A benzene ring derivative, composition and pharmaceutical use thereof

Abstract

Disclosed are compounds described by general formula (I) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and intermediates thereof, and uses thereof in AR or AR splice variant related diseases such as cancer. B-L-K (I).

Description

[0001] This application is based on the application with CN application number 202011329463.4, application date November 25, 2020; CN application number 202110006143.3, application date January 11, 2021; CN application number 202110123667.0, application date January 29, 2021; and CN application number 202110403688.8, application date April 16, 2021, which claims priority thereto, and the disclosure of this CN application is incorporated herein in its entirety. TECHNICAL FIELD

[0002] The present application relates to a compound of general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and intermediates and methods of preparation, and uses in AR or AR splice variant related diseases such as tumors or autoimmune system diseases. BACKGROUND

[0003] Androgen receptor (AR) is a hormone nuclear receptor, which can be divided into N-terminal activation region (NTD), DNA binding region (DBD) and ligand binding region (LTD) in structure, and can regulate the expression of genes inducing prostate cancer. Therefore, inhibiting androgen receptor is an effective method for treating prostate cancer. The currently marketed androgen receptor inhibitors such as enzalutamide and bicalutamide mainly play an inhibitory effect by acting on the ligand binding region (LTD) of androgen receptor, but some patients will develop drug resistance due to androgen receptor splice variants (AR-Vs) caused by deletion of LTD fragment during treatment. Preclinical studies have shown that androgen receptor splice variants can accelerate the progression of enzalutamide-resistant prostate cancer, and how to solve the problem of drug resistance has become a concern in clinical medicine.

[0004] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing degradation of the target protein, which can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases, and this technology has received widespread attention in recent years.

[0005] Therefore, it is necessary to develop new AR or AR splice variants (AR-Vs) inhibitors and E3 ubiquitin ligase PROTAC drugs for treating tumor diseases associated with AR or AR splice variants. SUMMARY

[0006] The present application aims to provide a compound with novel structure, good efficacy, high bioavailability, safety, and the ability to inhibit and degrade androgen receptor splice variants for treating diseases associated with AR or AR splice variants, such as autoimmune diseases, inflammatory diseases or cancers.

[0007] The compound of the present application has good activity in inhibiting and / or degrading AR or AR splice variants, good pharmacokinetic properties and bioavailability, oral performance and good safety.

[0008] The present application provides a compound or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the compounds represented by general formula (I),

[0009] B-L-K (I);

[0010] In certain embodiments, L is selected from a bond or C 1-50 hydrocarbyl, wherein 0 to 20 methylene units in said hydrocarbyl are replaced by -Ak-, -Cy-;

[0011] In certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4 or Ak5;

[0012] In certain embodiments, each -Ak- is independently selected from -(CH2) q -, -(CH2) q -, -O-, -O-(CH2) q -, -(CH2) q -NR L -, -NR L -(CH2) q -, -(CH2)q-NR L C(=O)-, -(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q -, -CH=CH-, -Si(R L )2-, -Si(OH)(R L)-, -Si(OH)2-, -P(=O)(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2-, or a bond;

[0013] In certain embodiments, each -Cy- is independently selected from Cy1, Cy2, Cy3, or Cy4;

[0014] In certain embodiments, each -Cy- is independently selected from a bond, 4-8 membered heteromonocyclic, 4-10 membered heteroannular, 5-12 membered heterospiro, 7-10 membered heterobridged, 3-7 membered monocyclic alkyl, 4-10 membered annular alkyl, 5-12 membered spirocyclic alkyl, 7-10 membered bridged alkyl, 5-10 membered heteroaryl, or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic, heteroannular, heterospiro, or heterobridged being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, or C 1-4 alkoxy, said heteroaryl, heteromonocyclic, heteroannular, heterospiro, or heterobridged containing 1 to 4 heteroatoms selected from O, S, N;

[0015] 在某些实施方案中,L选自-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、- Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;

[0016] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5are each independently selected from -(CH2) q -, -(CH2) q -, -(CH2) q -, -(CH2) q -, -(CH2) L -, -(CH2) L -, -(CH2) q -, -(CH2) L -, -(CH2) q -, -(CH2) L -, -(CH2) q -, -(CH2) L -, -(CH2) q -, -(CH2)

[0017] In certain embodiments, L is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;

[0018] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5are each independently selected from -0-, -OCH2-, -CH20-, -OCH2CH2-, -CH2CH20-, -C≡C-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=0)-, -C(=0)CH2NH-, -CH2C(=0)NH-, -C(=0)NH-, or -NHC(=0)-;

[0019] In certain embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-; in certain embodiments, Ak1, Ak2, Ak3, Ak4are each independently selected from -(CH2) q -, O, -(CH2) q -NR L , NR L C(=0), C(=0), C(=0)-(CH2) q -NR L , -C≡C-, or a bond;

[0020] In certain embodiments, L is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, and -Cy1-Ak1-Cy2-Ak2-Cy3-; Ak1, Ak2, and Ak3are each independently selected from -C≡C-, -CH2-, and -CH2-N(CH3)-; Cy1, Cy2, and Cy3are each independently selected from 4-7 membered heteromonocyclic, 4-10 membered heteroannular, 5-12 membered heterospirocyclic ring, said heteromonocyclic, heteroannular, or heterospirocyclic ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =0, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, or C 1-4 alkoxy, said heteromonocyclic, heteroannular, or heterospirocyclic ring contains 1 to 4 heteroatoms selected from O, S, N (preferably N);

[0021] In certain embodiments, L is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, and -Cy1-Ak1-Cy2-Ak2-Cy3-; each Ak1, Ak2, and Ak3is independently selected from -CºC-, -CH2-, and -CH2-N(CH3)-; each Cy1, Cy2, and Cy3is independently selected from

[0022] In certain embodiments, R L each is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl;

[0023] In certain embodiments, R L each is independently selected from H or C 1-6 alkyl;

[0024] In certain embodiments, R L each is independently selected from H or C 1-4 alkyl;

[0025] In certain embodiments, R L each is independently selected from H, methyl, or ethyl;

[0026] In certain embodiments, each Cy1, Cy2, Cy3, Cy4is independently selected from a bond, 4-7 membered heteromonocyclic ring, 4-10 membered heteroannular ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocyclic alkyl, 4-10 membered annular alkyl, 5-12 membered spirocyclic alkyl, 7-10 membered bridged alkyl, 5-10 membered heteroaryl, or 6-10 membered aryl, which aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heteroannular ring, heterospiro ring, or heterobridged ring is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, or C 1-4 alkoxy, which heteroaryl, heteromonocyclic ring, heteroannular ring, heterospiro ring, or heterobridged ring contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0027] In certain embodiments, each of Cy1, Cy2, Cy3, and Cy4is independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocyclic ring (e.g., 4, 5, 6, 7 membered), a 4-10 membered nitrogen-containing heteroannulated ring (e.g., 4, 5, 6, 7, 8, 9, 10 membered), a 5-12 membered nitrogen-containing heterospirocyclic ring (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered), a 7-10 membered nitrogen-containing heterobridged ring (e.g., 7, 8, 9, 10 membered), a 3-7 membered monocyclic alkyl group (e.g., 3, 4, 5, 6, 7 membered), a 4-10 membered annulated alkyl group (e.g., 4, 5, 6, 7, 8, 9, 10 membered), a 5-12 membered spirocyclic alkyl group (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered), a 7-10 membered bridged alkyl group (e.g., 7, 8, 9, 10 membered), a 5-10 membered heteroaryl group (e.g., 5, 6, 7, 8, 9, 10 membered), or a 6-10 membered aryl group (e.g., 6, 7, 8, 9, 10 membered), said heteromonocyclic ring, heteroannulated ring, heterobridged ring, heterospirocyclic ring, cycloalkyl group, aryl group, or heteroaryl group optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =0, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, or C 1-4 alkoxy, said heteromonocyclic ring, heteroannulated ring, heterobridged ring, heterospirocyclic ring, or heteroaryl group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0028] In certain embodiments, Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond or a substituted or unsubstituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spirocyclohexyl, Cyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl Heterocyclohexyl, cyclohexylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazahexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclohexyl, azetidinylpiperidine, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl , cyclopentylspiroazahexyl, cyclohexylspiroazetidinyl, cyclohexylspiroazapentyl, cyclohexylspiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazapentyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazapentyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, azetidinyl spiroazahexyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) moieties selected from H, F, Cl, Br, I, OH, NH2, COOH, CN, ═O, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0029] In certain embodiments, each Cy1, Cy2, Cy3, Cy4is independently selected from one of the following groups:

[0030] when substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, CF3, methyl, =0, hydroxymethyl, COOH, CN, or NH2;

[0031] In certain embodiments, L is selected from a bond, where the left side is connected to B;

[0032] In certain embodiments, L is selected from

[0033]

[0034] where the left side is connected to B;

[0035] In certain embodiments, L is selected from

[0036]

[0037]

[0038]

[0039]

[0040] where the left side is connected to B;

[0041] In certain embodiments, L is selected from where the left side is attached to B;

[0042] In certain embodiments, L is selected from

[0043]

[0044] where the left side is attached to B;

[0045] In certain embodiments, L is selected from where the left side is attached to B;

[0046] In certain embodiments, L is selected from one of the groups in Table L-1, where the left side is attached to B;

[0047] In certain embodiments, B is selected from

[0048] In certain embodiments, B3is selected from 5-6 membered heteroaryl, said heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0049] In certain embodiments, B3is selected from pyrazolyl, oxazolyl, dioxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl;

[0050] In certain embodiments, each W1is independently selected from a bond, -O-, -S-, -NR w1 -, -NR w1 C(=O)-, -NR w1 S(=O)2-, -NR w1 S(=O)2NR w1 -, the left side of which is directly attached to phenyl;

[0051] In certain embodiments, each W1is independently selected from a bond, -O-, -NH-, -NHC(=O)-, -NHS(=O)2-, -NHS(=O)2NH-, -NHS(=O)2N(CH3)-, the left side of which is directly attached to phenyl;

[0052] In certain embodiments, each W2is independently selected from -NR w1 -, - (CR w2 R w3 ) r -, which is directly attached at its left side to the phenyl group;

[0053] In certain embodiments, each W3is independently selected from -O(CR w2 R w3 ) t -, -S(CR w2 R w3 ) t -, -NR w1 (CR w2 R w3 ) t -, which is directly attached at its left side to the phenyl group;

[0054] In certain embodiments, W4is selected from -O-, -S-, -NR w1 -, -NR w1 C(=O)-, -NR w1 S(=O)2-, -NR w1 S(=O)2NR w1 -, which is directly attached at its left side to the phenyl group;

[0055] In certain embodiments, each W4is independently selected from -O-, -NH-, -NHC(=O)-, -NHS(=O)2-, -NHS(=O)2NH-, -NHS(=O)2N(CH3)-, which is directly attached at its left side to the phenyl group;

[0056] In certain embodiments, B is selected from

[0057] In certain embodiments, B is selected from

[0058] In certain embodiments, each R w1 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl;

[0059] In certain embodiments, each R w1 is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl;

[0060] In certain embodiments, each R w2 or Rw3 each independently selected from H, F, Cl, Br, I, OH, CN, COOH, CONH2, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, cyclopropyl, or cyclobutyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, cyclopropyl, or cyclobutyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, -N(R b21 )2, -C(=O)N(R b21 )2, or C 3-6 cycloalkyl, said alkyl, alkoxy, alkenyl, alkynyl, or cycloalkyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0061] In certain embodiments, R w2 , R w3 each independently selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, cyclopropyl, or cyclobutyl, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, cyclopropyl, or cyclobutyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, C

[0062] In certain embodiments, R w2 , R w3 and the carbon atom to which both are attached together form a C 3-6 cycloalkyl or 3- to 8-membered heterocyclyl, said cycloalkyl or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0063] In certain embodiments, R w2 , R w3and the carbon atoms to which they are attached join to form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl group, which is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, CI, Br, I, OH, NH2, CN, CF3, CHF2;

[0064] In certain embodiments, R b1 or R b2 each independently is selected from H, F, CI, Br, I, =0, OH, CN, NO2, COOH, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, C 1-4 alkylthio, -(CH2) n -R b21 , -OR b21 , -N(R b21 )2, -C(=O)N(R b21 )2, -C(=O)OR b21 , -C(=O)R b22 , -NR b21 C(=O)R b22 , -NR b21 S(=O)2R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, CI, Br, I, OH, =0, -N(R b21 )2, CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0065] In certain embodiments, R b1each independently selected from H, F, Cl, Br, I, =O, OH, NH2, NO2, COOH, NHCH3, NHCH2CH3, NHCH(CH3)2, N(CH3)2, N(CH2CH3)2, CN, CF3, CHF2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropyloxy, deuterated methoxy, methylthio, ethylthio, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, wherein the methoxy, ethoxy, propoxy, isopropyloxy, methylthio and ethylthio are optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH and NH2;

[0066] In certain embodiments, R b1 Each independently selected from H, F, Cl, Br, I, =O, OH, NH2, NO2, COOH, NHCH3, NHCH2CH3, NHCH(CH3)2, N(CH3)2, N(CH2CH3)2, CN, CF3, CHF2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropyloxy, OCD3, methylthio, ethylthio, OCH2CH2Cl, OCH2CH2CH2Cl;

[0067] In certain embodiments, R b2 each independently selected from H, F, Cl, Br, I, =O, OH, NH2, NO2, COOH, NHCH3, NHCH2CH3, NHCH(CH3)2, N(CH3)2, N(CH2CH3)2, CN, CF3, CHF2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, NH2;

[0068] In certain embodiments, R b3 Each independently selected from H, F, Cl, Br, I, =O, OH, CN, COOH, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -(CH2) n -R b21 、-OR b21 、-N(R b21)2, -NR b21 )2, -NR b21 C(=O)R b22 , -S(=O)2N(R b21 )2, -NR b21 S(=O)2R b22 , -C(=O)R b22 , -S(=O)2R b22 , said alkyl, alkoxy, alkenyl, alkynyl or alkylthio is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =O, -N(R b21 )2, CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl;

[0069] In certain embodiments, R b3 each independently is selected from the group consisting of H, F, Cl, Br, I, =O, CF3, CHF2, OH, CN, COOH, NH2, CONH2, S(=O)2NH2, S(=O)2CH3, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylthio or ethylthio, said methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylthio or ethylthio is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, NH2;

[0070] In certain embodiments, R b21 each independently is selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, said heteroaryl or heterocyclyl contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0071] In certain embodiments, R b21 each independently is selected from the group consisting of H, C 1-3 alkyl, C 3-6cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 4-6 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, NH2, CN, CF3, COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, said heteroaryl or heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0072] In certain embodiments, R b21 each independently selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br;

[0073] In certain embodiments, R b22 each independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, NH2, CN, CF3, COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, said heteroaryl or heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0074] In certain embodiments, R b22 each independently selected from the group consisting of H, methyl, ethyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, said methyl, ethyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br;

[0075] In certain embodiments, B is selected from the group consisting of

[0076] In certain embodiments, B is selected from the group consisting of

[0077] In certain embodiments, R b11 Each independently selected from F, Cl, Br, CF3, CN, NO2;

[0078] In certain embodiments, R b12 Each independently selected from H, OCH3, OCD3, OCH2CH3, OCH2CH2Cl;

[0079] In certain embodiments, R b12 Each independently selected from H, OCH3, OCH2CH3, OCH2CH2Cl, OCH2CH2CH2Cl;

[0080] In certain embodiments, B is selected from

[0081] In certain embodiments, B is selected from

[0082] In certain embodiments, B is selected from one of the groups in Table B-1, the right side of which is directly connected to L;

[0083] In certain embodiments, B is selected from one of the groups in Table B-2, the right side of which is directly connected to L;

[0084] In certain embodiments, K is selected from

[0085] In certain embodiments, K is selected from

[0086] In certain embodiments, K is selected from

[0087] In certain embodiments, K is selected from

[0088]

[0089] In certain embodiments, K is selected from

[0090] In certain embodiments, Q is each independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -CO-, -NR q CO-, -CONR q -, or a 3-12 membered heterocyclyl, said heterocyclyl optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0091] In certain embodiments, Q is each independently selected from -O-, -S-, -CH2-, -NR q -, -CO-, -NR q CO-, -CONR q -, or a 4-7 membered heterocyclyl, said heterocyclyl optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0092] In certain embodiments, R q is selected from H or C 1-6 alkyl;

[0093] In certain embodiments, R q is selected from H or C 1-4 alkyl;

[0094] In certain embodiments, R q is selected from H, methyl, ethyl;

[0095] In certain embodiments, E is each independently selected from C 3-10 carbocyclyl, C6-10 Aryl, 3-12 membered heterocyclic group or 5-12 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0096] In certain embodiments, each E is independently selected from C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0097] In certain embodiments, each E is independently selected from C 3-8 a carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring, an 8-12 membered heterocyclic ring, a 7-12 membered heteroaryl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic ring or heteroaryl group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0098] In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, oxazolyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl, or 1,2,3,4-tetrahydroisoquinolinyl;

[0099] In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;

[0100] In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl;

[0101] In certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;

[0102] In certain embodiments, A, H1, or H2 are each independently selected from C 3-8 A carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring or a 5-6 membered heteroaryl group, wherein the heterocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0103] In certain embodiments, A, H1 or H2 are each independently selected from phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl; In certain embodiments, A, H1 or H2 are each independently selected from phenyl or pyridinyl;

[0104] In certain embodiments, each F is independently selected from C 3-20 Carbocyclic group, C 6-20aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl, the heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0105] In certain embodiments, each F is independently selected from 3-7 membered monocyclic alkyl, 4-10 membered annulated alkyl, 5-12 membered spirocyclic alkyl, 5-10 membered bridged alkyl, 4-7 membered heteromonocyclic, 4-10 membered heteroannulated, 5-12 membered heterosprio, 5-10 membered heterobridged, C 6-14 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl, the heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0106] In certain embodiments, each F is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthryl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazoloimidazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridinopyridinyl, pyridinopyrazinyl, pyridinopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl, or pyrazinopyrazinyl;

[0107] In certain embodiments, each R k2 is independently selected from a bond, -CO-, -SO2-, -SO-, or -C(R k3 )2-;

[0108] In certain embodiments, each R k2 is independently selected from -CO-, -SO2-, or -C(R k3 )2-;

[0109] In certain embodiments, each R k1 is independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 alkyl, or C 1-6 alkoxy, the alkyl or alkoxy optionally further being substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C1-4 alkyl or C 1-4 substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C

[0110] In certain embodiments, R k3 each is independently selected from the group consisting of H, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0111] In certain embodiments, R k1 , R k3 each is independently selected from the group consisting of H, F, CI, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from the group consisting of H, F, CI, Br, I, OH, NH2;

[0112] In certain embodiments, R k1 , R k3 each is independently selected from the group consisting of H, F, CI, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy being optionally further substituted by 0 to 4 substituents selected from the group consisting of H, F, CI, Br, I, OH, NH2;

[0113] In certain embodiments, two R k3 and the carbon atom or ring skeleton to which both are directly attached together form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring being optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0114] In certain embodiments, two R k3 and the carbon atom or ring backbone to which they are both attached together form a 3-6 membered carbocyclic ring or a 3-7 membered heterocyclic ring, which is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 heteroatoms selected from O, S, N;

[0115] In certain embodiments, R k4 are each independently selected from the group consisting of H, OH, NH2, CN, CONH2, C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, which alkyl, cycloalkyl, or heterocyclyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 heteroatoms selected from O, S, N;

[0116] In certain embodiments, R k4 are each independently selected from the group consisting of H, OH, NH2, CF3, CN, C 1-4 alkyl;

[0117] In certain embodiments, R k5 are each independently selected from the group consisting of CO, CH2, SO2, or

[0118] In certain embodiments, R k6 are each independently selected from the group consisting of CO, CH, SO, SO2, CH2, or N;

[0119] In certain embodiments, R k7 are each independently selected from the group consisting of CO, CH, N, CH2, O, S, N(CH3), or NH;

[0120] In certain embodiments, R k7 are each independently selected from the group consisting of CH2, O, N(CH3), or NH;

[0121] In certain embodiments, R k8 are each independently selected from the group consisting of C, N, or CH;

[0122] In certain embodiments, R k9 are each independently selected from the group consisting of CO, SO2, or CH2;

[0123] In certain embodiments, M1is selected from a bond, -CH2-C(=O)NH-, or -C(=O)CH2NH-;

[0124] In certain embodiments, M2is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl, or 4-10 membered heterocyclyl, said alkyl, cycloalkyl, or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, =O, OH, NH2, C 1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0125] In certain embodiments, M3is selected from -NH- or -O-;

[0126] In certain embodiments, R k10 is selected from C 1-6 alkyl, said alkyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, =O, OH, C 1-6 alkyl, or C 3-6 alkenyl, or C

[0127] In certain embodiments, G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =O, CF3, CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 alkyl, said heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of N, O, S;

[0128] In certain embodiments, R k11 are each independently selected from the group consisting of H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylthio, or -O-C(=O)-C 1-6 alkyl, said alkyl, alkoxy, or alkylthio being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, C 1-4 alkyl, or C1-4 substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, =0, OH, NH2, C

[0129] In certain embodiments, R k12 , R k13 are each independently selected from the group consisting of H, C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, =0, OH, NH2, C 1-4 alkyl or C 1-4 alkoxy;

[0129] In certain embodiments, R k14 is selected from the group consisting of 5-6 membered heteroaryl, said heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, CF3, CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of N, O, S;

[0129] In certain embodiments, K is selected from the group consisting of

[0130] In certain embodiments, K is selected from the group consisting of

[0131] In certain embodiments, K is selected from the group consisting of

[0132]

[0133] In certain embodiments, K is selected from the group consisting of

[0134] In certain embodiments, K is selected from the group consisting of

[0135] In certain embodiments, K is selected from the group consisting of

[0136] In certain embodiments, K is selected from the group consisting of

[0137] In certain embodiments, K is selected from one of the groups in Table K-1, with L attached to the left side;

[0138] In certain embodiments, K is selected from one of the groups in Table K-1, with L attached to the left side;

[0139] In certain embodiments, each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0140] In certain embodiments, each of n, q, r, t is independently selected from 0, 1, 2, 3, or 4;

[0141] In certain embodiments, each of m1, m2, m3, n1, n2, n3 is independently selected from 0, 1, 2, or 3;

[0142] In certain embodiments, r is selected from 1 or 2;

[0143] In certain embodiments, each t is independently selected from 0, 1, or 2;

[0144] In certain embodiments, each q is independently selected from 0, 1, or 2;

[0145] In certain embodiments, each of p1or p2is independently selected from 0, 1, 2, 3, 4, or 5;

[0146] In certain embodiments, each of p1or p2is independently selected from 0, 1, or 2;

[0147] In certain embodiments, when B is selected from then at least one of Cy1, Cy2, Cy3, Cy4cannot be a bond, and when three of them are selected from a bond, the remaining one cannot be selected from triazolyl;

[0148] In certain embodiments, when B is selected from then at least one of Cy1, Cy2, Cy3, Cy4cannot be a bond, and when three of them are selected from a bond, the remaining one cannot be selected from triazolyl.

