587] To a solution of (R)-tert-butyl 3-(((3-(2-ethoxy-2-oxoethyl)benzo[d]isoxazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (86-7) (621 mg, 1.53 mmol, 1.0 eq.) in DMF (6 mL) at 0° C., t-BuOK (171 mg, 1.53 mmol, 1.0 eq.) and acrylamide (108 mg, 1.53 mmol, 1.0 eq.) were added, and the reaction mixture was stirred at room temperature under N for 2 hours. After the reaction was complete, the mixture was diluted with H O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na SO and concentrated. The residue was purified by silica gel column chromatography (PE / EA=1:2) to give tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (86-8) (95 mg, yield: 14.4%) as a white solid. MS: m / z=330 [M+H-100] + .

[0588] To a solution of tert-butyl (3R)-3-(((3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylate (86-8) (95 mg, 0.22 mmol, 1.0 eq.) in EA (2 mL) was added 4M HCl / EA (2 mL) and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated in vacuo to give 3-(7-(((R)-pyrrolidin-3-yl)methoxy)benzo[d]isoxazol-3-yl)piperidine-2,6-dione hydrochloride (86-9) (71 mg, crude) as a white solid. The crude material was used in the next step without purification. MS: m / z = 330 [M+H] + .

[0589] To a solution of 3-(7-(((R)-pyrrolidin-3-yl)methoxy)benzo[d]isoxazol-3-yl)piperidine-2,6-dione hydrochloride (86-9) (35 mg, 0.1 mmol, 1.0 eq.) and N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide (53 mg, 0.1 mmol, 1.0 eq.) in DMF (2 mL) was added TEA (42 mg, 0.42 mmol, 4.0 eq.) and the reaction mixture was stirred at room temperature for 2 hours. Then, NaBH(OAc)3 (32 mg, 0.15 mmol, 1.5 eq.) was added to the mixture and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was purified by reverse phase chromatography eluting with MeCN:H2O=56% to give N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((3R)-3-(((3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl)oxy)methyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)-2-fluorobenzamide (86) (20.1 mg, yield: 23.3%) as a white solid. MS: m / z=814 [M+H] + .

[0590] 1 H NMR (400 MHz, DMSO-d 6)δ11.11(s,1H),9.08(d,J=8.3Hz,1H),8.64(dd,J=8.5,1.7Hz,1H),8.29(d,J=8.3Hz,1H),7.78–7.65(m,2H),7.51(t,J=8.8H z,1H),7.42(d,J=7.9Hz,1H),7.33(dd,J=8.3,6.3Hz,2H),7.26(d,J=7.8Hz,1H),6.86–6.73(m,2H),4.75(brs,1H),4.61(dd, J=12.0,4.9Hz,1H),4.39–4.21(m,2H),3.90(d,J=13.0Hz,4H),3.71(brs,1H),3.25–3.12(m,3H),3.09–2.96(m,1H),2.91–2. 73(m,4H),2.70–2.53(m,2H),2.31–2.12(m,4H),2.08–1.91(m,4H),1.87–1.80(m,2H),1.72–1.53(m,4H),1.32–1.20(m,2H).

[0591] The following compounds were prepared by referring to the preparation methods of the above examples:

[0592] The nuclear magnetic data (H-NMR) of the compound of the present invention are as follows:

[0593] Biological test evaluation

[0594] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0595] Test Example 1 Detection of the AR protein degradation level of the compounds of the present invention in human prostate cancer cells LNCaP and VCaP

[0596] Cell culture: Human prostate cancer cells LNCaP and VCaP were subcultured in culture medium (90% 1640 medium, 10% FBS fetal bovine serum, 1× P / S antibiotics).

[0597] Cell seeding and compound treatment:

[0598] 1. Ensure cell viability > 90% during cell culture. Digest the cultured cells, resuspend and dilute to 100,000 cells per ml in culture medium, seed 100 μL of cells into a cell culture plate at 10,000 cells per well, and incubate in a cell culture incubator at 37°C, 5% CO2 for 4-8 hours.

