Pyrrolone-containing compounds

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a compound containing pyrrolidone, in particular to a compound shown as a formula I, a stereoisomer or pharmaceutically acceptable salt of the compound, a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound to treatment of related diseases (such as cancer). # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to compounds containing pyrrolidone, methods for preparing the same, pharmaceutical compositions containing the compounds, and their use in the treatment of related diseases (such as cancer). Background Art

[0002] The p53 tumor suppressor plays an important role in controlling cell cycle progression, senescence, and apoptosis. p53 is frequently mutated in many types of cancers, and in cancers carrying the wild-type p53 gene, p53 may be inactivated due to overexpression and amplification of MDM2.

[0003] MDM2 (mouse double minute-2, an E3 ligase that regulates the degradation of p53 protein) is an oncogene and has a regulatory effect on cell growth. MDM2 can form an MDM2-p53 negative feedback loop by binding to the p53 protein and exert p53-dependent activity. MDM2 is a key negative regulator of p53. Studies have shown that MDM2 can not only bind to p53 to block its tumor suppressor transactivation domain; this protein itself is also an E3 ligase that can label p53 for degradation by the proteasome.

[0004] Small molecule inhibitors that block the MDM2-p53 interaction may achieve the purpose of treating human cancers by restoring the tumor suppressor function of wild-type p53. The inhibitory activity of MDM2 and MDM2-related proteins can effectively treat, improve, or prevent cell hyperproliferative diseases. Currently, several small molecule MDM2 inhibitors have entered clinical trials. By blocking the MDM2-p53 interaction and restoring p53 anti-cancer activity, their clinical effects have been verified. However, small molecule inhibitors can induce negative feedback loops, resulting in upregulation of MDM2 and reduced therapeutic effects.

[0005] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to a target protein and an E3 ubiquitin ligase. Such compounds can induce the target protein to be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, it becomes possible to apply PROTAC technology to the treatment of various diseases, and this technology has received extensive attention in recent years. MDM2-PROTAC can overcome the negative feedback upregulation of MDM2 by degrading MDM2. Compared with small molecules, MDM2-PROTAC can induce an acute apoptotic response in tumor cells and improve the therapeutic effect. Detailed Description of the Invention

[0007] The present disclosure relates to compounds of formula I, their stereoisomers, or their pharmaceutically acceptable salts,

[0008]

[0009] wherein,

[0010] represents a single bond or a double bond;

[0011] CLM is selected from small molecule E3 ubiquitin ligase binding moieties that bind to an E3 ubiquitin ligase;

[0012] L is selected from linking groups;

[0013] R is selected from hydrogen, halogen, CN, or the following optionally substituted groups: OH, NH2, -CHO, -COOH, -CONH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylNH-, (C 1-12 alkyl)2N-, C 1-12 alkylCOO-, C 1-12 alkylOCO-, C 1-12 alkylCONH-, C 1-12 alkylNHCO-, (C 1-12 alkyl)2NCO-, C 1-12 alkylS(O)2NH-, C 1-12 alkylNHS(O)2-, (C 1-12 alkyl)2NS(O)2-, C 3-12 cycloalkyl of from 3 to 12 members, heterocycloalkyl of from 3 to 12 members, C 3-12 cycloalkenyl of from 3 to 12 members, heterocycloalkenyl of from 3 to 12 members, C 6-12 aryl or heteroaryl of from 5 to 12 members;

[0014] m is selected from 0, 1, 2, 3, 4 or 5;

[0015] R 1 and R 2 are each independently selected from optionally substituted rings of from 3 to 12 members;

[0016] R 3 is selected from H, halogen, CN, or the following optionally substituted groups: OH, NH2, C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl;

[0017] ring K is selected from heteroaryl of from 5 to 12 members or C 6-12 aryl.

[0018] In some embodiments of the present disclosure, the small molecule E3 ubiquitin ligase binding moiety of the E3 ubiquitin ligase is selected from a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety. In some embodiments of the present disclosure, the small molecule E3 ubiquitin ligase binding moiety of the E3 ubiquitin ligase is selected from a cereblon E3 ubiquitin ligase binding moiety.