[0149] As a first embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

[0150] L is selected from a bond or C 1-50hydrocarbyl, wherein 0 to 20 methylene units in said hydrocarbyl are replaced by -Ak-, -Cy-;

[0151] each -Ak- is independently selected from -(CH2) q -, -(CH2) q -O-, -O-(CH2) q -, -(CH2) q -NR L -, -NR L -(CH2) q -, -(CH2)q-NR L C(=O)-, -(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q -, -CH=CH-, -Si(R L )2-, -Si(OH)(R L )-, -Si(OH)2-, -P(=O)(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond;

[0152] each q is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0153] R L is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;

[0154] each -Cy- is independently selected from a bond, 4-8 membered heteromonocyclic, 4-10 membered heteroannulated, 5-12 membered heterospiro, 7-10 membered heterobridged, 3-7 membered monocycloalkyl, 4-10 membered annulocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridgedcycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic, heteroannulated, heterospiro or heterobridged optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl or C 1-4 alkoxy, said heteroaryl, heteromonocyclic, heteroannulated, heterospiro or heterobridged containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0155] B is selected from

[0156] W1is independently at each occurrence selected from a bond, -O-, -S-, -NR w1 -, -NR w1 C(=O)-, -NR w1 S(=O)2-, -NR w1 S(=O)2NR w1 - which is directly attached at its left side to the phenyl group;

[0157] W2is independently at each occurrence selected from -NR w1 -, -(CR w2 R w3 ) r - which is directly attached at its left side to the phenyl group;

[0158] W3is independently at each occurrence selected from -O(CR w2 R w3 ) t -, -S(CR w2 R w3 ) t -, -NR w1 (CR w2 R w3 ) t - which is directly attached at its left side to the phenyl group;

[0159] W4is selected from -O-, -S-, -NR w1 -, -NR w1 C(=O)-, -NR w1 S(=O)2-, -NR w1 S(=O)2NR w1 - which is directly attached at its left side to the phenyl group;

[0160] B3is selected from a 5-6 membered heteroaryl, said heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0161] R w1 is independently at each occurrence selected from H, C 1-4 alkyl, C 3-6 cycloalkyl;

[0162] R w2 or R w3 is independently at each occurrence selected from H, F, Cl, Br, I, OH, CN, COOH, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, -N(R b21)2, -C(=O)N(R b21 )2, or C 3-6 cycloalkyl, said alkyl, alkoxy, alkenyl, alkynyl, or cycloalkyl optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 alkyl, C 1-4 halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0163] R w2 , R w3 and the carbon atoms to which both are attached together form a C 3-6 cycloalkyl, said cycloalkyl optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 alkyl, C 1-4 halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0164] R b1 or R b2 each independently selected from the group consisting of H, F, Cl, Br, I, =O, OH, CN, NO2, COOH, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, C 1-4 deuterated alkoxy, C 1-4 alkylthio, -(CH2) n -R b21 , -OR b21 , -N(R b21 )2, -C(=O)N(R b21 )2, -C(=O)OR b21 , -C(=O)R b22 , -NR b21 C(=O)R b22 , -NR b21 S(=O)2R b22 , C 3-6 cycloalkyl, C 6-10aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with from 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, -N(R b21 )2, CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing from 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0165] R b3 each independently selected from the group consisting of H, F, Cl, Br, I, =0, OH, CN, COOH, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -(CH2) n -R b21 , -OR b21 , -N(R b21 )2, -C(=0)N(R b21 )2, -NR b21 C(=0)R b22 , -S(=0)2N(R b21 )2, -NR b21 S(=0)2R b22 , -C(=0)R b22 , -S(=0)2R b22 , said alkyl, alkoxy, alkenyl, alkynyl, or alkylthio is optionally further substituted with from 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, -N(R b21 )2, CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl;

[0166] R b21 each independently selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, NH2, CN, CF3, COOH, CONH2, CH2OH, CH2NH2, CH2NH-C(=0)-NH2, C(=0)NH2, C(=0)OH, C(=0)OR 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, said heteroaryl or heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0167] R b22 each independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, NH2, CN, CF3, COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, said heteroaryl or heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0168] wherein K is selected from the group consisting of

[0169] Q is each independently selected from the group consisting of a bond, -0-, -S-, -CH2-, -NR q -, -CO-, -NR q CO-, -CONR q or 3-12 membered heterocyclyl, said heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from the group consisting of H, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from the group consisting of O, S, N;

[0170] R q selected from the group consisting of H or C 1-6 alkyl;

[0171] A is selected from the group consisting of C 3-10 carbocyclyl, C 6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0172] F is each independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0173] R k2 is each independently selected from a bond, -CO-, -SO2-, -SO-, or -C(R k3 )2-;

[0174] R k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 alkyl, or C 1-6 alkoxy, said alkyl or alkoxy optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl, or C 1-4 alkoxy;

[0175] R k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, or heterocyclyl optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0176] or two R k3 and the carbon atom or ring backbone to which they are both directly attached together form a 3-8 membered carbocyclic or 3-8 membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl, or C 1-4The heterocyclic ring is substituted by an alkoxy substituent, wherein the heterocyclic ring contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0177] R k4 Each independently selected from H, OH, NH2, CN, CONH2, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, 4) groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0178] M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-;

[0179] M2 is selected from -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, 4) groups selected from H, F, Cl, Br, I, =O, OH, NH2, C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0180] M3 is selected from -NH- or -O-;

[0181] R k10 Selected from C 1-6 Alkyl, wherein the alkyl is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, 4) selected from H, F, Cl, Br, I, ═O, OH, C 1-6 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0182] R k11 Each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio or -OC(=O)-C 1-6 Alkyl, the alkyl, alkoxy or alkylthio group is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, 4) groups selected from H, F, Cl, Br, I, OH, C 1-4alkyl or C 1-4 substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, =0, OH, NH2, C

[0183] R k12 , R k13 each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, =0, OH, NH2, C 1-4 alkyl or C 1-4 substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, =0, OH, NH2, C

[0184] R k14 selected from 5-6 membered heteroaryl, said heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, CF3, CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, O, S;

[0185] G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =0, CF3, CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, O, S;

[0186] n, r, t are each independently selected from 0, 1, 2, 3 or 4;

[0187] m1, m2, m3, n1, n2, n3 are each independently selected from 0, 1, 2 or 3;

[0188] p1or p2are each independently selected from 0, 1, 2, 3, 4 or 5.

[0189] As a second embodiment of the present application, the aforementioned compounds represented by the general formula (I) or a stereoisomer, a deuterated compound, a solvate, a pro-drug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

[0190] L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-;

[0191] Ak1, Ak2, Ak3, Ak4are each independently selected from -(CH2) q -, O, -(CH2) q -NR L , NR L C(=O), C(=O), C(=O)-(CH2) q -NR L , -C≡C- or a bond;

[0192] q is each independently selected from 0, 1, 2, 3 or 4;

[0193] R L is each independently selected from H or C 1-6 alkyl;

[0194] Cy1, Cy2, Cy3or Cy4is selected from a bond, 4-7 membered heteromonocyclic ring, 4-10 membered heteroannular ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocyclic alkyl, 4-10 membered annular alkyl, 5-12 membered spiroalkyl, 7-10 membered bridged alkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heteroannular ring, heterospiro ring or heterobridged ring optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy, said heteroaryl, heteromonocyclic ring, heteroannular ring, heterospiro ring or heterobridged ring containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0195] with the proviso that at least one of Cy1, Cy2, Cy3, Cy4cannot be a bond, and when three of them are selected from a bond, the remaining one cannot be selected from triazolyl;

[0196] the remaining groups are defined the same as in the first embodiment of the invention.

[0197] As a third embodiment of the present invention, the aforementioned compounds represented by the general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

[0198] Cy1, Cy2, Cy3and Cy4are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocyclic ring, a 4-10 membered nitrogen-containing heteroannular ring, a 5-12 membered nitrogen-containing heterospiro ring, a 7-10 membered nitrogen-containing heterobridged ring, a 3-7 membered monocyclic alkyl group, a 4-10 membered annular alkyl group, a 5-12 membered spirocyclic alkyl group, a 7-10 membered bridged alkyl group, a 5-10 membered heteroaryl group, or a 6-10 membered aryl group, said heteromonocyclic ring, heteroannular ring, heterobridged ring, heterospiro ring, annular alkyl group, aryl group, or heteroaryl group optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =0, C 1-4 halo-substituted C 1-4 halo-substituted C 1-4 halo-substituted C 1-4 halo-substituted C

[0199] R L each independently selected from H or C 1-4 alkyl;

[0200] R w1 each independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl;

[0201] R w2 or R w3 each independently selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, propoxy, cyclopropyl, or cyclobutyl, said methyl, ethyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, propoxy, cyclopropyl, or cyclobutyl optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, NH2;

[0202] alternatively, R w2 , R w3 and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl group, said cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl group optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2;

[0203] R b1each independently selected from H, F, CI, Br, I, =0, OH, NH2, N02, COOH, NHCH3, NHCH2CH3, NHCH(CH3)2, N(CH3)2, N(CH2CH3)2, CN, CF3, CHF2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, deuterated methoxy, methylthio, ethylthio, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, CI, Br, I, OH, NH2;

[0204] R b2 each independently selected from H, F, CI, Br, I, =0, OH, NH2, N02, COOH, NHCH3, NHCH2CH3, NHCH(CH3)2, N(CH3)2, N(CH2CH3)2, CN, CF3, CHF2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, deuterated methoxy, methylthio, ethylthio, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, CI, Br, I, OH, NH2;

[0205] R b3 each independently selected from H, F, CI, Br, I, =0, OH, NH2, N02, COOH, NHCH3, NHCH2CH3, NHCH(CH3)2, N(CH3)2, N(CH2CH3)2, CN, CF3, CHF2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, deuterated methoxy, methylthio, ethylthio, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) substituents selected from H, F, CI, Br, I, OH, NH2;

[0206] r is selected from 1 or 2;

[0207] t is each independently selected from 0, 1, or 2;

[0208] K is selected from

[0209] or K is selected from

[0210] the ring is selected from an aromatic or non-aromatic ring;

[0211] each Q is independently selected from -O-, -S-, -CH2-, -NR q -, -CO-, -NR q CO-, -CONR q - or a 4-7 membered heterocyclyl, said heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2;

[0212] R q is selected from H or C 1-4 alkyl;

[0213] R k1 , R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2;

[0214] or two R k3 and the carbon atom or ring backbone to which they are both directly attached together form a 3-6 membered carbocyclic ring or a 3-7 membered heterocyclic ring, said carbocyclic or heterocyclic ring being optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2;

[0215] R k4 are each independently selected from H, OH, NH2, CF3, CN, C 1-4 alkyl;

[0216] R k5 are each independently selected from CO, CH2, SO2or

[0217] R k6each independently selected from CO, CH, SO, SO2, CH2, or N;

[0218] R k7 each independently selected from CO, CH, N, CH2, O, S, N(CH3), or NH;

[0219] R k8 each independently selected from C, N, or CH;

[0220] R k9 each independently selected from CO, SO2, or CH2;

[0221] A, H1, or H2are each independently selected from C 3-8 carbocycle, phenyl ring, 4-7 membered heterocycle, or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

[0222] E are each independently selected from C 3-8 carbocycle, phenyl ring, 4-7 membered heterocycle, 8-12 membered heterocycle, 7-12 membered heteroaryl, or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0223] F are each independently selected from 3-7 membered monocycloalkyl, 4-10 membered bicycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4-7 membered heteromonocycle, 4-10 membered heterobicycle, 5-12 membered heterosprio, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, said heteromonocycle, heterobicycle, heterosprio, heterobridged ring, or heteroaryl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;

[0224] the remaining groups are defined the same as in any of the first, second, third, or fourth embodiments of the application.

[0225] As a fourth embodiment of the application, the aforementioned compounds represented by the general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

[0226] R L selected from H, methyl, or ethyl;

[0227] each q is independently selected from 0, 1, or 2;

[0228] Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spirocyclopentyl, cyclopropyl-cyclohex ... Spirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylpiperidine, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylazetidinyl, cyclopentylpiperidine, cyclohexylazetidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl, Cyclohexylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazahexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylpiperidine, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiro Spiroazahexyl, cyclohexylspiroazetidinyl, cyclohexylspiroazapentyl, cyclohexylspiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazapentyl, azetidinyl spiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazapentyl, azetidinyl spiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazapentyl, azetidinyl spiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazapentyl, azetidinyl spiroazahexyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) moieties selected from H, F, Cl, Br, I, OH, NH2, COOH, CN, ═O, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0229] B is selected from

[0230] or B is selected from

[0231] K is selected from

[0232]

[0233] or K is selected from

[0234] E is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;

[0235] A is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;

[0236] F is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthryl, phenanthryl, azetidinyl, azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzo pyridyl, benzo pyrazinyl, benzo pyrimidinyl, benzo pyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazolopyrimidinyl, imidazolopyridinyl, imidazolopyrazinyl, imidazolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl, or pyrazinopyrazinyl;

[0237] R k7 are each independently selected from CH2, O, N(CH3), or NH;

[0238] p1or p2are each independently selected from 0, 1, or 2;

[0239] the remaining groups are defined as in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, or fortieth embodiment of the application.

[0240] As a fifth embodiment of the application, compounds of general formula (I) as described before or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

[0241] Cy1, Cy2, Cy3, Cy4are each independently selected from the group consisting of a bond or a substituted or unsubstituted group: when substituted, optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) substituents selected from H, F, CF3, methyl, =0, hydroxymethyl, COOH, CN or NH2;

[0242] K is selected from

[0243]

[0244] or K is selected from

[0245] the remaining groups are defined as in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, or fortieth embodiment of the application.

[0246] As a sixth embodiment of the application, compounds of general formula (I) as described before or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

[0247] L is selected from a bond, wherein the left side is connected to B;

[0248] or L is selected from

[0249]

[0250] wherein the left side is attached to B;

[0251] or L is selected from

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] wherein the left side is attached to B;

[0258] or L is selected from wherein the left side is attached to B;

[0259] or L is selected from

[0260]

[0261]

[0262] wherein the left side is attached to B;

[0263] the remaining groups are the same as in any of the first, second, third, fourth, or fifth embodiments of the application.

[0264] As a seventh embodiment of the application, the foregoing compound represented by the general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

[0265] L is selected from -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-,- Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;

[0266] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -, -(CH2) q -, -(CH2) q -, -(CH2) q -, -(CH2) L -, -(CH2) L -, -(CH2) q -, -(CH2)q-NR L -, -(CH2) q -, -(CH2) L -, -(CH2) q -, -(CH2) L -, -(C≡C) q - or a bond;

[0267] q is each independently selected from 0, 1, 2, 3 or 4;

[0268] R L are each independently selected from H or C 1-6 alkyl;

[0269] Cy1, Cy2, Cy3and Cy4are defined as in the first embodiment of the present application.

[0270] As an eighth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

[0271] Ak1, Ak2, Ak3, Ak4, Ak5, q, R L , Cy1, Cy2, Cy3, Cy4, K, R b1 , R b2 , R b3 , R w1 , R w2 , R w3 , r or t is the same as defined in any one of the first or third embodiments of the present application.

[0272] As a ninth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

[0273] Ak1, Ak2, Ak3, Ak4, Ak5, q, r, t, R L , Cy1, Cy2, Cy3, Cy4, K, R b1 , R b2 , R b3 , R w1 , R w2 , R w3 , B or K is the same as defined in any one of the first, third, or fourth embodiments of the present application.

[0274] As a tenth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

[0275] Ak1, Ak2, Ak3, Ak4, Ak5, q, r, t, R L , Cy1, Cy2, Cy3, Cy4, K, R b1 , R b2 , R b3 , R w1 , R w2 , R w3 , B or K is the same as defined in any one of the first, third, fourth, or fifth embodiments of the present application.

[0276] As an eleventh embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

[0277] L is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;

[0278] Ak1, Ak2, Ak3, Ak4, Ak5are each independently selected from -O-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -CºC-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0279] the remaining groups are defined as in any one of the first, third, fourth, fifth embodiments of the present application.

[0280] As a twelfth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein

[0281] L is selected from wherein the left side is connected to B;

[0282] the remaining groups are defined as in any one of the first, third, fourth, fifth, eleventh embodiments of the present application.

[0283] As a thirteenth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein

[0284] B is selected from

[0285] or B is selected from

[0286] R b11 each independently selected from F, Cl, Br, CF3, CN, NO2;

[0287] R b12each independently selected from H, OCH3, OCD3, OCH2CH3, OCH2CH2Cl, OCH2CH2CH2Cl;

[0288] K is selected from

[0289] or K is selected from

[0290] the remaining groups are defined the same as in any of the first, second, third, fourth, fifth, sixth, eleventh, twelfth embodiments of the application.

[0291] As a fourteenth embodiment of the application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

[0292] B is selected from

[0293] or B is selected from

[0294] K is selected from

[0295] or K is selected from

[0296] the remaining groups are defined the same as in any of the first, second, third, fourth, fifth, sixth, eleventh, twelfth embodiments of the application.

[0297] As a fifteenth embodiment of the application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

[0298] B is each independently selected from one of the groups in Table B-1, preferably from one of the groups in Table B-2, which is right side connected to L;

[0299] R b11 each independently selected from F, Cl, Br, CF3, CN, NO2;

[0300] R b12 each independently selected from H, OCH3, OCD3, OCH2CH3, OCH2CH2Cl;

[0301] L is each independently selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Ak2-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-;

[0302] L is preferably selected from one of the groups in Table L-1, which is right side connected to K;

[0303] Ak1, Ak2, Ak3are each independently selected from -C≡C-, -CH2-, -CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)- or -CH2NH-;

[0304] Cy1, Cy2and Cy3are each independently selected from 4-7 membered heteromonocyclic, 4-10 membered heteroannular, 5-12 membered heterospiro ring, which is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy, which heteromonocyclic, heteroannular or heterospiro ring contains 1 to 4 heteroatoms selected from O, S, N (preferably N);

[0305] K is each independently selected from one of the groups in Table K-1, which is left side connected to L.

[0306] As a sixteenth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

[0307] Cy1, Cy2, Cy3are each independently selected from one of the following groups:

[0308] Ak1, Ak2, Ak3, R b11 , R b12 , L, B or K are defined as in the fifteenth embodiment of the present application.

[0309] As a seventeenth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein

[0310] each B is independently selected from one of the groups in Table B-2, which is connected to L on the right;

[0311] each L is independently selected from one of the groups in Table L-1, which is connected to K on the right;

[0312] each K is independently selected from one of the groups in Table K-1, which is connected to L on the left.

[0313] The present application relates to a compound selected from one of the following structures (Table D) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof:

[0314] Table D

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344] Table L-1

[0345]

[0346]

[0347]

[0348] Table B-1

[0349]

[0350] Compound R in Table B-1 b11 each independently selected from F, CI, Br, CF3, CN, N02, preferably from CF3or CN, R b12 each independently selected from H, OCH3, OCD3, OCH2CH3, OCH2CH2CI.

[0351] Table B-2

[0352]

[0353] Table K-1

[0354]

[0355] In certain embodiments, the pharmaceutically acceptable salt of the compound is a trifluoroacetate salt thereof.

[0356] The present application relates to a pharmaceutical composition comprising the above-mentioned compound of the present application or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

[0357] The present application relates to the use of the above-mentioned compound of the present application or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the manufacture of a medicament for treating a disease associated with AR or AR splice mutant activity or expression.

[0358] The present application relates to the use of the above-mentioned compound of the present application or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the manufacture of a medicament for treating a disease associated with inhibiting or degrading AR or AR splice mutant.

[0359] The present application relates to the use of the above-mentioned compound of the present application or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the manufacture of a medicament for treating a disease associated with inhibiting or degrading AR or AR splice mutant.

[0360] The present application relates to a method of inhibiting or degrading AR or AR splice mutant, comprising the step of contacting the above-mentioned compound or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof with a cell.

[0361] In certain embodiments, the cell is a cell from a subject.

[0362] The present application relates to a method of treating a disease associated with abnormal AR or AR splice mutant activity or expression, comprising the step of administering to a subject in need thereof an effective amount of the above-mentioned compound or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

[0363] In certain embodiments, the disease is selected from an autoimmune disease, an inflammatory disease, or a cancer. In certain embodiments, the cancer is prostate cancer, for example, enzalutamide-resistant prostate cancer.

[0364] The present application relates to the above-mentioned compounds or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, for use in inhibiting or degrading AR or AR splice variants.

[0365] The present application relates to the above-mentioned compounds or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, for use in treating diseases associated with abnormal activity or expression of AR or AR splice variants.

[0366] In certain embodiments, the disease is selected from an autoimmune disease, an inflammatory disease, or a cancer. In certain embodiments, the cancer is prostate cancer, for example, enzalutamide-resistant prostate cancer.

[0367] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0368] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present application include their isotopic cases, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0369] “Halogen” refers to F, Cl, Br or I.

[0370] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0371] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0372] "Hydrocarbyl" refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group consisting of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.

[0373] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X(CH2)vX(CH2)vX(CH2)vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, including but not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0374] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0375] "Heteroalkylene" refers to a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X(CH2)vX(CH2)vX(CH2)v-, where v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0376] "Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having from 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and the like. Cycloalkyl groups as they occur herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0377] "Heterocycloalkyl" means a substituted or unsubstituted saturated heteroatom-containing carbocyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, or S, and optionally substituted N, S in the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be attached at a heteroatom or a carbon atom, heterocycloalkyl groups can be attached to an aromatic ring or a non-aromatic ring, heterocycloalkyl groups can be attached with a bridged ring or a spirocyclic ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0378] "Alkenyl" means a substituted or unsubstituted straight chain and branched chain unsaturated hydrocarbon group having at least one, typically one, two, or three carbon-carbon double bonds, the main chain including but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms, examples of alkenyl groups include but are not limited to ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the like; alkenyl groups as they occur herein are as defined above. Alkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0379] "Alkynyl" refers to a substituted or unsubstituted linear or branched monovalent unsaturated hydrocarbon radical having at least one, typically one, two or three carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone chain. Examples of alkynyl radicals include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pent ... -methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0380] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0381] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be optionally a monocyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0382] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0383] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n heteroatoms.