[0599] 2. Dilute the test compound 4-fold in DMSO (300 μM to 18 nM). Add 1 μL of the test compound to the cell culture plate (final compound concentration 3000 nM to 0.18 nM). The positive reference well contains 3000 nM ARV110, and the negative reference well contains DMSO without compound.

[0600] 3. Incubate in an incubator at 37°C, 5% CO2 for 8 hours.

[0601] Elisa test:

[0602] 1. Discard the culture medium and add 1X cell lysis buffer to treat the cells. Transfer 100 μL of the supernatant to a microplate coated with capture antibody (ELISA reagents purchased from Cell Signaling Technology, Cat. No. 12850).

[0603] 2. Incubate at 4°C overnight, discard the liquid in the wells, and wash four times with 1X wash buffer, 200 μL each time. Add 100 μL of recombinant detection antibody to each well and incubate the plate at 37°C for 1 hour.

[0604] 3. Repeat the washing procedure. Add 100 μL of recombinant HRP-linked secondary antibody to each well and incubate the plate at 37°C for 30 minutes.

[0605] 4. Repeat the washing procedure and add 100 μL of TMB substrate to each well.

[0606] 5. After incubation for 5-15 minutes, read the absorbance OD450 value on the Envision instrument.

[0607] 6. Calculate the degradation rate using the OD450 value. %Degradation = 100 - (OD value of the compound well - OD value of the positive reference well) / (OD value of the negative reference well - OD value of the positive reference well) × 100.

[0608] DC was calculated using a 4-parameter model using Graphpad 8.0 software. 50 The results are shown in Table 1, Table 1-1 and Table 2:

[0609] Table 1. AR protein degradation rate of LNCaP cells at 100 nM and 10 nM concentrations of the compounds of the present invention

[0610] Table 1-1. AR protein degradation rate of VCaP cells at 30 nM and 3 nM concentrations of the present compounds

[0611] Table 2. AR protein degradation rate of VCaP cells by the compounds of the present invention

[0612] Test Example 2: Human prostate cancer cells VCaP, Western blotting to determine compound-induced AR degradation

[0613] 1. Cell Culture

[0614] The revived cells were cultured in T25 flasks with DMEM medium + 10% FBS + 1% P / S. When the cell confluence reached 80-90%, they were passaged. Before the experiment, VCaP cells were seeded into 96-well cell culture plates, with 3×10 cells per well. 5 cells, add 100 μL of culture medium, and culture the cells in a 37°C, 5% CO2 incubator overnight.

[0615] 2. Drug treatment

[0616] Compounds were added to a 96-well plate using an IDOT instrument, with 100 nL of the diluted compound added to each well. The cell culture plates were incubated in a 37°C, 5% CO2 incubator for 8 hours.

[0617] 3. Reagent Configuration

[0618] a) Cell lysis buffer: Add one protease inhibitor tablet and one phosphatase inhibitor tablet to 20 mL of cell lysis buffer and mix gently until completely dissolved.

[0619] b) 4× sample preparation working solution: Add DTT to a final concentration of 200 mM to 4× sample preparation buffer to prepare 4× sample preparation working solution.

[0620] c) Running buffer: Dilute 20× running buffer to 1× with ultrapure water.

[0621] d) Transfer buffer: Dilute 10× transfer buffer to 1× with ultrapure water and add 20% methanol.

[0622] e) TBST buffer: Dilute 10× electrophoresis buffer to 1× with ultrapure water.

[0623] f) Blocking solution: Dissolve 5 g of BSA in 1× TBST to 100 mL and store at 4°C.

[0624] g) Primary antibody working solution:

[0625] AR primary antibody working solution: add Androgen Receptor (D6F11) to 24 mL of blocking solution Rabbit mAb #5153 antibody 24 μL;

[0626] β-actin primary antibody working solution: add 2.4 μL of β-Actin (13E5) Rabbit mAb #4970 antibody to 24 mL of blocking solution;

[0627] h) Secondary antibody working solution: Dilute Anti-rabbit IgG and HRP-linked antibody 5000-fold and 10000-fold respectively in blocking solution.