[0384] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0385] "Fused" or "fused ring" means a polycyclic group in which each ring in the system shares a pair of adjacent atoms with another ring in the system, where one or more of the rings can contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and can be substituted or unsubstituted, and each ring in the fused ring system can contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=0) n or O, where n is 0, 1, or 2). The number of ring atoms in a fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

[0386] "Fused" or "fused ring" can be monovalent, divalent, trivalent, or tetravalent.

[0387] "Bridge" or "bridged ring" means a polycyclic group containing any two non-adjacent atoms, which can be substituted or unsubstituted, can contain 0 or more double bonds, and any ring in the bridged ring system can contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=0) n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane, adamantane. "Bridge" or "bridged ring" can be monovalent, divalent, trivalent, or tetravalent.

[0388] "Carbospiro" or "spiro carbocyclic group" or "spiro carbon ring group" or "carbospiro group" means a "spiro ring" in which the ring system consists only of carbon atoms. As used herein, "carbospiro" or "spiro carbocyclic group" or "spiro carbon ring group" or "carbospiro group" is defined as a spiro ring.

[0389] "Carbospiro" or "spiro carbocyclic group" or "spiro carbon ring group" or "carbospiro group" means a "spiro ring" in which the ring system consists only of carbon atoms. As used herein, "carbospiro" or "spiro carbocyclic group" or "spiro carbon ring group" or "carbospiro group" is defined as a spiro ring.

[0390] "Carbospiro" or "spiro carbocyclic group" or "spiro carbon ring group" or "carbospiro group" means a "spiro ring" in which the ring system consists only of carbon atoms. As used herein, "carbospiro" or "spiro carbocyclic group" or "spiro carbon ring group" or "carbospiro group" is defined as a spiro ring.

[0391] "Heteromonocyclic" or "monocyclic heterocyclic group" or "heteromonocyclic group" means a "heterocyclic group" or "heterocycle" of a monocyclic ring system. As used herein, "heterocyclic group," "monocyclic heterocyclic group," or "heteromonocyclic group" is defined as a heterocycle.

[0392] "Heteroannulated" or "heteroannulated ring" means an "annulated ring" containing heteroatoms. As used herein, "heteroannulated" or "heteroannulated ring" is defined in accordance with annulated rings.

[0393] "Heterospiro" or "heterospiro ring" means a "spiro ring" containing heteroatoms. As used herein, "heterospiro" or "heterospiro ring" is defined in accordance with spiro rings.

[0394] "Heterobridged" or "heterobridged ring" means a "bridged ring" containing heteroatoms. As used herein, "heterobridged" or "heterobridged ring" is defined in accordance with bridged rings.

[0395] "Aryl" or "aromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group having a single ring or fused rings, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring that is attached to the parent structure along with the aryl ring is an aryl ring, non-limiting examples including benzene, naphthalene, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the point of attachment is on the aryl ring.

[0396] "Heteroaryl" or "heteroaromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including, but not limited to, N, O, or S(=O) n , n is 0, 1, 2, and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring that is attached to the parent structure along with the heteroaryl ring is a heteroaryl ring, non-limiting examples including As used herein, "heteroaryl" is defined in accordance with the present definition. Heteroaryl can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the point of attachment is on the heteroaryl ring.

[0397] "5-membered ring fused 5-membered heteroaromatic ring" means a 5 fused 5-membered fused heteroaromatic ring, at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), the entire group is aromatic, non-limiting examples include pyrrolopyrrole, pyrazolopyrrole, pyrazolopyrazole, pyrrolofuran, pyrazolofuran, pyrrolothiophene, pyrazolothiophene.

[0398] "5-membered ring fused 5-membered heteroaromatic ring" means a 5 fused 5-membered fused heteroaromatic ring, at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), the entire group is aromatic, non-limiting examples include pyrrolopyrrole, pyrazolopyrrole, pyrazolopyrazole, pyrrolofuran, pyrazolofuran, pyrrolothiophene, pyrazolothiophene.

[0399] "substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanide, aryl, heteroaryl, heterocyclyl, bridged ring group, spiro ring group, annular ring group, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a , -O-(CH2) m -C(=O)-R a , -(CH2) m -C(=O)-NR b R c , -(CH2) m S(=O) n R a , -(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c , etc., wherein R b and R c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethylsulfonyl, optionally R b and R c form a five or six-membered ring alkyl or heterocyclyl, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring group, spiro ring group or annular ring group.

[0400] "1 to 5 heteroatoms selected from O, S, N" means 1, 2, 3, 4, or 5 heteroatoms selected from O, S, N.

[0401] "0 to X substituents selected from…" means 0, 1, 2, 3, … X substituents selected from…, where X is any integer between 1 and 10. For example, "0 to 4 substituents selected from…" means 0, 1, 2, 3, or 4 substituents selected from…. For example, "0 to 5 substituents selected from…" means 0, 1, 2, 3, 4, or 5 substituents selected from…. For example, "heterocyclo ring is optionally further substituted with 0 to 4 substituents selected from H or F" means the heterocyclo ring is optionally further substituted with 0, 1, 2, 3, or 4 substituents selected from H or F.

[0402] A ring of X-Y members (X is an integer less than Y and greater than or equal to 3, Y is any integer between 4 and 12) includes rings of X+1, X+2, X+3, X+4, … Y members. A ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterobicyclic ring, a heterospirocyclic ring, or a heterocyclo ring. For example, "4-7 membered heteromonocyclic ring" means a 4 membered, 5 membered, 6 membered, or 7 membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" means a 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, or 10 membered heterobicyclic ring.

[0403] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or free bases, and is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0404] "Pharmaceutical composition" means a mixture of one or more compounds of the present application, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, and other chemical components, where the "other chemical components" means a pharmaceutically acceptable carrier, excipient, and / or one or more other therapeutic or active agents.

[0405] "Carrier" means a material that does not itself induce an immune response, and does not abrogate the biological activity and properties of an administered compound.

[0406] "Excipient" means an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, including microcrystalline cellulose, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, and disintegrating agents.

[0407] "Prodrug" means a compound which is converted into a biologically active compound of the application after in vivo administration. Prodrugs of the application are prepared by modifying the amino or carboxyl groups of the compounds of the application in such a way that the modifications can be easily removed in vivo after administration to provide the parent compound. When a prodrug of the application is administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0408] "Co-crystal" means a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein both the pure state of the API and the pure state of the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystals are multi-component crystals, including both binary co-crystals formed between two neutral solids, and multi-component co-crystals formed between a neutral solid and a salt or a solvate.

[0409] "Animal" means including mammals, such as humans, companion animals, zoo animals, and farm animals, preferably humans, horses, or dogs.

[0410] "Stereoisomer" means isomers that have the same molecular formula but different three-dimensional structures due to the difference in spatial arrangement of atoms. This includes enantiomers and diastereomers.

[0411] "Interconvertible isomers" means isomers that are rapidly interconvertible due to the movement of an atom between two positions in the molecule, such as keto-enol isomerism and amide-imidol isomerism.

[0412] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group can or can not be present, and this description includes instances in which the heterocyclyl is substituted with alkyl, and instances in which the heterocyclyl is not substituted with alkyl.

[0413] "IC 50 " is the concentration of drug or inhibitor required to inhibit a given biological process (or a component of that process such as an enzyme, receptor, cell, etc.) by 50%. DETAILED DESCRIPTION

[0414] To accomplish the objectives of the present application, the compounds used in the reactions described herein are prepared according to the techniques of organic synthesis known to those skilled in the art, starting from commercially available chemicals and / or compounds described in chemical literature. The "commercially available chemicals" used in the reactions described herein are obtained from standard commercial sources, including Shanghai Aladdin Bio-Chem Technology Co., Ltd., Shanghai McLean Biochemical Science and Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Co., Ltd., Anjieke Chemicals, Shanghai Titan Science & Technology Co., Ltd., Kelong Chemical, Biotang Technologies Co., Ltd., etc.

[0415] The following examples illustrate the technical solutions of the present application, but the scope of protection of the present application includes but is not limited to this.

[0416] The compounds used in the reactions described herein are prepared according to the techniques of organic synthesis known to those skilled in the art, starting from commercially available chemicals and / or compounds described in chemical literature. The "commercially available chemicals" are obtained from standard commercial sources, including Titan Science & Technology, Anjieke Chemicals, Shanghai Demer, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yushi, Pharmaron and Biotang Technologies, etc.

[0417] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0418] The MS is measured by Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0419] The HPLC is measured by Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100x4.6mm, 3.5μM);

[0420] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography is 0.15mm-0.20mm, and the specification of the product used in thin layer chromatography separation and purification is 0.4mm-0.5mm;

[0421] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0422] SEM: THP: Boc: tert-butyloxycarbonyl; Ms: TBS: MTBE: methyl tert-butyl ether; Bn: DIPEA: N,N-diisopropylethylamine; DMAc: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; Cbz: NMP: N-methylpyrrolidone; DCE: dichloroethane; THF: tetrahydrofuran; DMF: N,N-dimethylformamide.

[0423] Intermediate 1:

[0424] tert-butyl 3-(4-(piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate 1)

[0425] tert-butyl 3-(4-(piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate

[0426]

[0427]

[0428] First step: benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate (1B)

[0429] benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate

[0430]

[0431] Benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate (1B) was prepared according to the following procedure. Benzyl piperazine-1-carboxylate (2.20 g, 10 mmol) (1A) was dissolved in 25 mL of 1,2-dichloroethane, and tert-butyl 4-oxopiperidine-1-carboxylate (3.0 g, 15 mmol) and 2 mL of acetic acid were added successively. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (6.4 g, 30 mmol) was added, and stirring was continued at room temperature for 16 h. To the reaction solution, 50 mL of saturated sodium bicarbonate solution was added slowly, and extraction was performed with 60 mL of dichloromethane. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane / methanol (v / v) = 15:1) to obtain benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate (1B) (2.8 g, yield: 69%).

[0432] LCMS m / z = 404.3 [M+1] +

[0433] Second Step: benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (1C)

[0434] benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate

[0435]

[0436] benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (1C) (1.8 g) was obtained from 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate benzyl ester (1B) (2.8 g, 6.94 mmol) by dissolving in 20 mL of dichloromethane, adding 20 mL of trifluoroacetic acid, stirring at room temperature for 1 h. The reaction system was concentrated under reduced pressure, 50 mL of dichloromethane was added, the pH was adjusted to 9 with saturated sodium bicarbonate solution, extracted with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product.

[0437] LCMS m / z = 304.2 [M+1] +

[0438] Third Step: benzyl 4-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-4-yl)piperazine-1-carboxylate (1D)

[0439] benzyl 4-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-4-yl)piperazine-1-carboxylate

[0440]

[0441] The above crude 4-(piperidin-4-yl)piperazine-1 -carboxylate benzyl ester (1C) (1.8 g) was dissolved in 20 mL of DCE, 3-oxoazetidine-1 -carboxylic acid tert-butyl ester (2.3 g, 13.5 mmol) and 1.5 mL of acetic acid were added sequentially, after stirring at room temperature for 60 min, sodium triacetoxyborohydride (4.2 g, 19.8 mmol) was added, stirring at room temperature for 16 h. 50 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with 60 mL of dichloromethane twice, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 4-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-4-yl)piperazine-1-carboxylate benzyl ester (1D) (2.1 g, total yield of two steps from compound 1B: 66%).

[0442] LCMS m / z = 459.3 [M+1] +

[0443] Fourth step: tert-butyl 3-(4-(piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate 1)

[0444] tert-butyl 3-(4-(piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate

[0445]

[0446] Benzyl 4-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-4-yl)piperazine-1-carboxylate (1D) (1.0 g, 2.18 mmol) was dissolved in 25 mL of methanol, 0.2 g of 10% palladium-carbon was added, and the mixture was stirred under a hydrogen balloon at room temperature for 20 h. The reaction solution was filtered and concentrated under reduced pressure to give crude tert-butyl 3-(4-(piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate 1) (0.7 g).

[0447] LCMS m / z = 325.4 [M+1] +

[0448] Intermediate 2:

[0449] tert-butyl 4-((4-(piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (Intermediate 2)

[0450] tert-butyl 4-((4-(piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0451]

[0452] First Step: Benzyl 4-(1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4- yl)piperazine-1-carboxylate (2A)

[0453] benzyl 4-(1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4- yl)piperazine-1-carboxylate

[0454]

[0455] Benzyl 4-(1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4- yl)piperazine-1-carboxylate (2A) (1.1 g, 2.2 mmol) was dissolved in 10 mL of DCE, and 1 mL of acetic acid was added. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (0.9 g, 4.2 mmol) was added, and the reaction was stirred at room temperature for 16 h. To the reaction mixture was slowly added 50 mL of saturated sodium bicarbonate solution, and the mixture was extracted twice with 60 mL of DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give benzyl 4-(1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4- yl)piperazine-1-carboxylate (2A) (1.1 g, two-step yield from compound 1B: 63%).

[0456] LCMS m / z = 501.3 [M+1] +

[0457] Second Step: tert-Butyl 4-((4-(piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (Intermediate 2)

[0458] tert-butyl 4-((4-(piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0459]

[0460] Benzyl 4-(1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4-yl)piperazine-1- carboxylate (2A) (1.1 g, 2.2 mmol) was dissolved in 25 mL of methanol, 0.2 g of 10% palladium on carbon was added and the reaction was stirred under a hydrogen balloon at room temperature for 20 h. The reaction was filtered under suction and the filtrate was concentrated under reduced pressure to give crude tert-butyl 4-((4-(piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (intermediate 2) (0.62 g).

[0461] LCMS m / z = 367.2 [M+1] +

[0462] Example 1:

[0463] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-{[(4-[(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)piperazin-1-yl)methyl]piperidin-1-yl)sulfonyl]amino}benzamide

[0464] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-{[(4-[(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)piperazin-1-yl)methyl]piperidin-1-yl)sulfonyl]amino}benzamide

[0465]

[0466]

[0467] First step: tert-butyl 4-[(1-[(4-chloro-2-[(2-chloro-4-(trifluoromethyl)phenyl)carbamoyl]phenyl)sulfamoyl]piperidin-4-yl)methyl]piperazine-1-carboxylate (1b)

[0468] tert-butyl 4-[(1-[(4-chloro-2-[(2-chloro-4-(trifluoromethyl)phenyl)carbamoyl]phenyl)sulfamoyl]piperidin-4-yl)methyl]piperazine-1-carboxylate

[0469]

[0470] Dissolve 1,1'-sulfonyldiimidazole (4.0 g, 20.2 mmol) in 50 mL of dichloromethane, cool to 0 °C under nitrogen protection, slowly add methyl trifluoromethanesulfonate (3.65 g, 22.2 mmol), after the addition is complete, warm to room temperature and react for 3 h. Concentrate the reaction solution under reduced pressure, dissolve the residue in 50 mL of acetonitrile, add 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 14.1 mmol) (synthesis method see WO2019195609), and react at room temperature for 18 h. Add 200 mL of dichloromethane and 50 mL of water to the reaction solution, separate the layers, wash the organic layer with 50 mL of saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product obtained after concentration under reduced pressure by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1-1:4) to obtain 2.4 g of an intermediate. Dissolve the intermediate (0.6 g) in 10 mL of dichloromethane, cool to 0 °C under nitrogen protection, add methyl trifluoromethanesulfonate (0.26 g, 1.58 mmol), after the addition is complete, warm to room temperature and react for 3 h. Concentrate the reaction solution under reduced pressure, dissolve the residue in 10 mL of acetonitrile, add 2-amino-5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)benzamide (1a) (0.350 g, 1.00 mmol) (synthesis method see WO2019179436), and warm the reaction to 90 °C and stir for 18 h. Cool the reaction to room temperature, concentrate under reduced pressure, and purify the crude product obtained after concentration under reduced pressure by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:2) to obtain 1b (0.1 g, yield: 14% from compound 1a).

[0471] LCMS m / z = 694.1 [M+1] +

[0472] Second step: 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-{[(4-[(piperazin-1-yl)methyl]piperidin-1-yl)sulfonyl]amino}benzamide (1c)

[0473] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-{[(4-[(piperazin-1-yl)methyl]piperidin-1-yl)sulfonyl]amino}benzamide

[0474]

[0475] Dissolve 1b (0.1 g, 0.144 mmol) in 4 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 h after completion of the addition. Concentrate the reaction solution under reduced pressure, add 20 mL of dichloromethane to the residue, adjust the pH to 8 with a 2 mol / L sodium hydroxide solution, separate the layers, extract the aqueous layer with an additional 10 mL of dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 1c (0.08 g).

[0476] Third step: 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-{[(4-[(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)piperazin-1-yl)methyl]piperidin-1-yl)sulfonyl]amino}benzamide (Compound 1)

[0477] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-{[(4-[(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)piperazin-1-yl)methyl]piperidin-1-yl)sulfonyl]amino}benzamide

[0478]

[0479] Dissolve the above crude 1c (0.08 g) in 2 mL of DMSO, add diisopropylethylamine (0.09 g, 0.7 mmol), and add 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method: see WO2017197056) (0.058 g, 0.21 mmol), and heat to 90°C for 7 h. Cool the reaction solution to room temperature, add 20 mL of water and 20 mL of ethyl acetate, separate the layers, wash the organic layer with a saturated sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography on silica gel (ethyl acetate) to obtain Compound 1 (0.036 g, two-step yield: 29% from Compound 1b).

[0480] 1H NMR (400 MHz, CDC13) δ 10.06 (s, 1H), 8.57 (d, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 7.76 - 7.59 (m, 5H), 7.51 (dd, 1H), 7.29 - 7.24 (m, 1H), 7.04 (dd, 1H), 4.93 (dd, 1H), 3.89 - 3.78 (m, 2H), 3.51 - 3.36 (m, 4H), 2.95 - 2.67 (m, 5H), 2.67 - 2.48 (m, 4H), 2.34 - 2.23 (m, 2H), 2.17 - 2.07 (m, 1H), 1.92 - 1.81 (m, 2H), 1.77 - 1.61 (m, 1H), 0.92 - 0.81 (m, 2H).

[0481] LCMS m / z = 850.2 [M+1] +

[0482] Example 2:

[0483] N-(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)phenyl)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)piperazine-1-sulfonamide

[0484] N-(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)phenyl)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)piperazine-1-sulfonamide

[0485]

[0486] First Step: 7-chloro-2-(5-chloro-2-nitrophenyl)-5-(trifluoromethyl)-1H-1,3-benzodiazole (2b)

[0487] 7-chloro-2-(5-chloro-2-nitrophenyl)-5-(trifluoromethyl)-1H-1,3-benzodiazole

[0488]

[0489] Dissolve 5-chloro-2-nitrobenzoic acid (4.79 g, 23.76 mmol) in 90 mL of phosphorus oxychloride, add 3-chloro-5-(trifluoromethyl)benzene-1,2-diamine (2a) (5.00 g, 23.74 mmol), and stir at 100 °C for 18 h. Cool the reaction mixture to room temperature, slowly add to 100 mL of ice water cooled in an ice bath, filter, extract the filtrate with 100 mL of ethyl acetate, dissolve the filter cake with 200 mL of ethyl acetate, combine the ethyl acetate solutions, wash with 100 mL of saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give crude 2b (8.5 g).

[0490] Second Step: 4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2- yl)aniline (2c)

[0491] 4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)aniline

[0492]

[0493] Dissolve the above crude 2b (8.5 g) in 160 mL of anhydrous ethanol, add 40 mL of water and solid ammonium chloride (6.04 g, 112.9 mmol) sequentially, then add iron powder (6.31 g, 112.7 mmol), and stir at 90 °C for 2 h. Cool the reaction mixture to room temperature, filter the reaction mixture through celite, add 200 mL of water and 500 mL of ethyl acetate to the filtrate, separate the layers, wash the organic layer with saturated sodium chloride (200 mL x 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v) = 20:1) to give 2c (3.70 g, overall yield of two steps from compound 2a: 45%).

[0494] LCMS m / z = 346.0 [M+1] +

[0495] Third Step: 3-(4-[(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2- yl)phenyl)aminosulfonyl]piperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (2d)

[0496] tert-butyl 3-(4-[(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)phenyl)sulfamoyl]piperazin-1-yl)azetidine-1-carboxylate

[0497]

[0498] To a solution of 1,1'-sulfonyldiimidazole (0.105 g, 0.53 mmol) in 10 mL of dichloromethane, cool to 0 °C under nitrogen protection, add methyl trifluoromethanesulfonate (0.095 g, 0.58 mmol), after addition, warm to room temperature and react for 3 h. Concentrate the reaction solution under reduced pressure, dissolve the residue in 10 mL of acetonitrile, add tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (synthesis method see WO2019195609) (0.200 g, 0.83 mmol), and react at room temperature for 18 h. Concentrate the reaction solution under reduced pressure, add 50 mL of dichloromethane and 30 mL of water, separate the layers, extract the aqueous layer with 20 mL of dichloromethane (20 mL x 2), combine the organic layers, wash with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Dissolve the crude product in 10 mL of dichloromethane, cool to 0 °C under nitrogen protection, add methyl trifluoromethanesulfonate (0.095 g, 0.58 mmol), after addition, warm to room temperature and react for 3 h. Concentrate the reaction solution under reduced pressure, dissolve the residue in 10 mL of acetonitrile, add 2c (0.18 g, 0.52 mmol), and react at 90 °C for 18 h. Concentrate the reaction solution under reduced pressure, add 30 mL of dichloromethane and 20 mL of water to the residue, separate the layers, extract the aqueous layer with 20 mL of dichloromethane, combine the organic layers, wash with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:2) to obtain 2d (0.16 g, yield: 47% from compound 2c).

[0499] Fourth step: 4-(azetidin-3-yl)-N-(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)phenyl)piperazine-1-sulfonamide (2e)

[0500] 4-(azetidin-3-yl)-N-(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)phenyl)piperazine-1-sulfonamide

[0501]

[0502] Dissolve 2d (0.15 g, 0.23 mmol) in 4 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 h after completion. Concentrate the reaction solution under reduced pressure, add 20 mL of dichloromethane to the residue, adjust the pH to 8 with a 2 mol / L sodium hydroxide solution, separate the layers, extract the aqueous layer with 10 mL of dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 2e (0.12 g).