[0628] 4. Protein Extraction

[0629] After aspirating the supernatant, centrifuge inverted at 300 rpm for 30 seconds. Add 45 μL of cell lysis buffer to each well and incubate on ice for 20 minutes. Pipette the cell lysate into a new centrifuge tube and add 15 μL of 4× sample preparation buffer to each sample. Heat at 70°C for 10 minutes. Store the remaining protein sample at -80°C.

[0630] 5. Western Blot

[0631] Take the protein precast gel, load 10 μL into each well, and perform electrophoresis at a constant voltage of 120V for 60 minutes. Use PVDF membrane for transfer, constant current of 300mA for 80 minutes. After transfer, block with blocking solution at room temperature for 60 minutes. Incubate with primary antibody working solution at 4°C overnight. Wash the membrane with 1×TBST buffer three times for 10 minutes each time. Incubate with secondary antibody working solution at room temperature for 1 hour. Wash the membrane with 1×TBST buffer three times for 10 minutes each time. Expose and develop with colorimetric solution. Data processing and analysis. After scanning the bands with a scanner, use image J to analyze the grayscale of the target gene AR band and the internal reference gene β-actin band. The ratio of AR / β-actin is used as the corrected AR content of the sample well, and the AR content of the sample well without compound is used as 100% AR, that is, 0% AR Degradation. The degradation rate of other sample wells is calculated by dividing the AR content of the sample well without compound. DC is calculated using the 4-parameter model of Graphpad 8.0 software. 50 The results are shown in Table 3.

[0632] Table 3. AR protein degradation rate of VCaP cells by the compounds of the present invention

[0633] Test Example 3 Pharmacokinetics Test in Mice

[0634] Male ICR mice were fasted overnight. Six mice were weighed before dosing, and the dose was calculated based on body weight. Three mice were administered intravenously or orally via gavage. The compound vehicle consisted of 5% DMSO + 10% solutol + 85% saline. The compound was administered orally via gavage at 3 mg / kg, and via tail vein injection at 1 mg / kg. IV administration was repeated 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after dosing. PO administration was repeated 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing. Blood was collected from the jugular vein, approximately 0.03 mL per sample, anticoagulated with sodium heparin, and placed on ice. Blood samples were placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800 g, 6 minutes, 2-8°C). Plasma samples were stored at -80°C until analysis. Intraday accuracy assessment of quality control samples was performed simultaneously with sample analysis, with a requirement that more than 66.7% of quality control samples have an accuracy between 80% and 120%. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 using plasma drug concentration data at different time points. These parameters, including AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, and T1 / 2, along with their means and standard deviations, were provided. The experimental results are shown in Table 4.