[0503] LCMS m / z = 549.1 [M+1] +

[0504] Fifth step: N-(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)phenyl)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)piperazine-1-sulfonamide (Compound 2)

[0505] N-(4-chloro-2-(7-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl)phenyl)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)piperazine-1-sulfonamide

[0506]

[0507] Dissolve the above crude 2e (0.12 g) in 2 mL of DMSO, add diisopropylethylamine (0.140 g, 1.08 mmol), and then add 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method: see WO2017197056) (0.091 g, 0.330 mmol), and stir at 90°C for 3 h after completion. Cool the reaction solution to room temperature, add 20 mL of water and 20 mL of ethyl acetate, separate the layers, wash the organic layer with saturated sodium chloride (20 mL x 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the obtained crude product by column chromatography on silica gel (ethyl acetate) to obtain Compound 2 (0.08 g, total yield of two steps from Compound 2d: 43%).

[0508] 1H NMR (400 MHz, DMSO-d6) δ 14.05 (br. s, 1H), 12.50 (br. s, 1H), 11.04 (s, 1H), 8.35 (br. s, 1H), 7.93 (br. s, 1H), 7.82 - 7.72 (m, 2H), 7.68 - 7.58 (m, 2H), 6.72 (d, 1H), 6.58 (dd, 1H), 5.04 (dd, 1H), 4.08 - 3.97 (m, 2H), 3.81 - 3.70 (m, 2H), 3.39 - 3.31 (m, 1H), 3.26 - 3.12 (m, 4H), 2.94 - 2.79 (m, 1H), 2.64 - 2.44 (m, 2H), 2.41 - 2.28 (m, 4H), 2.05 - 1.93 (m, 1H).

[0509] LCMS m / z = 805.1 [M+1] +

[0510] Example 3:

[0511] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine)-1-sulfonamido)benzamide

[0512] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine)-1-sulfonamido)benzamide

[0513]

[0514]

[0515] First Step: tert-Butyl 4-((1H-imidazol-1-yl)sulfonyl)piperazine-1-carboxylate (3b)

[0516] tert-Butyl 4-((1H-imidazol-1-yl)sulfonyl)piperazine-1-carboxylate

[0517]

[0518] Dissolve 1,1'-sulfonyldiimidazole (5.00 g, 25.23 mmol) in 15 mL of DCM, add methyl triflate (4.55 g, 27.73 mmol) under ice bath, and stir the reaction at room temperature for 3 h. Concentrate the reaction under reduced pressure, dissolve the residue in 20 mL of acetonitrile, and add tert-butyl piperazine-1-carboxylate (3a) (4.70 g, 25.23 mmol) at room temperature for 16 h. Concentrate the reaction under reduced pressure, and purify the crude product by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v) = 10:1-4:1) to obtain 3b (3.5 g, yield: 44%).

[0519] Second step: tert-butyl 4-(N-(4-chloro-2-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)phenyl)sulfamoyl)piperazine-1-carboxylate (3c)

[0520] tert-butyl 4-(N-(4-chloro-2-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)phenyl)sulfamoyl)piperazine-1-carboxylate

[0521]

[0522] Dissolve 3b (700 mg, 2.21 mmol) in 8 mL of DCM, add methyl triflate (798 mg, 4.86 mmol) under ice bath, and stir the reaction at room temperature for 3 h. Concentrate the reaction under reduced pressure, dissolve the residue in 15 mL of acetonitrile, and add 2-amino-5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)benzamide (1a) (0.350 g, 1.00 mmol) (384 mg, 1.10 mmol) (see WO2019179436 for the synthesis method) at reflux for 16 h. Cool the reaction to room temperature, concentrate under reduced pressure, and purify the crude product by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v) = 8:1-2:1) to obtain 3c (180 mg, yield: 27% from compound 1a).

[0523] Third step: 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(piperazine-1-sulfonamido)benzamide (3d)

[0524] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(piperazine-1-sulfonamido)benzamide

[0525]

[0526] Dissolve 3c (180 mg, 0.30 mmol) in 3 mL of dichloromethane, add 1 mL of trifluoroacetic acid, and react at room temperature for 2.5 h. Adjust the pH of the reaction solution to 10 with 2 mol / L aqueous sodium hydroxide solution, extract the aqueous phase with dichloromethane (10 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 3d (150 mg, yield: >99%).

[0527] Fourth step: tert-butyl 4-((4-(N-(4-chloro-2-((2-chloro-4- (trifluoromethyl)phenyl)carbamoyl)phenyl)sulfamoyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (3e)

[0528] tert-butyl 4-((4-(N-(4-chloro-2-((2-chloro-4- (trifluoromethyl)phenyl)carbamoyl)phenyl)sulfamoyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0529]

[0530] Dissolve 3d (150 mg, 0.30 mmol) in 5 mL of DCE, add N-Boc-piperidine-4-carboxaldehyde (128 mg, 0.60 mmol), glacial acetic acid (0.10 mL, 1.75 mmol), and anhydrous sodium sulfate (200 mg) sequentially at room temperature, stir for 30 min, add sodium triacetoxyborohydride (213 mg, 1.01 mmol), and stir at room temperature for 16 h. Add 20 mL of water to the reaction solution, adjust the pH of the aqueous phase to 10 with saturated aqueous sodium bicarbonate solution, extract with dichloromethane (30 mL x 3), wash the combined organic phases with water (20 mL x 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1-8:1) to obtain 3e (146 mg, yield: 70%).

[0531] Fifth step: 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-((4-(piperidin-4-ylmethyl)piperazine)-1-sulfonamido)benzamide (3f)

[0532] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-((4-(piperidin-4-ylmethyl)piperazine)-1-sulfonamido)benzamide

[0533]

[0534] The above crude 3f (124 mg) was dissolved in 8 mL of DMSO, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (69 mg, 0.25 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) were added at room temperature, and the reaction was heated to 80 °C for 3.5 h. The reaction was cooled to room temperature, and 20 mL of water was poured into the reaction, and the aqueous phase was extracted with dichloromethane / methanol (v / v) = 10:1 (30 mL x 3), and the organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1-8:1) to obtain compound 3 (18 mg, total yield of two steps from compound 3e: 10%).

[0535] Sixth step: 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine)-1-sulfonamido)benzamide (compound 3)

[0536] 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine)-1-sulfonamido)benzamide

[0537]

[0538] The above crude 3f (124 mg) was dissolved in 8 mL of DMSO, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (69 mg, 0.25 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) were added at room temperature, and the reaction was heated to 80 °C for 3.5 h. The reaction was cooled to room temperature, and 20 mL of water was poured into the reaction, and the aqueous phase was extracted with dichloromethane / methanol (v / v) = 10:1 (30 mL x 3), and the organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1-8:1) to obtain compound 3 (18 mg, total yield of two steps from compound 3e: 10%).

[0539] 1H NMR (400 MHz, DMSO-d6) δ 10.10 (br. s, 1 H), 8.59 - 8.47 (m, 2 H), 8.24 (s, 1 H), 7.78 - 7.71 (m, 2 H), 7.68 - 7.58 (m, 3 H), 7.51 (dd, 1 H), 7.26 - 7.24 (m, 1 H), 7.01 (dd, 1 H), 4.92 (dd, 1 H), 3.98 - 3.86 (m, 2 H), 3.38 - 3.22 (m, 4 H), 3.00 - 2.64 (m, 5 H), 2.54 - 2.37 (m, 4 H), 2.27 - 2.05 (m, 3 H), 1.89 - 1.68 (m, 3 H), 1.35 - 1.15 (m, 2 H).

[0540] LCMS m / z = 850.2 [M+1] +

[0541] Example 4:

[0542] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0543] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0544]

[0545]

[0546] First Step: tert-Butyl 4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (4b)

[0547] tert-butyl 4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0548]

[0549] Dissolve 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(piperazin-1-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)benzonitrile (4b) (1.98 g, 3.17 mmol) in 5 mL of DCM, add 5 mL of trifluoroacetic acid, and stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, dissolve the residue in 50 mL of DCM, adjust the pH to 9 with a saturated sodium bicarbonate solution, separate the layers, extract the aqueous layer with 100 mL of dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give crude 4c (1.6 g).

[0550] LCMS m / z = 626.2 [M+1] +

[0551] Second Step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(piperazin-1-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)benzonitrile (4c)

[0552] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0553]

[0554] Dissolve 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(piperazin-1-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)benzonitrile (4b) (1.98 g, 3.17 mmol) in 5 mL of DCM, add 5 mL of trifluoroacetic acid, and stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, dissolve the residue in 50 mL of DCM, adjust the pH to 9 with a saturated sodium bicarbonate solution, separate the layers, extract the aqueous layer with 100 mL of dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give crude 4c (1.6 g).

[0555] LCMS m / z = 526.1 [M+1]+

[0556] tert-butyl 3-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)azetidine-1-carboxylate

[0557] tert-butyl 3-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)azetidine-1-carboxylate

[0558]

[0559] The above crude 4c (810 mg) was dissolved in 25 mL of 1,2-dichloroethane, 1-Boc-3-azetidinone (530 mg, 3.1 mmol) was added, after stirring at room temperature for 1 h, sodium triacetoxyborohydride (980 mg, 4.62 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction solution was slowly added 20 mL of saturated sodium bicarbonate solution, and extraction was performed with 120 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0-9:1) to obtain 4d (950 mg, total yield of two steps from compound 4b: 87%).

[0560] LCMS m / z = 681.3 [M+1] +

[0561] 5-(2-(4-((2-(4-(azetidin-3-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

[0562] 5-(2-(4-((2-(4-(azetidin-3-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

[0563]

[0564] Dissolve 4d (1.1 g, 1.62 mmol) in 15 mL of DCM, add 10 mL of trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, dissolve with 50 mL of DCM, adjust pH to 9 with saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with 100 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give crude 4e (900 mg).

[0565] LCMS m / z = 581.2 [M+1] +

[0566] Fifth step: tert-butyl 3-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)-[1,3'- biazetidine]-1'-carboxylate (4f)

[0567] tert-butyl 3-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)-[1,3'-biazetidine]-1'-carboxylate

[0568]

[0569] Dissolve the above crude 4e (900 mg) in 25 mL of DCE, add 1-Boc-3-azetidinone (530 mg, 3.1 mmol), stir at room temperature for 60 min, then add sodium triacetoxyborohydride (980 mg, 4.62 mmol), stir at room temperature for 16 h. Slowly add 30 mL of saturated sodium bicarbonate solution to the reaction system, extract with 120 mL of DCM, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography on silica gel (dichloromethane / methanol (v / v) = 20:1) to give 4f (700 mg, overall yield of two steps from compound 4d: 59%).

[0570] LCMS m / z = 736.2 [M+1] +

[0571] Sixth step: 5-(2-(4-((2-(4-([1,3'-biazetidin]-3-yl)piperazin-1-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (4g)

[0572] 5-(2-(4-((2-(4-([1,3'-biazetidin]-3-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

[0573]

[0574] Dissolve 4f (700 mg, 0.95 mmol) in 15 mL DCM, add 6 mL trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, dissolve in 50 mL DCM, adjust pH to 9 with saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with 100 mL dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give crude 4g (460 mg).

[0575] LCMS m / z = 636.3 [M+1] +

[0576] Seventh Step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 4)

[0577] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0578]

[0579] The above crude 4g (150 mg) was dissolved in 10 mL of DMSO, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (66 mg, 0.24 mmol) were added, and the reaction was stirred at 80°C for 5h. The reaction was cooled to room temperature, 50 mL of water was added, extracted with 100 mL of ethyl acetate, the organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by silica gel column chromatography (dichloromethane / methanol (v / v)=15:1) to obtain compound 4 (45 mg, total yield of two steps from compound 4f: 16%).

[0580] 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H), 8.04 (s, 1H), 7.65 (d, 1H), 7.44 (d, 1H), 7.31 (d, 1H), 7.12-7.06 (m, 2H), 6.91-6.85 (m, 2H), 6.79 (d, 1H), 6.75 (d, 1H), 6.54 (dd, 1H), 4.98-4.88 (m, 3H), 4.41 (t, 2H), 4.11-4.03 (m, 2H), 4.00-3.53 (m, 11H), 3.38-3.02 (m, 3H), 2.93-2.69 (m, 3H), 2.60-2.26 (m, 4H), 2.18-2.08 (m, 1H), 1.63 (s, 6H).

[0581] LCMS m / z = 446.7 [M / 2+1] +

[0582] Example 5:

[0583] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 5) trifluoroacetate salt

[0584] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitriletrifluoroacetate

[0585]

[0586] First Step: tert-Butyl 4-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2- yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidine-1-carboxylate (5a)

[0587] tert-Butyl 4-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2- yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidine-1-carboxylate

[0588]

[0589] The above crude 4c (300 mg) was dissolved in 15 mL of 1,2-dichloroethane, tert-butyl 4-oxopiperidine-1-carboxylate (230 mg, 1.16 mmol) was added, and after stirring at room temperature for 1 h, sodium triacetoxyborohydride (360 mg, 1.70 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction solution was slowly added 20 mL of a saturated sodium bicarbonate solution, and extraction was performed with 120 mL of dichloromethane. The organic phase was washed with 50 mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0-9:1) to obtain 5a (200 mg, total yield of two steps from compound 4b: 48%).

[0590] LCMS m / z = 709.3 [M+1] +

[0591] Second Step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(piperidin-4-yl)piperazin-1- yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (5b)

[0592] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(piperidin-4-yl)piperazin-1- yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0593]

[0594] Dissolve 5a (0.20 g, 0.28 mmol) in 2 mL DCM, add 1 mL trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, dissolve the residue in 20 mL DCM, adjust pH to 8 with saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with 100 mL dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give crude 5b (0.15 g).

[0595] LCMS m / z = 609.2 [M+1] +

[0596] Third Step: tert-butyl 3-(4-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2- yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate (5c)

[0597] tert-butyl 3-(4-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2- yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate

[0598]

[0599] The above crude 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (5b) (150 mg) was dissolved in 15 mL of DCE, 1-Boc-3-azetidinone (86 mg, 0.5 mmol) was added, and after stirring at room temperature for 60 min, sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added. The reaction was stirred at room temperature for 16 h. To the reaction system, 30 mL of saturated sodium bicarbonate solution was slowly added, and the organic phase was extracted with 120 mL of DCM, washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 5c (180 mg, total yield of two steps from compound 5a: 84%).

[0600] LCMS m / z = 764.2 [M+1] +

[0601] Fourth step: trifluoroacetate salt of 5-(2-(4-((2-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (5d)

[0602] 5-(2-(4-((2-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[0603]

[0604] 5c (180 mg, 0.24 mmol) was dissolved in 2 mL of DCM, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 4 h. The reaction was concentrated under reduced pressure to obtain the trifluoroacetate salt of the crude 5d (185 mg).

[0605] LCMS m / z = 664.3 [M+1] +

[0606] Step 5: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 5)

[0607] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitriletrifluoroacetate

[0608]

[0609] Trifluoroacetate salt of the above crude 5d (185 mg) was dissolved in 10 mL of DMSO, solid sodium bicarbonate (100 mg, 1.19 mmol) was added, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (66 mg, 0.24 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, and the organic phase was extracted with 100 mL of ethyl acetate, washed with 100 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 5 was obtained by lyophilization (50 mg).

[0610] 1H NMR (400 MHz, CD3OD) δ 8.40 (d, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 7.44 (d, 1H), 7.19 - 7.14 (m, 2H), 6.96 - 6.87 (m, 4H), 6.74 (dd, 1H), 5.06 (dd, 1H), 5.02 (s, 2H), 4.47 - 3.93 (m, 10H), 3.93 - 3.84 (m, 3H), 3.56 - 3.34 (m, 7H), 2.92 - 2.80 (m, 1H), 2.78 - 2.67 (m, 2H), 2.67 - 2.56 (m, 2H), 2.44 - 2.34 (m, 2H), 2.15 - 2.05 (m, 1H), 2.04 - 1.91 (m, 2H), 1.65 (s, 6H).

[0611] LCMS m / z = 460.8 [M / 2 + 1] + .

[0612] Example 6:

[0613] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0614] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0615]

[0616] The trifluoroacetate salt of 5d (50 mg) was dissolved in 5 mL of DMAc, 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxaldehyde (synthesis method see WO2020113233) (43 mg, 0.15 mmol) was added, after stirring at room temperature for 60 min, sodium triacetoxyborohydride (340 mg, 1.6 mmol) was added, and stirring was carried out at room temperature for 16 h. 30 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with ethyl acetate (60 mL x 2), the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and freeze-drying obtained compound 6 trifluoroacetate salt (10 mg).

[0617] 1 H NMR (400 MHz, CD3OD) δ 8.40 (d, 1H), 7.52 (d, 1H), 7.44 (d, 1H), 7.29-7.11 (m, 5H), 6.97-6.86 (m, 3H), 5.42-5.34 (m, 1H), 5.02 (s, 2H), 4.82-4.57 (m, 6H), 4.42 (t, 2H), 4.33-4.23 (m, 2H), 4.17-4.06 (m, 2H), 3.89 (t, 2H), 3.68 (s, 3H), 3.60-3.30 (m, 5H), 3.30-3.23 (m, 1H), 3.13-3.01 (m, 2H), 2.99-2.73 (m, 3H), 2.29-2.12 (m, 3H), 2.12-2.01 (m, 2H), 1.90-1.74 (m, 2H), 1.65 (s, 6H).

[0618] LCMS m / z = 468.3 [M / 2+1] +

[0619] Example 7:

[0620] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0621] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0622]

[0623] tert-butyl 4-((4-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0624] tert-butyl 4-((4-(4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0625]

[0626] The crude product 5b (150 mg) was dissolved in 15 mL of DCE, and tert-butyl 4-formylpiperidine-1-carboxylate (106.5 mg, 0.5 mmol) was added. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added and the mixture was allowed to react at room temperature for 16 h. 30 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, and the mixture was extracted with 120 mL of dichloromethane. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 7a (180 mg, total yield of two steps based on compound 5a: 80%).

[0627] LCMS m / z=806.3[M+1] +

[0628] Step 2: Trifluoroacetate of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (7b)

[0629] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0630]

[0631] Dissolve 7a (180 mg, 0.22 mmol) in 2 mL of DCM, add 1 mL of trifluoroacetic acid, and stir at room temperature for 4 h. The reaction solution is concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 7b (185 mg).

[0632] Step 3: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 7)

[0633] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0634]

[0635] The trifluoroacetate salt of the above crude 7b (90 mg) was dissolved in 5 mL of DMSO, solid sodium bicarbonate (100 mg, 1.19 mmol) was added, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (33 mg, 0.12 mmol) were added, and the reaction was stirred at 80°C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, and the organic phase was extracted with 100 mL of ethyl acetate, the organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:15) to obtain compound 7 (50 mg, total yield of two steps from compound 7a: 49%).

[0636] 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 8.17 (br. s, 1H), 7.66 (d, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 7.12-7.00 (m, 3H), 6.92-6.84 (m, 2H), 6.71 (d, 1H), 5.00-4.88 (m, 3H), 4.42 (t, 2H), 4.00-3.75 (m, 8H), 3.05-2.92 (m, 4H), 2.92-2.60 (m, 7H), 2.45-2.28 (m, 1H), 2.28-2.15 (m, 2H), 2.15-2.07 (m, 1H), 2.06-1.94 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.61 (m, 9H), 1.35-1.17 (m, 4H).

[0637] LCMS m / z = 481.8 [M / 2 + 1] +

[0638] Example 8:

[0639] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0640] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0641]

[0642] The trifluoroacetate salt of the above crude 7b (90 mg) was dissolved in 5 mL of DMSO, solid sodium bicarbonate (100 mg, 1.19 mmol) was added, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (33 mg, 0.12 mmol) were added, and the reaction was stirred at 80°C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, extracted with 100 mL of ethyl acetate, the organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:15) to obtain compound 8 (45 mg, overall yield from compound 7a: 44%).

[0643] 1H NMR (400 MHz, CDC13) δ 8.31 (d, 1H), 7.98 (br. s, 1H), 7.59 - 7.53 (m, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 7.17 (d, 1H), 7.14 - 7.04 (m, 2H), 6.93 - 6.84 (m, 2H), 6.71 (d, 1H), 5.01 - 4.91 (m, 3H), 4.41 (t, 2H), 3.96 - 3.68 (m, 8H), 3.06 - 2.85 (m, 4H), 2.85 - 2.56 (m, 7H), 2.43 - 2.18 (m, 3H), 2.17 - 2.06 (m, 1H), 2.04 - 1.78 (m, 5H), 1.78 - 1.54 (m, 10H), 1.54 - 1.42 (m, 2H).

[0644] LCMS m / z = 481.8 [M / 2 + 1] +

[0645] Example 9:

[0646] 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0647] 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0648]

[0649]

[0650] First Step: 3-chloro-5-(2-hydroxypropan-2-yl)benzonitrile (9b)

[0651] 3-chloro-5-(2-hydroxypropan-2-yl)benzonitrile

[0652]

[0653] To a solution of 3-chloro-5-cyanobenzoic acid methyl ester (9a) (0.85 g, 4.34 mmol) in tetrahydrofuran (7 mL) was added 4 mL of 3 mol / L methyl magnesium bromide solution in tetrahydrofuran, cooled to 0 °C, and then stirred at 0 °C for 2 h. To the reaction solution was added dropwise 30 mL of saturated ammonium chloride solution at 0 °C, and then the temperature was raised to room temperature. The reaction mixture was extracted with 50 mL of ethyl acetate, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 3-chloro-5-(2-hydroxypropan-2-yl)benzonitrile (9b) (0.80 g).

[0654] Second step: 3-chloro-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile (9c)

[0655] 3-chloro-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile

[0656]

[0657] To a solution of the above crude 3-chloro-5-(2-hydroxypropan-2-yl)benzonitrile (9b) (0.80 g) in 15 mL of carbon tetrachloride was added phenol (0.42 g, 4.5 mmol), cooled to 0 °C, and then added dropwise with boron trifluoride etherate (1.16 g, 8.17 mmol). The temperature was then raised to room temperature and stirred for 3 h. To the reaction mixture was slowly added 20 mL of water, and then extracted with 30 mL of dichloromethane. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 0:1-1:5) to give 3-chloro-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile (9c) (0.50 g, overall yield of two steps from compound 9a: 42%).

[0658] Third step: 3-chloro-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (9d)

[0659] 3-chloro-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0660]

[0661] Dissolve 9c (0.50 g, 1.84 mmol) in 15 mL of acetonitrile, add 2-chloro-4- (chloromethyl)pyrimidine (0.30 g, 1.84 mmol) and potassium carbonate (0.51 g, 3.69 mmol) successively, and stir at 70°C for 20 h. Cool the reaction solution to room temperature, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 0:1-1:5) to obtain 9d (0.46 g, yield: 63%).

[0662] LCMS m / z = 398.2 [M+1] +

[0663] Fourth step: tert-butyl 3-(4-(4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate (9e)

[0664] tert-butyl 3-(4-(4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate

[0665]

[0666] Dissolve 9d (250 mg, 0.63 mmol) in 10 mL of DMF, add tert-butyl 3-(4-(piperazin-1- yl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate 1) (200 mg) and solid potassium bicarbonate (133 mg, 1.33 mmol) successively, and stir at 90°C for 4 h. Cool to room temperature, add 30 mL of water, extract twice with 30 mL of ethyl acetate, wash the organic phase with 50 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography on silica gel (dichloromethane / methanol (v / v) = 20:1) to obtain 9e (280 mg, yield: 65% from compound 9d).

[0667] LCMS m / z = 686.3 [M+1] +

[0668] Fifth step: 3-(2-(4-((2-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile (9f)

[0669] 3-(2-(4-((2-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile

[0670]

[0671] Dissolve 9e (280 mg, 0.41 mmol) in 5 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, add 50 mL of dichloromethane, adjust pH to 9 with saturated sodium bicarbonate solution, extract with 50 mL of dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give crude 9f (200 mg).

[0672] LCMS m / z = 586.3 [M+1] +

[0673] Sixth Step: Trifluoroacetate salt of 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 9)

[0674] 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0675]

[0676] The above crude 9f (46 mg) was dissolved in 5 mL of DMAc, 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxaldehyde (synthesis method see WO2020113233) (23 mg, 0.08 mmol) was added, stirred at room temperature for 60 min, then sodium triacetoxyborohydride (230 mg, 1.09 mmol) was added, stirred at room temperature for 16 h. 30 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with 60 mL of ethyl acetate twice, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 9 was obtained by freeze-drying (8 mg).

[0677] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.46 (d, 1H), 7.86-7.82 (m, 1H), 7.68-7.62 (m, 1H), 7.56-7.50 (m, 1H), 7.32 (s, 1H), 7.26-7.12 (m, 4H), 6.99-6.91 (m, 2H), 6.85 (d, 1H), 5.40 (dd, 1H), 5.02 (s, 2H), 4.98-4.44 (m, 4H), 4.40 (s, 2H), 4.19-4.01 (m, 4H), 3.53-3.41 (m, 1H), 3.36 (s, 3H), 3.34-2.98 (m, 9H), 2.98-2.84 (m, 1H), 2.81-2.58 (m, 2H), 2.22-1.96 (m, 3H), 1.79-1.58 (m, 8H).

[0678] LCMS m / z = 429.3 [M / 2+1] +

[0679] Example 10:

[0680] 3-chloro-5-(2-(4-((2-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 10)

[0681] 3-chloro-5-(2-(4-((2-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0682]

[0683] The above crude 9f (50 mg) was dissolved in 5 mL of DMSO, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (66 mg, 0.24 mmol) were added, and the reaction was stirred at 80°C for 5h. The reaction was cooled to room temperature, 50 mL of water was added, extracted with 100 mL of ethyl acetate, the organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain compound 10 (16 mg, total yield of two steps from compound 9e: 19%).

[0684] 1 H NMR (400 MHz, CDC13) δ 8.23 (d, 1H), 8.08 - 7.98 (m, 1H), 7.57 (d, 1H), 7.39 - 7.33 (m, 2H), 7.32 - 7.27 (m, 1H), 7.06 - 6.96 (m, 2H), 6.85 - 6.77 (m, 2H), 6.71 (d, 1H), 6.64 (d, 1H), 6.45 (dd, 1H), 4.93 - 4.77 (m, 3H), 4.03 (t, 2H), 3.94 - 3.60 (m, 6H), 3.34 - 3.22 (m, 1H), 2.95 - 2.85 (m, 2H), 2.85 - 2.48 (m, 7H), 2.45 - 2.26 (m, 1H), 2.11 - 2.00 (m, 1H), 1.94 - 1.79 (m, 2H), 1.70 - 1.45 (m, 10H).

[0685] LCMS m / z = 842.3 [M+1] +

[0686] Example 11:

[0687] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0688] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0689]

[0690] First step: Benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (11b)

[0691] Benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate

[0692]

[0693] Benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate

[0694] LCMS m / z = 318.2 [M+1] +

[0695] Second step: tert-butyl 4-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-[1,4'-bipiperidin]-1'-carboxylate (11c)

[0696] tert-butyl 4-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-[1,4'-bipiperidine]-1'-carboxylate

[0697]

[0698] The crude product 11b (1.0 g) was dissolved in 35 mL of DCE, and tert-butyl 4-oxopiperidine-1-carboxylate (1.38 g, 6.94 mmol) was added. After stirring at room temperature for 30 min, sodium triacetoxyborohydride (1.47 g, 6.94 mmol) was added and stirred at room temperature for 16 h. 50 mL of saturated aqueous sodium bicarbonate was slowly added to the reaction system, and the mixture was extracted with dichloromethane (60 mL x 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1-10:1) to obtain 11c (1.2 g, total yield of two steps based on compound 11a: 62%).

[0699] LCMS m / z=501.3[M+1] +

[0700] Step 3: tert-Butyl 4-(piperazin-1-ylmethyl)-[1,4'-bipiperidinyl]-1'-carboxylate (11d)

[0701] tert-butyl 4-(piperazin-1-ylmethyl)-[1,4'-bipiperidine]-1'-carboxylate

[0702]

[0703] Dissolve 11c (600 mg, 1.20 mmol) in 25 mL of methanol, add 0.15 g of 10% palladium on carbon, and stir at room temperature under a hydrogen balloon for 16 h. Filter the reaction mixture, wash the filter cake with methanol (5 mL x 3), and collect the filtrate, which is then concentrated under reduced pressure to yield crude product 11d (0.45 g).

[0704] LCMS m / z=367.3[M+1] +

[0705] Step 4: tert-Butyl 4-((4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)-[1,4'-bipiperidine]-1'-carboxylate (11e)

[0706] tert-butyl 4-((4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)-[1,4'-bipiperidine]-1'-carboxylate

[0707]

[0708] The above crude 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4a) (synthesis method see WO2020081999) (250 mg, 0.524 mmol) was dissolved in 15 ml of DMF, and solid potassium bicarbonate (105 mg, 1.05 mmol) and the crude 11d (225 mg) of the previous step were added, and the temperature was raised to 60°C for 3h. The reaction was cooled to room temperature, 20 mL of water was slowly added, extracted with ethyl acetate (50 mL x 3), the organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give 11e (300 mg, total yield of two steps from compound 11c: 62%).

[0709] LCMS m / z = 806.3 [M+1] +

[0710] Fifth step: trifluoroacetate salt of 5-(2-(4-((2-(4-([1,4'-bipiperidin]-4-ylmethyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (11f)

[0711] 5-(2-(4-((2-(4-([1,4'-bipiperidin]-4-ylmethyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[0712]

[0713] Dissolve 11e (60 mg, 0.074 mmol) in 5 mL DCM, add 2 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to get the trifluoroacetate salt of crude 11f (70 mg).

[0714] LCMS m / z = 706.3 [M+1] +

[0715] Sixth step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 11)

[0716] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0717]

[0718] Dissolve the above trifluoroacetate salt of crude 11f (70 mg) in 4 mL DMSO, add solid sodium bicarbonate (32 mg, 0.38 mmol), stir at room temperature for 10 min, then add 0.5 mL DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (41 mg, 0.15 mmol), warm to 80 °C and stir for 5 h. Cool the reaction to room temperature, add 50 mL water, filter, wash the filter cake with 10 mL water, dissolve the filter cake in 50 mL dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure, then purify the crude product by preparative plate (dichloromethane / methanol (v / v) = 15:1) to get Compound 11 (25 mg, overall yield from Compound 11e: 35%).

[0719] 1H NMR (400 MHz, CDC13) δ 8.30 (d, 1H), 8.01 (br. s, 1H), 7.68 (d, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.28 (d, 1H), 7.12 - 7.02 (m, 3H), 6.91 - 6.85 (m, 2H), 6.70 (d, 1H), 4.98 - 4.89 (m, 3H), 4.41 (t, 2H), 4.07 - 3.97 (m, 2H), 3.90 - 3.76 (m, 6H), 3.20 - 2.65 (m, 8H), 2.50 - 2.40 (m, 4H), 2.31 - 2.20 (m, 3H), 2.18 - 1.98 (m, 3H), 1.96 - 1.82 (m, 2H), 1.82 - 1.48 (m, 12H).

[0720] LCMS m / z = 962.3 [M+1] +

[0721] Example 12:

[0722] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0723] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0724]

[0725] The trifluoroacetate salt of the above crude 11f (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (26 mg, 0.31 mmol) was added, after stirring at room temperature for 10 min, 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the temperature was raised to 80°C and stirred for 5h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by preparative plate (dichloromethane / methanol (v / v)=15:1) to obtain compound 12 (20 mg, overall yield of two steps from compound 11e: 33%).

[0726] 1 H NMR (400 MHz, CDC13) δ 8.30 (d, 1H), 8.00 (br. s, 1H), 7.62-7.54 (m, 1H), 7.46-7.36 (m, 2H), 7.32 (d, 1H), 7.16 (d, 1H), 7.12-7.06 (m, 2H), 6.92-6.85 (m, 2H), 6.70 (d, 1H), 5.01-4.91 (m, 3H), 4.42 (t, 2H), 3.96-3.75 (m, 8H), 3.25-2.65 (m, 8H), 2.54-2.38 (m, 5H), 2.34-2.06 (m, 5H), 2.04-1.75 (m, 5H), 1.75-1.48 (m, 9H).

[0727] LCMS m / z = 962.3 [M+1] +

[0728] Example 13:

[0729] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 13)

[0730] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0731]

[0732] First Step: Benzyl 4-((1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (13a)

[0733] benzyl 4-((1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0734]

[0735] Benzyl 4-((1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (13a) was prepared according to the procedure described above for compound 13a using benzyl 4-((1-((1-(tert-butoxycarbonyl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (12a) (1.0 g, 2.0 mmol) and 4- formylpiperidine-1-carboxylic acid tert-butyl ester (0.62 g, 2.6 mmol). The crude product was purified by column chromatography on silica gel (dichloromethane / methanol (v / v) = 15:1-10:1) to give 13a (1.0 g, overall yield from compound 12a: 67%).

[0736] LCMS m / z = 515.3 [M+1] +

[0737] Second Step: tert-Butyl 4-((4-(piperazin-1-ylmethyl)piperidin-1-yl)methyl)piperidine-1- carboxylate (13b)

[0738] tert-butyl 4-((4-((4-(piperazin-1-ylmethyl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0739]

[0740] Dissolve 13a (600 mg, 1.17 mmol) in 25 mL of methanol, add 0.15 g of 10% palladium carbon, and stir at room temperature for 16 h under a hydrogen balloon atmosphere. Filter the reaction solution, wash the filter cake with methanol (5 mL x 3), collect the filtrate, and concentrate the filtrate under reduced pressure to obtain crude 13b (0.43 g).

[0741] LCMS m / z = 381.3 [M+1] +

[0742] Third step: tert-butyl 4-((4-((4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin-1- yl)methyl)piperidine-1-carboxylate (13c)

[0743] tert-butyl 4-((4-((4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0744]

[0745] Dissolve 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate (13d) (60 mg, 0.08 mmol) in 5 mL of DCM, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of 13d (60 mg).

[0746] LCMS m / z = 820.3 [M+1] +

[0747] Fourth step: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (13d)

[0748] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0749]

[0750] Dissolve 13c (50 mg, 0.061 mmol) in 5 mL of DCM, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of 13d (60 mg).

[0751] LCMS m / z = 720.3 [M+1] +

[0752] Step 5: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 13)

[0753] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0754]

[0755] The trifluoroacetate salt of the above crude 13d (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (26 mg, 0.31 mmol) was added, after stirring at room temperature for 10 min, 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved in 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by preparative plate separation (dichloromethane / methanol (v / v) = 15:1) to obtain Compound 13 (25 mg, total yield of two steps from Compound 13c: 42%).

[0756] 1H NMR (400 MHz, CDC13) δ 8.30 (d, 1H), 7.96 (br. s, 1H), 7.67 (d, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.30 - 7.26 (m, 1H), 7.13 - 7.01 (m, 3H), 6.91 - 6.85 (m, 2H), 6.70 (d, 1H), 4.98 - 4.88 (m, 3H), 4.42 (t, 2H), 4.00 - 3.90 (m, 2H), 3.90 - 3.75 (m, 6H), 3.07 - 2.93 (m, 2H), 2.93 - 2.66 (m, 5H), 2.51 - 2.39 (m, 4H), 2.30 - 2.17 (m, 3H), 2.17 - 2.08 (m, 2H), 2.03 - 1.70 (m, 6H), 1.64 (s, 6H), 1.61 - 1.47 (m, 6H).

[0757] LCMS m / z = 976.3 [M+1] +

[0758] Example 14:

[0759] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0760] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0761]

[0762]

[0763] The trifluoroacetate salt of the above crude 13d (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (26 mg, 0.31 mmol) was added, after stirring at room temperature for 10 min, 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the temperature was raised to 80 °C and stirred for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by preparative plate (dichloromethane / methanol (v / v) = 15:1) to obtain compound 14 (20 mg, total yield of two steps from compound 13c: 34%).

[0764] 1 H NMR (400 MHz, CDC13) δ 8.30 (d, 1H), 7.99 (br. s, 1H), 7.60 - 7.51 (m, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 7.17 (d, 1H), 7.13 - 7.04 (m, 2H), 6.93 - 6.84 (m, 2H), 6.70 (d, 1H), 5.02-4.90 (m, 3H), 4.42 (t, 2H), 3.92 - 3.68 (m, 8H), 3.00 - 2.65 (m, 7H), 2.52 - 2.40 (m, 4H), 2.40 - 2.17 (m, 4H), 2.17 - 2.06 (m, 1H), 2.04 - 1.86 (m, 3H), 1.86 - 1.70 (m, 3H), 1.70 - 1.42 (m, 12H).

[0765] LCMS m / z = 976.3 [M+1] +

[0766] Example 15:

[0767] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)-[4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (trifluoroacetate salt of compound 15)

[0768] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)-[4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitriletrifluoroacetate

[0769]

[0770] First Step: tert-butyl 1'-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidine]-1-carboxylate (15a)

[0771] tert-butyl 1'-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidine]-1-carboxylate

[0772]

[0773] tert-butyl 1'-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidine]-1-carboxylate

[0774] LCMS m / z = 708.2 [M+1] +

[0775] Second Step: 5-(2-(4-((2-([4,4'-Bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (15b)

[0776] 5-(2-(4-((2-([4,4'-Bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

[0777]

[0778] Dissolve 15a (1.98 g, 2.80 mmol) in 5 mL DCM, add 5 mL trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, dissolve the residue in 50 mL DCM, adjust the pH to 9 with saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with 100 mL dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude 15b (1.5 g).

[0779] LCMS m / z = 608.3 [M+1] +

[0780] Third Step: tert-Butyl 4-((1'-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidine-1-carboxylate (15c)

[0781] tert-Butyl 4-((1'-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidine-1-carboxylate

[0782]

[0783] To a solution of 15b (150 mg, 0.15 mmol) in 2 mL of DCM, 1 mL of trifluoroacetic acid was added and stirred at room temperature for 4 h. The reaction was concentrated under reduced pressure, the residue was dissolved in 50 mL of DCM, the pH was adjusted to 9 with saturated sodium bicarbonate solution, the liquid was separated, the aqueous phase was extracted with 100 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 15d (80 mg).

[0784] LCMS m / z = 805.3 [M+1] +

[0785] Fourth step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(1'-(piperidin-4-ylmethyl)- [4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (15d)

[0786] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(1'-(piperidin-4-ylmethyl)- [4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0787]

[0788] To a solution of 15c (120 mg, 0.15 mmol) in 2 mL of DCM, 1 mL of trifluoroacetic acid was added and stirred at room temperature for 4 h. The reaction was concentrated under reduced pressure, the residue was dissolved in 50 mL of DCM, the pH was adjusted to 9 with saturated sodium bicarbonate solution, the liquid was separated, the aqueous phase was extracted with 100 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 15d (80 mg).

[0789] LCMS m / z = 705.3 [M+1] +

[0790] Fifth step: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)- [4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (compound 15)

[0791] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)-[4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitriletrifluoroacetate

[0792]

[0793] The above crude 15d (80 mg) was dissolved in 5 mL DMSO, 0.2 mL DIPEA and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (33 mg, 0.12 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL water was added, extracted with 100 mL ethyl acetate, the organic phase was washed with 100 mL water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was passed through Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude was dissolved with methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.1% TFA). Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and freeze-dried to obtain trifluoroacetate salt of compound 15 (10 mg).

[0794] 1H NMR (400 MHz, CDC13) δ 8.29 (d, 1H), 8.04 (br. s, 1H), 7.60 - 7.51 (m, 1H), 7.43 (d, 1H), 7.38 - 7.30 (m, 2H), 7.16 (d, 1H), 7.12 - 7.05 (m, 2H), 6.92 - 6.85 (m, 2H), 6.65 (d, 1H), 5.00 - 4.89 (m, 3H), 4.87 - 4.76 (m, 2H), 4.41 (t, 2H), 3.87 (t, 2H), 3.80 - 3.67 (m, 2H), 3.05 - 2.60 (m, 9H), 2.32 - 2.06 (m, 3H), 2.00 - 1.84 (m, 3H), 1.83 - 1.75 (m, 3H), 1.74 - 1.66 (m, 2H), 1.63 (s, 6H), 1.55 - 1.44 (m, 2H), 1.30 - 1.18 (m, 4H), 1.18 - 1.09 (m, 1H), 0.93 - 0.87 (m, 2H).

[0795] LCMS m / z = 481.3 [M / 2 + 1] +

[0796] Example 16:

[0797] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0798] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0799]

[0800] Step 1: tert-Butyl (3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (16a)

[0801] tert-butyl(3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0802]

[0803] 3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4a) (synthesis method, see WO2020081999) (300 mg, 0.63 mmol) and (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (130 mg, 0.61 mmol) were dissolved in 15 mL of DMF, potassium bicarbonate (130 mg, 1.30 mmol) was added at room temperature, and the temperature was raised to 60°C for 3 h. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and the mixture was extracted with 30 mL of ethyl acetate. The mixture was washed with saturated sodium chloride solution (15 mL × 2). The organic phase was collected and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-5:1) to obtain 16a (0.31 g, yield: 75%).

[0804] Step 2: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (16b)

[0805] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0806]

[0807] Dissolve 16a (148 mg, 0.23 mmol) in 4 mL of DCM, add 2 mL of trifluoroacetic acid, and react at room temperature for 2 h. Concentrate the reaction solution under reduced pressure, adjust the pH to 10 with a saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 16b (120 mg).

[0808] Third step: tert-butyl 4-((3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)piperidine-l-carboxylate (16c)

[0809] tert-butyl 4-((3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)piperidine-l-carboxylate

[0810]

[0811] Dissolve the above crude 16b (120 mg) and N-Boc-piperidinone (88 mg, 0.44 mmol) in 8 mL of chloroform, add acetic acid (40 mg, 0.66 mmol) and anhydrous magnesium sulfate (100 mg) in sequence, warm to 70 °C, and react for 3 h. Cool to room temperature, add sodium triacetoxyborohydride (230 mg, 1.09 mmol), and react at room temperature for 16 h. Add 20 mL of water to the reaction solution, adjust the pH to 10 with a saturated aqueous sodium bicarbonate solution, extract with dichloromethane (30 mL x 3), wash the combined organic phases with water (20 mL x 2), dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography on silica gel (dichloromethane / methanol (v / v) = 20: 1-8: 1) to obtain 16c (102 mg, two-step yield of 60% from compound 16a).

[0812] Fourth step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(piperidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2- yl)benzonitrile (16d)

[0813] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0814]

[0815] Dissolve 16c (102 mg, 0.14 mmol) in 3 mL of DCM, add 1.5 mL of trifluoroacetic acid, and react at room temperature for 2 h. Concentrate the reaction solution under reduced pressure, adjust the pH to 10 with a saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 16d (85 mg).

[0816] Fifth step: tert-butyl 4-((4-((3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (16e)

[0817] tert-butyl 4-((4-((3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0818]

[0819] To a solution of 16d (85 mg) in 8 mL of CH2Cl2, acetic acid (10 mg, 0.167 mmol) and anhydrous magnesium sulfate (80 mg) were added, and the mixture was heated to 70 °C for 3 h. After cooling to room temperature, sodium triacetoxyborohydride (140 mg, 0.66 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction mixture was added 20 mL of water, and the pH was adjusted to 10 with saturated aqueous NaHC03solution. The mixture was extracted with CH2Cl2(30 mL x 3), and the combined organic layers were washed with water (20 mL x 2), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH (v / v) = 20:1-8:1) to give 16e (51 mg, 44% over two steps from compound 16c).

[0820] Step 6: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-(piperidin-4-ylmethyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0821] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-(piperidin-4-ylmethyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0822]

[0823] To a solution of 16e (51 mg, 0.061 mmol) in 3 mL of DCM, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2.5 h. The pH of the reaction mixture was adjusted to 10 with saturated aqueous NaHC03solution, and the aqueous phase was extracted with CH2Cl2(10 mL x 3). The combined organic layers were dried over anhydrous Na2S04and concentrated under reduced pressure to give crude 16f (49 mg).

[0824] Step 7: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (compound 16)

[0825] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0826]

[0827] The above crude 16f (49 mg) was dissolved in 8 mL of DMSO, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (19 mg, 0.069 mmol) and diisopropylethylamine (43 mg, 0.33 mmol) were added at room temperature, and the reaction was heated to 80°C for 3.5h. Cooled to room temperature, the reaction was poured into 30 mL of ethyl acetate, washed with saturated aqueous sodium chloride solution (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1-8:1) to obtain compound 16 (51 mg, two-step yield from compound 16e: 84%).

[0828] 1 H NMR (400 MHz, CDC13) δ 8.36 - 8.20 (m, 2H), 7.66 (d, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.29 - 7.26 (m, 1H), 7.13 - 6.99 (m, 3H), 6.93 - 6.86 (m, 2H), 6.73 (d, 1H), 5.00 - 4.88 (m, 3H), 4.41 (t, 2H), 3.98 - 3.82 (m, 4H), 3.80 - 3.68 (m, 2H), 3.63 - 3.50 (m, 2H), 3.10 - 2.65 (m, 11H), 2.55 - 2.43 (m, 2H), 2.28 - 2.07 (m, 4H), 2.06 - 1.93 (m, 2H), 1.93 - 1.81 (m, 4H), 1.81 - 1.72 (m, 1H), 1.70 - 1.52 (m, 8H), 1.30 - 1.24 (m, 2H).