[0635] Table 4. PK data of the compounds of the present invention

[0636] The experimental results show that the compound of the present invention has good bioavailability and excellent pharmacokinetic properties.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: M1 is selected from N or CR1; M2 is selected from N or CR2; M3 is selected from N or CR3; M4 is selected from N or CR4; M5 is selected from N or CR5; R1, R2, R3, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, cycloalkyl or heterocyclyl; Ring A, Ring B and Ring C are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; L1 is selected from a bond, -C(O)NH-, -NH-, -O-, -NHC(O)-, -C(O)-, -S(=O)-, -S(=O)2-, -CH2- or -(CH2)2-; L2 is -Ak1-Cy1-Ak2-Cy2-Ak3-, Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -、-(CH2) n4 -S-(CH2) n5 、-(CH2) n6 -C(O)NH-(CH2) n7 -、-(CH2) n8 -NH-(CH2) n9 、-(CH2) n10 -NHC(O)-(CH2) n11 、-(CH2) n12 -C(O)-(CH2) n13 、-(CH2) n14 -S(=O)-(CH2) n15 -or-(CH2) n16 -S(=O)2-(CH2) n17 -, the -(CH2) n1 -O-(CH2) n2 -、-(CH2) n3 -、-(CH2) n4 -S-(CH2) n5 、-(CH2) n6 -C(O)NH-(CH2) n7 -、-(CH2) n8 -NH-(CH2) n9 、-(CH2) n10 -NHC(O)-(CH2) n11 、-(CH2) n12 -C(O)-(CH2) n13 、-(CH2) n14 -S(=O)-(CH2) n15 - and -(CH2) n16 -S(=O)2-(CH2) n17 -, optionally may be further substituted; Cy1 and Cy2 are each independently selected from a bond, a cyclohexylene, a piperidinylene, a piperazinylene, an azetidinylene, an azocyclopentylene, a cyclobutylene or a cyclopentylene, and the cyclohexylene, piperidinylene, piperazinylene, an azetidinylene, an azocyclopentylene, a cyclobutylene and a cyclopentylene may optionally be further substituted; or, any two atoms on the cyclohexylene, piperidinylene, piperazinylene, an azetidinylene, an azocyclopentylene, a cyclobutylene and a cyclopentylene may be linked to form a cycloalkyl or heterocyclic group; R a , R b and R c Each is independently selected from hydrogen, deuterium, halogen, oxo, cyano, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; Or, any two R c Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted; Or, R a Linked with L1 to form a cycloalkyl group, a heterocyclic group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group and the heteroaryl group may be further substituted; x, y and z are each independently selected from 0, 1, 2 or 3; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, n13, n14, n15, n16 and n17 are each independently selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is further shown in the general formula (II): Where: R d Selected from hydrogen, halogen or C 1-3 Alkyl; p1 and p2 are each independently selected from 0, 1, 2, 3 or 4; L4 is selected from a bond, -CH2-, -NH-, -O-, -S- or -C(O)-.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl or 9-10 membered bicyclic heterocyclic group; Preferably, ring A is selected from phenyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, benzopyridazinone, benzopyrazolyl or benzopyrrolidinyl; Alternatively, Ring B is selected from cyclohexyl or cyclobutane; Alternatively, ring C is selected from phenyl, 5-6 membered monocyclic heteroaryl, 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic heteroaryl; Preferably, ring C is selected from benzopyridyl, phenyl, pyridyl, benzothiazolyl, benzopyrazinyl, pyridopyrazolyl, pyridotriazolyl, pyridophenyl, benzothiadiazole or benzopyridazinyl.

4. The compound according to claim 1 or 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (II-A): in: Selected from and, when Selected from When ring A is not 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from phenyl, pyridyl, 6. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R a , R b and R c Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkyl, hydroxyl C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group.

7. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R1, R2, R3, R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl C 1-3 Alkyl, hydroxyl C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group.

8. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The L1 is selected from a bond, -C(O)NH-, -NH-, -O-, -NHC(O)-, -C(O)-, -CH2- or -(CH2)2-; L2 is selected from 9. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (II-B): in: L3 and L4 are each independently selected from a bond, -CH2-, -NH-, -O-, -S- or -C(O)-; M6 and M7 are each independently selected from -CR6R7- or -C(O)-; M8 is selected from N or CR8; R6, R7 and R8 are each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; R d Selected from hydrogen, halogen or C 1-3 alkyl; j, p1 and p2 are each independently selected from 0, 1, 2, 3 or 4.

10. The compound according to any one of claims 2, 3, 5-7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of general formula (II) is further represented by general formula (II-C): wherein: M2 is selected from N or CR2; M3 is selected from N or CR3; M4 is selected from N or CR4; M5 is selected from N or CR5; Ring B is selected from cyclohexyl or cyclobutane; Ring C is selected from phenyl, 5-6-membered monocyclic heteroaryl or 10-membered bicyclic heteroaryl; preferably, Ring C is selected from phenyl, pyridyl or benzopyridyl; R a Selected from hydrogen, halogen or C 1-3 Alkyl; R d Selected from hydrogen, halogen or C 1-3 Alkyl; R b are each independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Hydroxyalkyl; R c are each independently selected from hydrogen, cyano, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 Hydroxyalkoxy; R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 y and z are each independently selected from 0, 1, 2 or 3.

11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the compounds in Table 5.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, and the composition according to claim 12 in the preparation of a drug for androgen receptor-regulated related diseases.

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