[0829] LCMS m / z = 988.3 [M+1] +

[0830] Example 17: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 17)

[0831] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0832]

[0833] First Step: tert-butyl 3-(4-((3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)azetidine-1-carboxylate (17a)

[0834] tert-butyl 3-(4-((3aR,6aS)-5-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)azetidine-1-carboxylate

[0835]

[0836] To a solution of 16d (85 mg) in 10 mL of CHCl3, acetic acid (11 mg, 0.183 mmol) and anhydrous magnesium sulfate (120 mg) were added successively, and the mixture was heated to 70 °C for 3 h. After cooling to room temperature, sodium triacetoxyborohydride (141 mg, 0.67 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction mixture was added 20 mL of water, and the pH was adjusted to 10 with saturated aqueous NaHC03solution. The mixture was extracted with CH2Cl2(30 mL x 3), and the combined organic phase was washed with water (20 mL x 2), dried over anhydrous Na2S04, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (CH2Cl2 / MeOH (v / v) = 20:1-8:1) to give 17a (73 mg, 66% over two steps from compound 16c).

[0837] Second step: 5-(2-(4-((2-((3aR,6aS)-5-(1-(azetidin-3-yl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (17b)

[0838] 5-(2-(4-((2-((3aR,6aS)-5-(1-(azetidin-3-yl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

[0839]

[0840] To a solution of 17a (73 mg, 0.092 mmol) in 4 mL of DCM was added 1.5 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1.5 h. The pH of the reaction mixture was adjusted to 10 with saturated aqueous NaHC03solution, and the aqueous phase was extracted with CH2Cl2(10 mL x 3). The combined organic phase was dried over anhydrous Na2S04and concentrated under reduced pressure to give the crude product 17b (60 mg).

[0841] Third step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (compound 17)

[0842] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-((3aR,6aS)-5-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0843]

[0844] The above crude 17b (60 mg) was dissolved in 5 mL of DMSO, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (24 mg, 0.087 mmol) and diisopropylethylamine (56 mg, 0.43 mmol) were added at room temperature, and the reaction was heated to 80 °C for 3.5 h. Cooled to room temperature, the reaction was poured into 35 mL of ethyl acetate, washed with saturated aqueous sodium chloride solution (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1-8:1) to give compound 17 (52 mg, two-step yield from compound 17a: 60%).

[0845] 1 H NMR (400 MHz, CDC13) δ 8.32 (d, 1H), 8.00 (s, 1H), 7.63 (d, 1H), 7.44 (d, 1H), 7.31 (d, 1H), 7.13 - 7.04 (m, 2H), 6.93 - 6.84 (m, 2H), 6.81 - 6.70 (m, 2H), 6.51 (dd, 1H), 5.00 - 4.85 (m, 3H), 4.41 (t, 2H), 4.07 (t, 2H), 3.91 - 3.81 (m, 4H), 3.80 - 3.45 (m, 4H), 3.42 - 3.27 (m, 1H), 3.20 - 2.65 (m, 8H), 2.65 - 2.40 (m, 2H), 2.18 - 2.06 (m, 1H), 2.06 - 1.84 (m, 4H), 1.74 - 1.46 (m, 10H).

[0846] LCMS m / z = 946.6 [M+1] +

[0847] Example 18:

[0848] 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-2-ethoxybenzonitrile

[0849] 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-2-ethoxybenzonitrile

[0850]

[0851] First Step: methyl 3-chloro-4-hydroxy-5-iodobenzoate (18b)

[0852] methyl 3-chloro-4-hydroxy-5-iodobenzoate

[0853]

[0854] methyl 3-chloro-4-hydroxy-5-iodobenzoate (18b) was prepared from methyl 3-chloro-4-hydroxybenzoate (18a) (8.0 g, 42.9 mmol) following the procedure described in the first step. To a solution of methyl 3-chloro-4-hydroxy-5-iodobenzoate (18b) (12 g, 35.9 mmol) in 100 mL of dichloromethane was added ethylmagnesium bromide (2.5 M in diethyl ether, 71 mL, 177.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then quenched with 100 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 100 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 18c (12 g).

[0855] Second Step: methyl 3-chloro-4-ethoxy-5-iodobenzoate (18c)

[0856] methyl 3-chloro-4-ethoxy-5-iodobenzoate

[0857]

[0858] Dissolve the above crude 18b (12 g) in 100 mL of DMF, add iodoethane (9.0 g, 57.7 mmol), add potassium carbonate (10.66 g, 77.1 mmol), and raise the temperature to 60 °C for 2 h. Cool to room temperature, slowly add 200 mL of water to the reaction, and extract with 200 mL of ethyl acetate. Wash the organic phase with saturated sodium chloride solution (50 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give 18c (9 g, 62% yield over two steps from compound 18a).

[0859] Third Step: 3-Chloro-2-ethoxy-5-(2-hydroxypropan-2-yl)benzonitrile (18d)

[0860] 3-chloro-2-ethoxy-5-(2-hydroxypropan-2-yl)benzonitrile

[0861]

[0862] Dissolve 18c (9.0 g, 26.4 mmol) in 100 mL of N-methylpyrrolidone, add cuprous cyanide (2.6 g, 29.03 mmol), and raise the temperature to 160 °C for 2 h. Cool the reaction to room temperature, filter the reaction, slowly add 100 mL of water to the filtrate, extract with 200 mL of ethyl acetate, wash the organic phase with saturated sodium chloride solution (50 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give 18d (5.0 g, 79% yield).

[0863] Fourth Step: 3-Chloro-2-ethoxy-5-(2-hydroxypropan-2-yl)benzonitrile (18e)

[0864] 3-chloro-2-ethoxy-5-(2-hydroxypropan-2-yl)benzonitrile

[0865]

[0866] Add 8 mL of 3 mol / L methylmagnesium bromide in 2-methyltetrahydrofuran to 7 mL of tetrahydrofuran, cool to 0 °C, then add a tetrahydrofuran solution (14 mL) of 18d (1.4 g, 5.84 mmol) dropwise, and continue the reaction at 0 °C for 2 h. Add 60 mL of saturated ammonium chloride solution to the reaction, extract with 50 mL of ethyl acetate, wash with 50 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give crude 18e (1.3 g).

[0867] Fifth Step: 3-Chloro-2-ethoxy-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile (18f)

[0868] 3-chloro-2-ethoxy-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile

[0869]

[0870] To the above crude 18e (1.3 g) was dissolved in 15 mL of carbon tetrachloride, phenol (0.57 g, 6.06 mmol) was added, cooled to 0 °C, boron trifluoride diethyl ether (1.58 g, 11.13 mmol) was added, and then warmed to room temperature for 3 h. To the reaction solution was slowly added 20 mL of water, extracted with 30 mL of dichloromethane, the organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0:1-3:7) to obtain 18f (1.50 g, two-step yield: 81% from compound 18d).

[0871] Sixth step: 3-chloro-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-2-ethoxybenzonitrile

[0872] 3-chloro-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-2-ethoxybenzonitrile

[0873]

[0874] To 18f (0.58 g, 1.84 mmol) was dissolved in 15 mL of acetonitrile, 2-chloro-4- (chloromethyl)pyrimidine (0.30 g, 1.84 mmol) and potassium carbonate (0.51 g, 3.69 mmol) were sequentially added, and warmed to 70 °C for 20 h. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the crude was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0:1-3:7) to obtain 18g (0.38 g, yield: 47%).

[0875] LCMS m / z = 442.3 [M+1] +

[0876] Seventh step: tert-butyl 3-(4-(4-(4-((4-(2-(3-chloro-5-cyano-4-ethoxyphenyl)propan-2- yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate (18h)

[0877] tert-butyl 3-(4-(4-(4-((4-(2-(3-chloro-5-cyano-4-ethoxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylate

[0878]

[0879] To 18 g (270 mg, 0.61 mmol) dissolved in 10 mL of DMF, 3-(4-(piperazin-1-yl)piperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (intermediate 1) (200 mg) and solid potassium bicarbonate (133 mg, 1.33 mmol) were added sequentially, and the temperature was raised to 90°C with stirring for 4 h. After cooling to room temperature, 30 mL of water was added, and extraction was performed twice with 30 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane / methanol (v / v) = 20:1) to obtain 18h (380 mg, yield: 85% from compound 18g).

[0880] LCMS m / z = 730.5 [M+1] +

[0881] Eighth step: 5-(2-(4-((2-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-ethoxybenzonitrile (18i)

[0882] 5-(2-(4-((2-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-ethoxybenzonitrile

[0883]

[0884] To 18h (380 mg, 0.52 mmol) dissolved in 5 mL of DCM, 2 mL of trifluoroacetic acid was added, and stirring was performed at room temperature for 4 h. The reaction system was concentrated under reduced pressure, dissolved in 50 mL of DCM, and the pH was adjusted to 10 with a saturated sodium bicarbonate solution. Extraction was performed with 50 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 18i (300 mg).

[0885] LCMS m / z = 630.3 [M+1] +

[0886] Ninth step: 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-2-ethoxybenzonitrile (Compound 18)

[0887] 3-chloro-5-(2-(4-((2-(4-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-2-ethoxybenzonitrile

[0888]

[0889] The above crude 18i (100 mg) was dissolved in 10 mL of DMAc, 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxaldehyde (synthesis method see WO2020113233) (46 mg, 0.16 mmol), 0.1 mL of acetic acid and 1 g of molecular sieve powder were added in turn, and the temperature was raised to 80°C for 120 min, and sodium triacetoxyborohydride (230 mg, 1.085 mmol) was added. After cooling to room temperature, 30 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, and extracted with 60 mL of ethyl acetate twice, and the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1-9:1) to obtain compound 18 (10 mg, two-step yield from compound 18h: 6%).

[0890] 1H NMR (400 MHz, CDC13) δ 8.30 - 8.04 (m, 2H), 7.35 (s, 1H), 7.23 (s, 1H), 7.10 - 6.58 (m, 8H), 5.20 - 5.05 (m, 1H), 4.87 (s, 2H), 4.28 - 4.10 (m, 2H), 3.98 - 3.55 (m, 8H), 3.48 - 3.30 (m, 2H), 3.10 - 2.21 (m, 12H), 2.20 - 2.06 (m, 1H), 1.95 - 1.67 (m, 5H), 1.67 - 1.45 (m, 9H), 1.45 - 1.37 (m, 3H).

[0891] LCMS m / z = 451.4 [M / 2 + 1] +

[0892] Example 19:

[0893] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0894] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0895]

[0896]

[0897] First Step: Benzyl 4-((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (19a)

[0898] Benzyl 4-((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0899]

[0900] The crude benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (11b) (1.0 g) was dissolved in 15 mL of DCE, and 3-formyl tert-butyl azetidine-1-carboxylate (875 mg, 4.72 mmol) and 0.5 mL of acetic acid were added successively. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (1.34 g, 6.32 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction mixture was slowly added 80 mL of saturated sodium bicarbonate solution, and the mixture was extracted with 200 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane / methanol (v / v) = 20:1) to give 19a (1.2 g, two-step yield: 64% from compound 11a).

[0901] LCMS m / z = 487.2 [M+1] +

[0902] Second step: tert-butyl 3-((4-(piperazin-1-ylmethyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (19b)

[0903] tert-butyl 3-((4-(piperazin-1-ylmethyl)piperidin-1-yl)methyl)azetidine-1-carboxylate

[0904]

[0905] The crude 19a (1.2 g, 2.47 mmol) was dissolved in 20 mL of methanol, and 0.2 g of 10% palladium-carbon was added. The reaction was stirred at room temperature for 16 h under a hydrogen balloon atmosphere. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give the crude 19b (860 mg).

[0906] LCMS m / z = 353.2 [M+1] +

[0907] Step 3: tert-butyl 3-((4-((4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin- 1-yl)methyl)azetidine-1-carboxylate (19c)

[0908] tert-butyl 3-((4-((4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin- 1-yl)methyl)azetidine-1-carboxylate

[0909]

[0910] tert-butyl 3-((4-((4-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin- 1-yl)methyl)azetidine-1-carboxylate

[0911] LCMS m / z = 792.3 [M+1] +

[0912] Step 4: trifluoroacetate salt of 5-(2-(4-((2-(4-((1-(azetidin-3-ylmethyl)piperidin-4- yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2- chloroethoxy)benzonitrile (19d)

[0913] 5-(2-(4-((2-(4-((1-(azetidin-3-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[0914]

[0915] Dissolve 19c (60 mg, 0.076 mmol) in 5 mL DCM, add 2 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 19d (75 mg).

[0916] LC-MS m / z = 692.3 [M+1] +

[0917] Fifth Step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 19) trifluoroacetate salt

[0918] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0919]

[0920] The trifluoroacetate salt of the above crude 19d (75 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (32 mg, 0.38 mmol) was added, after stirring at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (42 mg, 0.15 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude was dissolved with methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 19 (10 mg) was obtained by lyophilization.

[0921] 1 H NMR (400 MHz, CDCl3) δ 9.25 (br. s, 1H), 8.34 (d, 1H), 7.55 (d, 1H), 7.45 (d, 1H), 7.28 (d, 1H), 7.09 (d, 2H), 6.94-6.79 (m, 3H), 6.70-6.58 (m, 1H), 6.48-6.34 (m, 1H), 5.04-4.85 (m, 3H), 4.40 (t, 2H), 4.23-4.07 (m, 2H), 3.86 (t, 2H), 3.78-3.63 (m, 2H), 3.62-3.47 (m, 2H), 3.45-3.13 (m, 7H), 3.13-2.94 (m, 4H), 2.94-2.78 (m, 4H), 2.78-2.60 (m, 3H), 2.51-2.36 (m, 1H), 2.24-2.00 (m, 3H), 2.00-1.75 (m, 2H), 1.63 (s, 6H).

[0922] LCMS m / z = 948.3 [M+1] + .

[0923] Example 20:

[0924] 3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 20)

[0925] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-5-yl)azeti din-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0926]

[0927] Step 1: tert-Butyl 7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (20a)

[0928] tert-butyl 7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0929]

[0930] Dissolve 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4a) (synthesis method see WO2020081999) (300 mg, 0.63 mmol) in 20 mL of DMF, add 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (171 mg, 0.76 mmol) and potassium bicarbonate (126 mg, 1.26 mmol) successively, and warm to 60°C for 3 h. Cool to room temperature, add 50 mL of water to the reaction system, extract with ethyl acetate (40 mL x 3), wash the organic phase with water (50 mL x 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to obtain 20a (370 mg, yield: 88%).

[0931] LCMS m / z = 666.2 [M+1] +

[0932] Second step: trifluoroacetate salt of 5-(2-(4-((2-(2,7-diazaspiro[3.5]non-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (20b)

[0933] 5-(2-(4-((2-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[0934]

[0935] Dissolve 20a (0.37 g, 0.56 mmol) in 10 mL of DCM, add 4 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction solution under reduced pressure to obtain the trifluoroacetate salt of the crude product 20b (0.44 g).

[0936] LCMS m / z = 566.2 [M+1] +

[0937] Third step: 4-(7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidine-1-carboxylic acid tert-butyl ester (20c)

[0938] tert-butyl 4-(7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidine-1-carboxylate

[0939]

[0940] The trifluoroacetate salt of the above crude 20b (440 mg) was dissolved in 15 mL of DCE, and solid sodium bicarbonate (132 mg, 1.57 mmol) was added. After stirring at room temperature for 20 min, N-Boc-4-piperidone (210 mg, 1.06 mmol) and 0.1 mL of acetic acid were added in sequence. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (220 mg, 1.04 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction system was slowly added 30 mL of saturated sodium bicarbonate solution, and the mixture was extracted with 120 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 20c (400 mg, two-step yield of 95% from compound 20a).

[0941] LCMS m / z = 749.3 [M+1] +

[0942] Fourth step: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (20d)

[0943] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0944]

[0945] Dissolve 20c (200 mg, 0.27 mmol) in 10 mL DCM, add 4 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 20d (240 mg).

[0946] LCMS m / z = 649.3 [M+1] +

[0947] Fifth step: tert-butyl 3-(4-(7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan- 2-yl)piperidin-1-yl)azetidine-1-carboxylate (20e)

[0948] tert-butyl 3-(4-(7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)azetidine-1-carboxylate

[0949]

[0950] Dissolve the above trifluoroacetate salt of crude 20d (240 mg) in 15 mL DCE, add solid sodium bicarbonate (112 mg, 1.33 mmol), stir at room temperature for 20 min, then add 1-Boc-3-azetidinone (91 mg, 0.53 mmol) and 0.05 mL acetic acid successively, stir at room temperature for 60 min, then add sodium triacetoxyborohydride (115 mg, 0.54 mmol), react at room temperature for 16 h. Slowly add 30 mL saturated sodium bicarbonate solution to the reaction system, extract with 120 mL DCM, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 20e (200 mg, two-step yield of 92% from compound 20c).

[0951] LCMS m / z = 804.3 [M+1] +

[0952] Step 6: Trifluoroacetate salt of 5-(2-(4-((2-(2-(1-(azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (20f)

[0953] 5-(2-(4-((2-(2-(1-(azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[0954]

[0955] Dissolve 20e (50 mg, 0.062 mmol) in 5 mL DCM, add 2 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 20f (60 mg).

[0956] LCMS m / z = 704.3 [M+1] +

[0957] Step 7: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 20)

[0958] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0959]

[0960] The trifluoroacetate salt of the above crude 20f (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, after stirring at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80°C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to obtain compound 20 (15 mg, two-step yield: 25% from compound 20e).

[0961] 1 H NMR (400 MHz, CDC13) δ 8.29 (d, 1H), 8.04 (br. s, 1H), 7.64 (d, 1H), 7.44 (d, 1H), 7.31 (d, 1H), 7.13 - 7.04 (m, 2H), 6.92 - 6.84 (m, 2H), 6.78 (d, 1H), 6.68 (d, 1H), 6.52 (dd, 1H), 5.00 - 4.85 (m, 3H), 4.41 (t, 2H), 4.15 - 4.02 (m, 2H), 3.94 - 3.82 (m, 4H), 3.82 - 3.70 (m, 4H), 3.43 - 3.33 (m, 1H), 3.33 - 2.94 (m, 4H), 2.94 - 2.65 (m, 5H), 2.29 - 2.07 (m, 2H), 2.07 - 1.95 (m, 2H), 1.93 - 1.70 (m, 6H), 1.70 - 1.52 (m, 8H).

[0962] LCMS m / z = 960.2 [M+1] + .

[0963] Example 21:

[0964] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 21)

[0965] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0966]

[0967] First Step: tert-butyl 4-((4-(7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (21a)

[0968] tert-butyl 4-((4-(7-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0969]

[0970] The trifluoroacetate salt of the above crude 20d (240 mg) was dissolved in 15 mL of DCE, and solid sodium bicarbonate (112 mg, 1.33 mmol) was added. After stirring at room temperature for 20 min, tert-butyl 4-formylpiperidine-1-carboxylate (114 mg, 0.53 mmol) and 0.05 mL of acetic acid were added in turn. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (115 mg, 0.54 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction system, 30 mL of saturated sodium bicarbonate solution was slowly added, and the organic phase was extracted with 120 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 21a (210 mg, two-step yield of 92% from compound 20c).

[0971] LCMS m / z = 846.4 [M+1] +

[0972] Second Step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(1-piperidin-4- ylmethyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan- 2-yl)benzonitrile trifluoroacetate

[0973] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0974]

[0975] Dissolve 21a (50 mg, 0.059 mmol) in 5 mL DCM, add 2 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give crude trifluoroacetate salt of 21b (60 mg).

[0976] LC-MS m / z = 746.4 [M+1] +

[0977] Third Step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 21)

[0978] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0979]

[0980] The trifluoroacetate salt of the above crude 21b (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, after stirring at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80°C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to obtain compound 21 (20 mg, two-step yield from compound 21a: 34%).

[0981] 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 8.19 (br. s, 1H), 7.66 (d, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.29-7.26 (m, 1H), 7.16-6.98 (m, 3H), 6.94-6.82 (m, 2H), 6.68 (d, 1H), 5.00-4.86 (m, 3H), 4.14 (t, 2H), 4.02-3.82 (m, 4H), 3.82-3.70 (m, 4H), 3.40-2.55 (m, 11H), 2.32-2.08 (m, 4H), 2.07-1.93 (m, 2H), 1.93-1.84 (m, 2H), 1.84-1.77 (m, 4H), 1.77-1.67 (m, 3H), 1.67-1.56 (m, 7H), 1.54-1.34 (m, 1H), 1.34-1.19 (m, 2H).

[0982] LCMS m / z = 1002.3 [M+1] + .

[0983] Example 22:

[0984] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0985] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(2-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[0986]

[0987] The trifluoroacetate salt of the above crude 20f (60 mg) was dissolved in 4 mL of anhydrous THF, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, after stirring at room temperature for 10 min, 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carbaldehyde (synthesis method see WO2020113233) (40 mg, 0.14 mmol) and acetic acid (0.02 mL, 0.35 mmol) were added in turn, after stirring at room temperature for 2 h, sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added, and the reaction was carried out at room temperature for 16 h. Solid sodium bicarbonate (100 mg, 1.19 mmol) was added to the reaction solution, after stirring at room temperature for 15 min, filtration was carried out, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved with methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.1% TFA). Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 22 (12 mg) was obtained by freeze-drying.

[0988] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.36 (d, 1H), 7.61 (d, 1H), 7.57 (d, 1H), 7.27 - 7.05 (m, 5H), 6.97 - 6.90 (m, 2H), 6.70 (d, 1H), 5.42 (dd, 1H), 4.97 (s, 2H), 4.80 - 4.60 (m, 2H), 4.45 - 4.38 (m, 2H), 4.25 - 4.13 (m, 2H), 4.08 - 3.90 (m, 8H), 3.85 - 3.73 (m, 2H), 3.73 - 3.63 (m, 2H), 3.59 (s, 3H), 3.51 - 3.35 (m, 1H), 3.35 - 3.17 (m, 2H), 3.14 - 2.97 (m, 2H), 2.97 - 2.80 (m, 1H), 2.79 - 2.58 (m, 2H), 2.08 - 1.90 (m, 4H), 1.90 - 1.80 (m, 2H), 1.80 - 1.70 (m, 2H), 1.63 (s, 6H), 1.50 - 1.28 (m, 2H).

[0989] LCMS m / z = 975.4 [M+1] + .

[0990] Example 23:

[0991] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0992] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[0993]

[0994] Step 1: tert-butyl 2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (23a)

[0995] tert-butyl 2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (23a)

[0996]

[0997] tert-butyl 2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (23a)

[0998] LCMS m / z = 666.2 [M+1] +

[0999] Step 2: trifluoroacetate salt of 5-(2-(4-((2-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (23b)

[1000] 5-(2-(4-((2-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[1001]

[1002] Dissolve 23a (0.30 g, 0.45 mmol) in 10 mL of DCM, add 4 mL of trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 23b (0.36 g).

[1003] LCMS m / z = 566.2 [M+1] +

[1004] Third step: tert-butyl 4-(2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-7- yl)piperidine-1-carboxylate (23c)

[1005] tert-butyl 4-(2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)piperidine-1-carboxylate

[1006]

[1007] Dissolve the above trifluoroacetate salt of crude 23b (0.36 g) in 15 mL of DCE, add solid sodium bicarbonate (115 mg, 1.37 mmol), stir at room temperature for 20 min, then add N-Boc-4-piperidone (180 mg, 0.90 mmol) and 0.1 mL of acetic acid, stir at room temperature for 60 min, then add sodium triacetoxyborohydride (191 mg, 0.90 mmol), react at room temperature for 16 h. Slowly add 30 mL of saturated sodium bicarbonate solution to the reaction system, extract with 120 mL of DCM, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 23c (320 mg, two-step yield of 95% from compound 23a).

[1008] LCMS m / z = 749.3 [M+1] +

[1009] Fourth step: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (23d)

[1010] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1011]

[1012] Dissolve 23c (160 mg, 0.21 mmol) in 10 mL DCM, add 4 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 23d (200 mg).

[1013] LCMS m / z = 649.3 [M+1] +

[1014] Fifth Step: tert-butyl 3-(4-(2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-7- yl)piperidin-1-yl)azetidine-1-carboxylate (23e)

[1015] tert-butyl 3-(4-(2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)piperidin-1-yl)azetidine-1-carboxylate

[1016]

[1017] The trifluoroacetate salt of crude 23d (200 mg) was dissolved in 15 mL of DCE, and solid sodium bicarbonate (74 mg, 0.88 mmol) was added. After stirring at room temperature for 20 min, 1-Boc-3-azetidinone (75 mg, 0.44 mmol) and 0.05 mL of acetic acid were added successively. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (94 mg, 0.44 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction system was slowly added 30 mL of saturated sodium bicarbonate solution, and the organic phase was extracted with 120 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 23e (140 mg, two-step yield of 83% from compound 23c).

[1018] LCMS m / z = 804.3 [M+1] +

[1019] Sixth step: trifluoroacetate salt of 5-(2-(4-((2-(7-(1-(azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (23f)

[1020] 5-(2-(4-((2-(7-(1-(azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[1021]

[1022] 23e (50 mg, 0.062 mmol) was dissolved in 5 mL of DCM, and 2 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h. The reaction liquid was concentrated under reduced pressure to give the trifluoroacetate salt of crude 23f (60 mg).

[1023] LC-MS m / z = 704.3 [M+1] +

[1024] Step 7: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 23)

[1025] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1026]

[1027] The trifluoroacetate salt of the above crude 23f (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, stirred at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to obtain Compound 23 (20 mg, two-step yield: 34% from Compound 23e).

[1028] 1H NMR (400 MHz, CDC13) δ 8.31 (d, 1H), 8.04 (br. s, 1H), 7.64 (d, 1H), 7.44 (d, 1H), 7.31 (d, 1H), 7.15 - 7.05 (m, 2H), 6.94 - 6.73 (m, 4H), 6.52 (dd, 1H), 5.00 - 4.87 (m, 3H), 4.41 (t, 2H), 4.18 - 4.03 (m, 2H), 3.95 - 3.79 (m, 8H), 3.42 - 3.29 (m, 1H), 3.02 - 2.92 (m, 2H), 2.92 - 2.66 (m, 4H), 2.66 - 2.30 (m, 4H), 2.21 - 2.08 (m, 1H), 2.02 - 1.78 (m, 6H), 1.75 - 1.51 (m, 10H).

[1029] LCMS m / z = 960.2 [M+1] + .

[1030] Example 24:

[1031] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1032] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1033]

[1034] First Step: tert-Butyl 4-((4-(2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (24a)

[1035] tert-butyl 4-((4-(2-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[1036]

[1037] The trifluoroacetate salt of the above crude 23d (185 mg) was dissolved in 15 mL of DCE, solid sodium bicarbonate (74 mg, 0.88 mmol) was added, after stirring at room temperature for 20 min, tert-butyl 4-formylpiperidine-1-carboxylate (91 mg, 0.46 mmol) and 0.05 mL of acetic acid were added in turn, after stirring at room temperature for 60 min, sodium triacetoxyborohydride (94 mg, 0.44 mmol) was added, and the reaction was carried out at room temperature for 16 h. 30 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with 120 mL of DCM, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 24a (180 mg, two-step yield from compound 23c: >99%).

[1038] LCMS m / z = 846.4 [M+1] +

[1039] Second step: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (24b)

[1040] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1041]

[1042] Dissolve 24a (50 mg, 0.059 mmol) in 5 mL DCM, add 2 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 24b (60 mg).

[1043] LC-MS m / z = 746.4 [M+1] +

[1044] Third step: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 24)

[1045] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1046]

[1047] Dissolve the above trifluoroacetate salt of crude 24b (60 mg) in 4 mL DMSO, add solid sodium bicarbonate (25 mg, 0.30 mmol), stir at room temperature for 10 min, then add 0.2 mL DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol), stir the reaction at 80 °C for 5 h. Cool the reaction to room temperature, add 50 mL water, filter, wash the filter cake with 10 mL water, dissolve the filter cake in 50 mL dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure, separate and purify the obtained crude product using thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to give Compound 24 (25 mg, two-step yield from Compound 24a: 42%).

[1048] 1H NMR (400 MHz, CDC13) δ 8.32 (d, 1H), 7.67 (d, 1H), 7.44 (d, 1H), 7.31 (d, 1H), 7.29 - 7.24 (m, 2H), 7.14 - 6.98 (m, 3H), 6.93 - 6.83 (m, 2H), 6.79 (m, 1H), 4.99 - 4.87 (m, 3H), 4.42 (t, 2H), 4.00 - 3.70 (m, 8H), 3.15 - 2.55 (m, 16H), 2.30 - 2.20 (m, 2H), 2.18 - 2.09 (m, 1H), 2.04 - 1.97 (m, 2H), 1.94 - 1.83 (m, 4H), 1.83 - 1.68 (m, 3H), 1.64 (s, 6H), 1.33 - 1.21 (m, 2H).

[1049] LCMS m / z = 501.9 [M / 2 + 1] + .

[1050] Example 25: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 25)

[1051] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1052]

[1053] The trifluoroacetate salt of the above crude 24b (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, after stirring at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80°C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to obtain compound 25 (20 mg, two-step yield from compound 24a: 34%).

[1054] 1 H NMR (400 MHz, CDC13) δ 8.31 (d, 1H), 7.97 (s, 1H), 7.61 - 7.51 (m, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.31 (d, 1H), 7.17 (d, 1H), 7.13 - 7.05 (m, 2H), 6.92 - 6.84 (m, 2H), 6.81 - 6.73 (m, 1H), 5.00 - 4.90 (m, 3H), 4.40 - 3.64 (m, 8H), 3.15 - 2.42 (m, 12H), 2.32 - 2.17 (m, 2H), 2.17 - 2.06 (m, 2H), 2.06 - 1.76 (m, 8H), 1.74 - 1.52 (m, 11H), 1.52 - 1.38 (m, 3H).

[1055] LCMS m / z = 1002.3 [M+1] + .

[1056] Example 26: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 26)

[1057] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(7-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1058]

[1059] To a solution of the above crude 24b trifluoroacetate salt (60 mg) in 4 mL of anhydrous THF was added solid sodium bicarbonate (25 mg, 0.30 mmol), stirred at room temperature for 10 min, then 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carbaldehyde (synthesis method see WO2020113233) (40 mg, 0.14 mmol) and acetic acid (0.02 mL, 0.35 mmol) were added in turn, stirred at room temperature for 2 h, then sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. Solid sodium bicarbonate (100 mg, 1.19 mmol) was added to the reaction mixture, stirred at room temperature for 15 min, then filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to give compound 26 (15 mg, two-step yield from compound 24a: 26%).

[1060] 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.32 (d, 1H), 7.62 (d, 1H), 7.56 (d, 1H), 7.23 - 7.12 (m, 2H), 7.09 - 7.00 (m, 1H), 7.00 - 6.87 (m, 4H), 6.72 (d, 1H), 5.36 (dd, 1H), 4.96 (s, 2H), 4.47 - 4.37 (m, 2H), 3.99 - 3.91 (m, 2H), 3.86 - 3.66 (m, 6H), 3.63 (s, 3H), 3.38 - 3.30 (m, 2H), 2.97 - 2.78 (m, 4H), 2.78 - 2.57 (m, 5H), 2.57 - 2.51 (m, 2H), 2.49 - 2.35 (m, 2H), 2.35 - 2.06 (m, 2H), 2.06 - 1.95 (m, 1H), 1.86 - 1.66 (m, 6H), 1.62 (s, 6H), 1.52 - 1.36 (m, 2H).

[1061] LCMS m / z = 975.4 [M+1] +

[1062] Example 27:

[1063] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1064] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1065]

[1066] First Step: tert-butyl 9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (27a)

[1067] tert-butyl 9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[1068]

[1069] tert-butyl 9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[1070] LCMS m / z = 694.2 [M+1] +

[1071] Second Step: 5-(2-(4-((2-(3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[1072] 5-(2-(4-((2-(3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[1073] 5-(2-(4-((2-(3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[1074] DCE (15 mL) and stirred at room temperature for 20 min. N-Boc-4-piperidone (143 mg, 0.72 mmol) and 0.1 mL acetic acid were added and stirred at room temperature for 60 min. Sodium triacetoxyborohydride (153 mg, 0.72 mmol) was added and stirred at room temperature for 16 h. To the reaction mixture was slowly added 30 mL saturated sodium bicarbonate solution and extracted with 120 mL DCM. The organic phase was washed with 50 mL water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 27c (270 mg, 97% yield over two steps from compound 27a).

[1075] LCMS m / z = 594.2 [M+1] +

[1076] Third Step: tert-butyl 4-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan- 3-yl)piperidine-1-carboxylate (27c)

[1077] tert-butyl 4-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidine-1-carboxylate

[1078]

[1079] DCE (15 mL) and stirred at room temperature for 20 min. N-Boc-4-piperidone (143 mg, 0.72 mmol) and 0.1 mL acetic acid were added and stirred at room temperature for 60 min. Sodium triacetoxyborohydride (153 mg, 0.72 mmol) was added and stirred at room temperature for 16 h. To the reaction mixture was slowly added 30 mL saturated sodium bicarbonate solution and extracted with 120 mL DCM. The organic phase was washed with 50 mL water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 27c (270 mg, 97% yield over two steps from compound 27a).

[1080] LCMS m / z = 777.3 [M+1] +

[1081] Fourth Step: Trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (27d)

[1082] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1083]

[1084] Dissolve 27c (100 mg, 0.13 mmol) in 10 mL DCM, add 4 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 27d (120 mg).

[1085] LCMS m / z = 677.3 [M+1] +

[1086] Fifth Step: tert-Butyl 4-((4-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (27e)

[1087] tert-Butyl 4-((4-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

[1088]

[1089] The trifluoroacetate salt of the above crude 27d (120 mg) was dissolved in 15 mL of DCE, and solid sodium bicarbonate (45 mg, 0.54 mmol) was added. After stirring at room temperature for 20 min, tert-butyl 4-formylpiperidine-1-carboxylate (55 mg, 0.26 mmol) and 0.05 mL of acetic acid were added successively. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (55 mg, 0.26 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction system was slowly added 30 mL of saturated sodium bicarbonate solution, and the organic phase was extracted with 120 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 27e (110 mg, two-step yield: 97% from compound 27c).

[1090] LCMS m / z = 874.4 [M+1] +

[1091] Sixth step: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (27f)

[1092] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1093]

[1094] 27e (100 mg, 0.11 mmol) was dissolved in 5 mL of DCM, and 2 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to give the trifluoroacetate salt of the crude 27f (120 mg).

[1095] LC-MS m / z = 774.4 [M+1] +

[1096] Step 7: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 27)

[1097] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1098]

[1099] The trifluoroacetate salt of the above crude 27f (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, stirred at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to obtain Compound 27 (25 mg, two-step yield: 44% from Compound 27e).

[1100] 1H NMR (400 MHz, CDC13) δ 8.30 (d, 1H), 8.07 (br. s, 1H), 7.66 (d, 1H), 7.44 (d, 1H), 7.31 (d, 1H), 7.29 - 7.26 (m, 1H), 7.15 - 6.97 (m, 3H), 6.94 - 6.83 (m, 2H), 6.68 (d, 1H), 4.99 - 4.87 (m, 3H), 4.42 (t, 2H), 4.00 - 3.72 (m, 8H), 3.05 - 2.37 (m, 12H), 2.25 - 2.07 (m, 3H), 2.04 - 1.82 (m, 7H), 1.82 - 1.60 (m, 12H), 1.60 - 1.47 (m, 4H), 1.33 - 1.20 (m, 2H).

[1101] LCMS m / z = 1030.3 [M+1] + .

[1102] Example 28:

[1103] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1104] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1105]

[1106] The trifluoroacetate salt of the above crude 27f (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, stirred at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude was separated and purified by thick preparative plate (methanol / dichloromethane (v / v) = 1:12) to obtain compound 28 (25 mg, two-step yield: 44% from compound 27e).

[1107] 1 H NMR (400 MHz, CDC13) δ 8.29 (d, 1H), 8.04 (br. s, 1H), 7.60 - 7.50 (m, 1H), 7.44 (d, 1H), 7.35 (d, 1H), 7.32 (d, 1H), 7.17 (d, 1H), 7.13 - 7.04 (m, 2H), 6.92 - 6.83 (m, 2H), 6.67 (d, 1H), 5.00 - 4.90 (m, 3H), 4.41 (t, 2H), 3.92 - 3.66 (m, 8H), 3.05 - 2.32 (m, 12H), 2.30 - 2.17 (m, 2H), 2.16 - 2.06 (m, 1H), 2.04 - 1.80 (m, 7H), 1.79 - 1.59 (m, 12H), 1.59 - 1.49 (m, 4H), 1.49 - 1.37 (m, 2H).

[1108] LCMS m / z = 1030.4 [M+1] + .

[1109] Example 29:

[1110] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 29) trifluoroacetate salt

[1111] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1112]

[1113] First Step: tert-butyl 3-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)azetidine-1-carboxylate (29a)

[1114] tert-butyl 3-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)azetidine-1-carboxylate

[1115]

[1116] The trifluoroacetate salt of 27b (0.12 g) was dissolved in 15 mL of DCE, solid sodium bicarbonate (36 mg, 0.43 mmol) was added, after stirring at room temperature for 20 min, N-Boc-3-azetidinone (50 mg, 0.29 mmol) and 0.05 mL of acetic acid were added in turn, after stirring at room temperature for 60 min, sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added, and the reaction was carried out at room temperature for 16 h. 30 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with 120 mL of DCM, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 29a (110 mg, two-step yield from compound 27a: 99%).

[1117] LCMS m / z = 749.3 [M+1]+

[1118] Trifluoroacetate salt of 5-(2-(4-((2-(9-(azetidin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile

[1119] 5-(2-(4-((2-(9-(azetidin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[1120]

[1121] Dissolve 29a (50 mg, 0.067 mmol) in 5 mL DCM, add 2 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 29b (65 mg).

[1122] LCMS m / z = 649.3 [M+1] +

[1123] Trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 29)

[1124] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1125]

[1126] To a solution of the above crude 29b trifluoroacetate salt (65 mg) in 4 mL of anhydrous THF was added solid sodium bicarbonate (25 mg, 0.30 mmol), stirred at room temperature for 10 min, then 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carboxaldehyde (synthesis method see WO2020113233) (40 mg, 0.14 mmol) and acetic acid (0.02 mL, 0.35 mmol) were added, stirred at room temperature for 2 h, then sodium triacetoxyborohydride (28 mg, 0.13 mmol) was added, reacted at room temperature for 16 h, then solid sodium bicarbonate (100 mg, 1.19 mmol) was added, stirred at room temperature for 15 min, then filtered, the filtrate was concentrated under reduced pressure, the crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved with methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 29 (15 mg) was obtained by lyophilization.

[1127] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.34 (d, 1H), 7.61 (d, 1H), 7.56 (d, 1H), 7.28-6.89 (m, 7H), 6.67 (d, 1H), 5.41 (dd, 1H), 4.97 (s, 2H), 4.53-4.28 (m, 4H), 4.24-3.84 (m, 7H), 3.82-3.68 (m, 4H), 3.62 (s, 3H), 3.25-2.96 (m, 4H), 2.96-2.82 (m, 1H), 2.81-2.57 (m, 2H), 2.07-1.93 (m, 1H), 1.93-1.40 (m, 14H).

[1128] LCMS m / z = 920.2 [M+1] + .

[1129] Example 30:

[1130] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1131] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1132]

[1133] First Step: tert-butyl 3-(4-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)azetidine-1-carboxylate (30a)

[1134] tert-butyl 3-(4-(9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)azetidine-1-carboxylate

[1135]

[1136] The trifluoroacetate salt of the above crude 27d (190 mg) was dissolved in 15 mL of DCE, and solid sodium bicarbonate (64 mg, 0.76 mmol) was added. After stirring at room temperature for 20 min, 1-Boc-3-azetidinone (66 mg, 0.39 mmol) and 0.05 mL of acetic acid were added successively. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction system was slowly added 30 mL of saturated sodium bicarbonate solution, and the organic phase was extracted with 120 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 30a (160 mg, two-step yield: 94% from compound 27c).

[1137] LCMS m / z = 832.3 [M+1] +

[1138] Second step: trifluoroacetate salt of 5-(2-(4-((2-(9-(1-(azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (30b)

[1139] 5-(2-(4-((2-(9-(1-(azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile trifluoroacetate

[1140]

[1141] 30a (50 mg, 0.07 mmol) was dissolved in 5 mL of DCM, and 2 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to give the trifluoroacetate salt of the crude 30b (60 mg).

[1142] LC-MS m / z = 732.3 [M+1] +

[1143] Step 3: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1144] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1145]

[1146] The trifluoroacetate salt of the above crude 30b (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, stirred at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude was dissolved with methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and freeze-drying obtained 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate (15 mg).

[1147] 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.35 (d, 1H), 7.72 (d, 1H), 7.65 - 7.53 (m, 2H), 7.22 - 7.10 (m, 2H), 6.98 - 6.90 (m, 2H), 6.90 - 6.85 (m, 1H), 6.79 - 6.70 (m, 1H), 6.67 (d, 1H), 5.07 (dd, 1H), 4.97 (s, 2H), 4.45 - 4.37 (m, 2H), 4.36 - 4.26 (m, 2H), 4.25 - 4.15 (m, 2H), 4.15 - 4.04 (m, 1H), 4.00 - 3.91 (m, 2H), 3.85 - 3.67 (m, 4H), 3.48 - 3.30 (m, 4H), 3.22 - 3.00 (m, 3H), 2.97 - 2.68 (m, 3H), 2.65 - 2.52 (m, 2H), 2.43 - 2.28 (m, 2H), 2.12 - 1.76 (m, 5H), 1.75 - 1.50 (m, 10H), 1.46 - 1.32 (m, 2H).

[1148] LCMS m / z = 988.3 [M+1] + .

[1149] Example 31:

[1150] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1151] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(1-(1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1152]

[1153] The trifluoroacetate salt of the above crude 30b (60 mg) was dissolved in 4 mL of anhydrous THF, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, after stirring at room temperature for 10 min, 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carboxaldehyde (synthesis method see WO2020113233) (40 mg, 0.14 mmol) and acetic acid (0.02 mL, 0.35 mmol) were added, after stirring at room temperature for 2 h, sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added, after reaction at room temperature for 16 h, solid sodium bicarbonate (100 mg, 1.19 mmol) was added, after stirring at room temperature for 15 min, filtration was performed, the filtrate was concentrated under reduced pressure, the crude was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, the preparation column model was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude was dissolved with methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 31 (10 mg) was obtained by lyophilization.

[1154] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.35 (d, 1H), 7.61 (d, 1H), 7.57 (d, 1H), 7.30 - 7.05 (m, 5H), 7.04 - 6.88 (m, 2H), 6.67 (d, 1H), 5.42 (dd, 1H), 4.97 (s, 2H), 4.74 - 4.60 (m, 2H), 4.45 - 4.38 (m, 2H), 4.23 - 4.09 (m, 2H), 4.09 - 3.98 (m, 2H), 3.98 - 3.91 (m, 2H), 3.82 - 3.68 (m, 4H), 3.60 (s, 3H), 3.52 - 3.32 (m, 3H), 3.32 - 3.18 (m, 1H), 3.17 - 3.02 (m, 2H), 2.98 - 2.83 (m, 1H), 2.80 - 2.58 (m, 2H), 2.54 - 2.50 (m, 4H), 2.25 - 1.85 (m, 7H), 1.76 - 1.50 (m, 10H), 1.44 - 1.30 (m, 2H).

[1155] LCMS m / z = 1003.4 [M+1] + .

[1156] Example 32: 3-chloro-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 32)

[1157] 3-chloro-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1158]

[1159]

[1160] First Step: tert-butyl 4-((4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)-[1,4'-bipiperidine]-1'-carboxylate (32a)

[1161] tert-butyl 4-((4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)-[1,4'-bipiperidine]-1'-carboxylate

[1162]

[1163] Dissolve 3-chloro-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2- yl)benzonitrile (9d) (250 mg, 0.63 mmol) in 15 mL of DMF, add solid potassium bicarbonate (105 mg, 1.05 mmol) and the above crude 4-(piperazin-l-ylmethyl)-[l,4'-bipiperidin]-l'- carboxylic acid tert-butyl ester (11d) (250 mg) successively, and warm to 60 °C for 3 h. Cool the reaction to room temperature, slowly add 20 mL of water, extract with ethyl acetate (50 mL x 3), wash the organic phase with water (50 mL x 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain 32a (300 mg, yield: 65% from compound 9d).

[1164] LCMS m / z = 728.3 [M + 1] +

[1165] Second Step: Trifluoroacetate salt of 3-(2-(4-((2-(4-([l,4'-bipiperidin]-4- ylmethyl)piperazin-l-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile (32b)

[1166] 3-(2-(4-((2-(4-([l,4'-bipiperidin]-4-ylmethyl)piperazin-l-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile trifluoroacetate

[1167]

[1168] Dissolve 32a (60 mg, 0.08 mmol) in 5 mL of DCM, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to obtain the crude trifluoroacetate salt of 32b (70 mg).

[1169] LCMS m / z = 628.3 [M + 1] +

[1170] Third Step: 3-Chloro-5-(2-(4-((2-(4-((l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- [l,4'-bipiperidin]-4-yl)methyl)piperazin-l-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (compound 32)

[1171] 3-chloro-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1172]

[1173] The trifluoroacetate salt of the above crude 32b (70 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (32 mg, 0.38 mmol) was added, after stirring at room temperature for 10 min, 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (41 mg, 0.15 mmol) were added, and the reaction was heated to 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by preparative plate (dichloromethane / methanol (v / v) = 15:1) to give compound 32 (20 mg, two-step yield: 28% from compound 32a).

[1174] 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, 1H), 8.08 (br. s, 1H), 7.67 (d, 1H), 7.46-7.41 (m, 2H), 7.39-7.35 (m, 1H), 7.31-7.26 (m, 1H), 7.13-7.00 (m, 3H), 6.94-6.83 (m, 2H), 6.70 (d, 1H), 5.00-4.88 (m, 3H), 4.06-3.94 (m, 2H), 3.88-3.76 (m, 4H), 3.07-2.93 (m, 4H), 2.93-2.65 (m, 3H), 2.61-2.51 (m, 1H), 2.50-2.39 (m, 4H), 2.28-2.16 (m, 4H), 2.16-2.08 (m, 1H), 2.02-1.90 (m, 2H), 1.89-1.76 (m, 2H), 1.73-1.60 (m, 8H), 1.60-1.46 (m, 1H), 1.34-1.18 (m, 2H).

[1175] LCMS m / z = 442.8 [M / 2+1] +

[1176] Example 33:

[1177] 3-chloro-5-(2-(4-((2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1178] 3-chloro-5-(2-(4-((2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1179]

[1180] First Step: tert-butyl 4-((4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (33b)

[1181] tert-butyl 4-((4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[1182]

[1183] Dissolve 3-chloro-5-(2-(4-((2-(4-(piperidin-4-ylmethyl)piperazin-1- yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate (33c) (70 mg, 0.09 mmol) in 5 mL of DCM, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of 33c (70 mg) as a crude product.

[1184] LCMS m / z = 645.3 [M + 1] +

[1185] Second step: trifluoroacetate salt of 3-chloro-5-(2-(4-((2-(4-(piperidin-4- ylmethyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (33c)

[1186] 3-chloro-5-(2-(4-((2-(4-(piperidin-4-ylmethyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1187]

[1188] Dissolve 33b (60 mg, 0.09 mmol) in 5 mL of DCM, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of 33c (70 mg) as a crude product.

[1189] LCMS m / z = 545.3 [M + 1] +

[1190] Third step: 3-chloro-5-(2-(4-((2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 33)

[1191] 3-chloro-5-(2-(4-((2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1192]

[1193] The trifluoroacetate salt of the above crude 33c (70 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (32 mg, 0.38 mmol) was added, after stirring at room temperature for 10 min, 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (41 mg, 0.15 mmol) were added, and the mixture was stirred at 80 °C for 5 h. The reaction solution was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved in 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative plate separation (dichloromethane / methanol (v / v) = 15:1) to obtain compound 33 (28 mg, two-step yield: 39% from compound 33b).

[1194] 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 8.04 (s, 1H), 7.67 (d, 1H), 7.47-7.41 (m, 2H), 7.40-7.34 (m, 1H), 7.29 (d, 1H), 7.14-7.01 (m, 3H), 6.92-6.84 (m, 2H), 6.71 (d, 1H), 5.01-4.89 (m, 3H), 4.05-3.70 (m, 6H), 3.07-2.93 (m, 2H), 2.93-2.65 (m, 3H), 2.56-2.39 (m, 4H), 2.35-2.19 (m, 2H), 2.19-2.07 (m, 1H), 2.00-1.89 (m, 2H), 1.89-1.75 (m, 1H), 1.65 (s, 6H), 1.38-1.24 (m, 2H).

[1195] LCMS m / z = 801.3 [M+1] +

[1196] Example 34:

[1197] 3-chloro-5-(2-(4-((2-(4-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1198] 3-chloro-5-(2-(4-((2-(4-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1199]

[1200] First Step: tert-Butyl 4-(4-(4-((4-(2-(3-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidine-1-carboxylate (34b)

[1201] tert-Butyl 4-(4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidine-1-carboxylate

[1202]

[1203] Dissolve 3-chloro-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2- yl)benzonitrile (9d) (400 mg, 1.00 mmol) in 20 mL of DMF, add 4-(piperazin-1-yl)piperidine-1- carboxylic acid tert-butyl ester (34a) (synthesis method see WO2013163262) (325 mg, 1.20 mmol) and potassium bicarbonate (201 mg, 2.00 mmol) successively, and warm to 60 °C for 3 h. Cool the reaction solution to room temperature, slowly add 50 mL of water, extract with ethyl acetate (50 mL x 3), wash the organic phase with water (50 mL x 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 34b (540 mg, yield: 86% from compound 9d).

[1204] LCMS m / z = 631.3 [M+1] +

[1205] Second step: trifluoroacetate salt of 3-chloro-5-(2-(4-((2-(4-(piperidin-4- yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (34c)

[1206] 3-chloro-5-(2-(4-((2-(4-(piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1207]

[1208] Dissolve 34b (60 mg, 0.095 mmol) in 10 mL of DCM, add 4 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction solution under reduced pressure to obtain the trifluoroacetate salt of the crude product 34c (75 mg).

[1209] LCMS m / z = 531.3 [M+1] +

[1210] Third step: tert-butyl 2-(4-(4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (34d)

[1211] tert-butyl 2-(4-(4-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperazin-1-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane--7-carboxylate

[1212]

[1213] The trifluoroacetate salt of the above crude 34c (70 mg) was dissolved in 15 mL of DCE, and solid sodium bicarbonate (32 mg, 0.38 mmol) was added. After stirring at room temperature for 20 min, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (45 mg, 0.19 mmol) and 0.05 mL of acetic acid were added in turn. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (41 mg, 0.19 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction system was slowly added 20 mL of saturated sodium bicarbonate solution, and the organic phase was extracted with 80 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 8:1) to give 34d (55 mg, two-step yield of 82% from compound 34b).

[1214] LCMS m / z = 754.4 [M+1] +

[1215] Fourth step: trifluoroacetate salt of 3-(2-(4-((2-(4-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile (34e)

[1216] 3-(2-(4-((2-(4-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile trifluoroacetate

[1217]

[1218] Dissolve 34d (55 mg, 0.073 mmol) in 5 mL DCM, add 2 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 34e (70 mg).

[1219] LCMS m / z = 654.4 [M+1] +

[1220] Fifth Step: 3-chloro-5-(2-(4-((2-(4-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan- 2-yl)benzonitrile trifluoroacetate salt of Compound 34

[1221] 3-chloro-5-(2-(4-((2-(4-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan- 2-yl)benzonitrile trifluoroacetate

[1222]

[1223] The trifluoroacetate salt of the above crude 34e (70 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (30 mg, 0.36 mmol) was added, stirred at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (40 mg, 0.14 mmol) were added, the reaction was stirred at 80 °C for 5 h. The reaction was cooled to room temperature, 50 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude was dissolved with methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 34 (10 mg) was obtained by freeze-drying.

[1224] 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.46 (d, 1H), 7.87-7.83 (m, 1H), 7.70-7.62 (m, 2H), 7.56-7.50 (m, 1H), 7.37-7.32 (m, 1H), 7.30-7.23 (m, 1H), 7.21-7.14 (m, 2H), 7.00-6.91 (m, 2H), 6.86 (d, 1H), 5.12-4.98 (m, 3H), 4.60-4.30 (m, 4H), 3.78-3.65 (m, 1H), 3.65-3.53 (m, 2H), 3.53-3.45 (m, 2H), 3.45-3.37 (m, 2H), 3.35-2.96 (m, 4H), 2.96-2.72 (m, 3H), 2.65-2.52 (m, 3H), 2.45-2.30 (m, 2H), 2.30-2.15 (m, 2H), 2.12-1.96 (m, 3H), 1.96-1.80 (m, 2H), 1.76-1.52 (m, 10H).

[1225] LCMS m / z = 910.3 [M+1] + .

[1226] Example 35:

[1227] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1228] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1229]

[1230]

[1231] First Step: tert-butyl 4-((9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidine-1-carboxylate (35a)

[1232] tert-butyl 4-((9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidine-1-carboxylate

[1233]

[1234] The trifluoroacetate salt of the above crude 27b (70 mg) was dissolved in 15 mL of DCE, and solid sodium bicarbonate (15 mg, 0.18 mmol) was added. After stirring at room temperature for 20 min, tert-butyl 4-formylpiperidine-1-carboxylate (30 mg, 0.14 mmol) and 0.05 mL of acetic acid were added in turn. After stirring at room temperature for 60 min, sodium triacetoxyborohydride (30 mg, 0.14 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. To the reaction system, 30 mL of saturated sodium bicarbonate solution was slowly added, and the organic phase was extracted with 80 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give 35a (50 mg, two-step yield: 73% from compound 27a).

[1235] LCMS m / z = 791.3 [M+1] +

[1236] Second step: trifluoroacetate salt of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (35b)

[1237] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1238]

[1239] 35a (50 mg, 0.06 mmol) was dissolved in 5 mL of DCM, and 2 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give the trifluoroacetate salt of the crude 35b (60 mg).

[1240] LC-MS m / z = 691.3 [M+1] +

[1241] Step 3: 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 35)

[1242] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(9-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1243]

[1244] The trifluoroacetate salt of the above crude 35b (60 mg) was dissolved in 4 mL of DMSO, solid sodium bicarbonate (25 mg, 0.30 mmol) was added, after stirring at room temperature for 10 min, 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (34 mg, 0.12 mmol) were added, and the reaction was heated to 80 °C for 5 h. The reaction was cooled to room temperature, 20 mL of water was added, filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was purified by preparative plate (dichloromethane / methanol (v / v) = 12:1) to give Compound 35 (25 mg, two-step yield: 44% from Compound 35a).

[1245] 1H NMR (400 MHz, CDC13) δ 8.30 (d, 1H), 8.09 (br. s, 1H), 7.67 (d, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.28 (d, 1H), 7.13 - 6.99 (m, 3H), 6.93 - 6.84 (m, 2H), 6.67 (d, 1H), 4.99 - 4.88 (m, 3H), 4.42 (t, 2H), 4.03 - 3.70 (m, 8H), 3.08 - 2.92 (m, 2H), 2.92 - 2.66 (m, 3H), 2.60 - 2.30 (m, 4H), 2.30 - 2.06 (m, 3H), 2.00 - 1.83 (m, 2H), 1.74 - 1.44 (m, 15H), 1.40 - 1.17 (m, 2H).

[1246] LCMS m / z = 947.5 [M+1] + .

[1247] Example 36:

[1248] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1249] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(4-(1-((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1250]

[1251] The trifluoroacetate salt of the above crude 7b (50 mg) and 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbaldehyde (synthesis method see WO2020113233) (20 mg, 0.07 mmol) were dissolved in 4 mL of DMAc, 0.02 mL of acetic acid was added, stirred at room temperature for 2 h, sodium triacetoxyborohydride (75 mg, 0.35 mmol) was added, stirred at room temperature for 12 h. 30 mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 36 was obtained by lyophilization (10 mg).

[1252] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.34 (d, 1H), 7.68 - 7.52 (m, 2H), 7.35 - 7.05 (m, 5H), 6.94 (d, 2H), 6.66 (d, 1H), 5.50 - 5.40 (m, 1H), 4.97 (s, 2H), 4.80 - 4.66 (m, 2H), 4.66 - 4.55 (m, 2H), 4.46 - 4.38 (m, 2H), 4.03 - 3.90 (m, 2H), 3.70 - 3.42 (m, 6H), 3.37 - 3.02 (m, 2H), 3.02 - 2.56 (m, 7H), 2.54 - 2.47 (m, 3H), 2.21 - 1.81 (m, 5H), 1.80 - 1.68 (m, 2H), 1.63 (s, 6H), 1.57 - 1.28 (m, 6H), 1.19 - 1.00 (m, 2H).

[1253] LCMS m / z = 488.8 [M / 2+1]+

[1254] LCMS m / z = 488.8 [M / 2+1] +

[1255] Example 37:

[1256] 3-chloro-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1257] 3-chloro-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1258]

[1259] First step: tert-butyl 4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4'-bipiperidine]-1-carboxylate (37a)

[1260] tert-butyl 1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4'-bipiperidine]-1-carboxylate

[1261]

[1262] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (300 mg, 1.09 mmol) in 10 mL of DMF, add tert-butyl [4,4'-bipiperidine]-1-carboxylate (37A) (290 mg, 1.08 mmol) and solid potassium bicarbonate (266 mg, 2.66 mmol) successively, and warm to 90°C and stir for 4 h. Cool to room temperature, add 30 mL of water, extract twice with 30 mL of ethyl acetate, wash the organic phase with 50 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 37a (500 mg, yield: 87%).

[1263] Second Step: 5-([4,4'-Bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (37b)

[1264] 5-([4,4'-Bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1265]

[1266] Dissolve 37a (500 mg, 0.95 mmol) in 5 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, add 50 mL of dichloromethane, adjust pH to 10 with saturated sodium bicarbonate solution, extract with 50 mL of dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude 37b (300 mg).

[1267] Third Step: tert-Butyl 4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidine-1-carboxylate (37c)

[1268] tert-Butyl 4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidine-1-carboxylate

[1269]

[1270] Dissolve the above crude 37b (250 mg) in 15 mL of 1,2-dichloroethane, add tert-butyl 4-formylpiperidine-1-carboxylate (200 mg, 0.94 mmol), after stirring for 1 h, add sodium triacetoxyborohydride (300 mg, 1.42 mmol), react at room temperature for 16 h. Slowly add 20 mL of saturated sodium bicarbonate solution to the reaction, extract twice with 60 mL of ethyl acetate, dry the organic phase over 50 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to obtain 37c (300 mg, two-step yield from compound 37a: 61%).

[1271] LCMS m / z = 622.3 [M+1] +

[1272] Fourth Step: 2-(2,6-dioxopiperidin-3-yl)-5-(1'-(piperidin-4-ylmethyl)-[4,4'- bipiperidin]-1-yl)isoindoline-1,3-dione (37d)

[1273] 2-(2,6-dioxopiperidin-3-yl)-5-(1'-(piperidin-4-ylmethyl)-[4,4'- bipiperidin]-1-yl)isoindoline-1,3-dione

[1274]

[1275] Dissolve 37c (300 mg, 0.48 mmol) in 2 mL DCM, add 1 mL trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, dissolve with 50 mL DCM, adjust pH to 10 with saturated sodium bicarbonate solution, extract with 50 mL dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure to get crude 37d (200 mg).

[1276] LCMS m / z = 522.2 [M+1] +

[1277] Fifth Step: 3-chloro-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidin-1-yl)pyrimidin-4- yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate salt of compound 37

[1278] 3-chloro-5-(2-(4-((2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- [4,4'-bipiperidin]-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan- 2-yl)benzonitrile trifluoroacetate

[1279]

[1280] The above crude 37d (200 mg) was dissolved in 15 mL DMF, 3-chloro-5-(2-(4-((2- chloropyrimidin-4-yl)methoxy)phenyl)prop-2-yl)benzonitrile (9d) (150 mg, 0.38 mmol) and solid potassium bicarbonate (110 mg, 1.10 mmol) were added successively, and the mixture was stirred at 90 °C for 4 h. After cooling to room temperature, 30 mL of water was added, and the mixture was extracted twice with 30 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 37 was obtained by lyophilization (75 mg).

[1281] 1 H NMR (400 MHz, CD3OD) δ 8.29 (d, 1H), 7.66 (d, 1H), 7.62 - 7.56 (m, 1H), 7.54 - 7.45 (m, 2H), 7.34 (d, 1H), 7.26 - 7.10 (m, 3H), 7.00 - 6.87 (m, 2H), 6.77 (d, 1H), 5.13 - 4.95 (m, 3H), 4.82 - 4.73 (m, 2H), 4.17 - 4.00 (m, 2H), 3.75 - 3.59 (m, 2H), 3.10 - 2.62 (m, 11H), 2.29 - 1.99 (m, 4H), 1.99 - 1.78 (m, 4H), 1.72 - 1.20 (m, 14H).

[1282] LCMS m / z = 442.3 [M / 2 + 1] +

[1283] Example 38: Trifluoroacetate salt of 3-chloro-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)prop-2-yl)benzonitrile (Compound 38)

[1284] 3-chloro-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1285]

[1286] First Step: tert-butyl 1'-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidine]-1-carboxylate (38a)

[1287] tert-butyl 1'-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidine]-1-carboxylate

[1288]

[1289] tert-butyl 1'-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidine]-1-carboxylate

[1290] LCMS m / z = 630.2 [M+1] +

[1291] Second Step: 3-(2-(4-((2-([4,4'-Bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile (38b)

[1292] 3-(2-(4-((2-([4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)-5-chlorobenzonitrile

[1293]

[1294] Dissolve 38a (800 mg, 1.27 mmol) in 15 mL of dichloromethane, add 5 mL of trifluoroacetic acid, stir at room temperature for 4 h. Concentrate the reaction under reduced pressure, add 100 mL of dichloromethane, adjust pH to 9 with saturated sodium bicarbonate solution, extract with 100 mL of dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude 38b (600 mg).

[1295] LCMS m / z = 530.3 [M+1] +

[1296] Third step: tert-butyl 4-((1'-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidine-1-carboxylate (38c)

[1297] tert-butyl 4-((1'-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-[4,4'-bipiperidin]-1-yl)methyl)piperidine-1-carboxylate

[1298]

[1299] Dissolve the above crude 38b (190 mg) in 15 mL of 1,2-dichloroethane, add tert-butyl 4-formylpiperidine-1-carboxylate (150 mg, 0.70 mmol), after stirring for 1 h, add sodium triacetoxyborohydride (220 mg, 1.04 mmol), react at room temperature for 16 h. Slowly add 50 mL of saturated sodium bicarbonate solution to the reaction, extract twice with 100 mL of ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to obtain 38c (150 mg, two-step yield from compound 38a: 51%).

[1300] LCMS m / z = 727.3 [M+1] +

[1301] Fourth Step: Trifluoroacetate salt of 3-chloro-5-(2-(4-((2-(1'-(piperidin-4-ylmethyl)- [4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (38d)

[1302] 3-chloro-5-(2-(4-((2-(1'-(piperidin-4-ylmethyl)- [4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1303]

[1304] Dissolve 38c (0.15 g, 0.21 mmol) in 2 mL DCM, add 1 mL trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure to give the trifluoroacetate salt of crude 38d (155 mg).

[1305] LCMS m / z = 627.2 [M+1] +

[1306] Sixth Step: Trifluoroacetate salt of 3-chloro-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 38)

[1307] 3-chloro-5-(2-(4-((2-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[4,4'-bipiperidin]-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile trifluoroacetate

[1308]

[1309] The trifluoroacetate salt of the above crude 38d (155 mg) was dissolved in 5 mL of DMSO, 1 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (60 mg, 0.22 mmol) were added, and the reaction was stirred at 80 °C for 8 h. Cooled to room temperature, 30 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with 60 mL of ethyl acetate twice, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile / water containing 0.1% TFA. Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and the trifluoroacetate salt of compound 38 (15 mg) was obtained by lyophilization.

[1310] 1 H NMR (400 MHz, CDC13) δ 8.35 - 8.24 (m, 1H), 8.03 (br. s, 1H), 7.66 (d, 1H), 7.49 - 7.34 (m, 3H), 7.30 - 7.25 (m, 1H), 7.13 - 7.00 (m, 3H), 6.93 - 6.83 (m, 2H), 6.66 (d, 1H), 4.99 - 4.88 (m, 3H), 4.87 - 4.75 (m, 2H), 4.00 - 3.88 (m, 2H), 3.07 - 2.65 (m, 9H), 2.28 - 2.07 (m, 3H), 2.00 - 1.62 (m, 15H), 1.62 - 1.47 (m, 4H), 1.40 - 1.05 (m, 4H).

[1311] LCMS m / z = 442.3 [M / 2+1] +

[1312] Example 39:

[1313] 3-chloro-5-(2-(4-((2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)prop-2- yl)benzonitrile (trifluoroacetate salt of compound 39)

[1314] 3-chloro-5-(2-(4-((2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1315]

[1316] First step: tert-butyl 4-((1-(4-((4-(2-(3-(3-chloro-5-cyanophenyl)prop-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (39a)

[1317] tert-butyl 4-((1-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[1318]

[1319] Dissolve 9d (200 mg, 0.5 mmol) in 5 mL of DMF, add tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (synthesis method see WO2020201080) (200 mg, 0.7 mmol) and solid potassium bicarbonate (138 mg, 1.38 mmol) successively, and warm to 70 °C for 2 h. Cool to room temperature, add 30 mL of water, extract twice with 30 mL of ethyl acetate, wash the organic phase with 50 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain 39a (250 mg, yield: 78%).

[1320] LCMS m / z = 645.3 [M+1] +

[1321] Second step: tert-butyl 4-((1-(4-((4-(2-(3-(3-chloro-5-cyanophenyl)prop-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (39a)

[1322] 3-chloro-5-(2-(4-((2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1323]

[1324] Dissolve 39a (250 mg, 0.39 mmol) in 8 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir at room temperature for 2 h. Concentrate the reaction under reduced pressure, add 30 mL of dichloromethane, adjust pH to 9 with saturated sodium bicarbonate solution, extract with 30 mL of dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give crude 39b (180 mg).

[1325] LCMS m / z = 545.3 [M+1] +

[1326] Third Step: Trifluoroacetate salt of 3-chloro-5-(2-(4-((2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound 39)

[1327] 3-chloro-5-(2-(4-((2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile

[1328]

[1329] DMSO, 0.1 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (0.1 g, 0.36 mmol) were added, and the temperature was raised to 85 °C for 3 h. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate, and the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 preparation liquid phase was used, and the preparation column type was Sunfire C18, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered with a 0.45 μm filter to prepare a sample...

Claims

1. A compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compounds represented by general formula (I), BLK(I); B is selected from R b11 Each independently selected from F, Cl, Br, CF3, CN and NO2; R b12 Each independently selected from H, OCH3, OCD3, OCH2CH3 and OCH2CH2Cl; K is selected from L is selected from The left side is connected to B.

2. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: K is selected from 3. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: B is selected from 4. A compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of the compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating prostate cancer.

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