[0019] In some embodiments of the present disclosure, CLM is selected from structural fragment Ic:

[0020]

[0021] Ring C is selected from 5- to 20-membered rings (including monocyclic, bicyclic, or tricyclic structures, which may be carbocyclic or heterocyclic);

[0022] Each R 5 is independently selected from halogen, -CN, or the following optionally substituted groups: -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl, or 3- to 12-membered heteroalkyl;

[0023] q’ is selected from 0, 1, 2, 3, or 4;

[0024] L a is selected from a bond, O, S, -CO-, -COO-, or the following optionally substituted groups: NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-;

[0025] X is independently selected from C(R d ) or N;

[0026] X 1 and X 2 are independently selected from O, S, C(R d )), C(R d )2, N, or N(R e ); or, X and X 2 , or X and X a2 are connected to each other to form a 7- to 12-membered bridged heteroalkyl ring.

[0027] In some embodiments of the present disclosure, ring C is selected from 5- to 15-membered rings, and the rings include monocyclic, bicyclic, or tricyclic structures.

[0028] In some embodiments of the present disclosure, ring C is selected from 5- to 15-membered heterocyclic groups or carbocyclic groups, and the ring includes a monocyclic, bicyclic or tricyclic structure.

[0029] In some embodiments of the present disclosure, ring C is selected from 5- to 15-membered heterocyclic alkyl groups, heteroaryl groups, partially unsaturated heterocyclic groups or partially unsaturated carbocyclic groups, and the ring includes a monocyclic, bicyclic or tricyclic structure.

[0030] In some embodiments of the present disclosure, ring C is selected from 5- to 7-membered monocyclic groups or 8- to 11-membered bicyclic or tricyclic structures.

[0031] In some embodiments of the present disclosure, CLM is selected from structural fragments Ia or Ib:

[0032]

[0033] represents a single bond or a double bond;

[0034] Ring E is absent or is selected from C 5-15 -membered cycloalkenyl groups, 5- to 15-membered heterocycloalkenyl groups, phenyl groups or 5- to 6-membered heteroaryl groups;

[0035] Ring F is selected from phenyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups or pyrazinyl groups;

[0036] Ring G is absent or is selected from imidazolone groups, pyrrolidione groups, pyrrolone groups, pyrazolyl groups, imidazolyl groups, oxazolyl groups, isoxazolyl groups or furyl groups;

[0037] Each R 5 or R 6 is independently selected from halogen, -CN, or the following optionally substituted groups: -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocyclic alkyl;

[0038] q' and r are each independently selected from 0, 1, 2, 3 or 4;

[0039] L a and L b are each independently selected from a bond, O, S, -CO-, -COO-, or the following optionally substituted groups: NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-;

[0040] X is independently selected from C(R d) or N;

[0041] X 1 , X 2 , X a1 and X a2 are independently selected from O, S, C(R d )、C(R d )2、N or N(R e ); or, X and X 2 , or X and X a2 Connected to each other to form a 7-12 membered bridged heterocycloalkyl group;

[0042] R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy;

[0043] X a , X f , X g , X h and X k are independently selected from C, CH or N;

[0044] X b , X c , X d and X e Each is independently selected from O, S, CH2 or NH.

[0045] In some embodiments of the present disclosure, CLM is selected from fragment Ia

[0046]

[0047] Among them, ring E, ring F, ring G, R 5 ,q',L a , X 1 , X 2 and X are as defined in this disclosure.

[0048] In some embodiments of the present disclosure, CLM is selected from fragment Ib

[0049]

[0050] Among them, X a , X f , X g , X h , X k , X b , X c , X d , X e, R 6 , r, L b , X a1 , X a2 and the definitions of X are as described in the present disclosure.

[0051] In some embodiments of the present disclosure, ring E is selected from absent, or from C 5-15 cycloalkenyl, 5-15 membered hetero cycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0052] Ring F is selected from phenyl ring, pyridine ring, pyrimidine ring, pyridazine ring or pyrazine ring;

[0053] Ring G is absent, or selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or furyl.

[0054] In some embodiments of the present disclosure, ring E is selected from absent, or from C 5-12 cycloalkenyl, 5-12 membered hetero cycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0055] In some embodiments of the present disclosure, ring E is selected from absent, or from C 5-10 cycloalkenyl, 5-10 membered hetero cycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0056] In some embodiments of the present disclosure, ring E is selected from absent, or from C 5-8 cycloalkenyl, 5-10 membered hetero cycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0057] In some embodiments of the present disclosure, ring E is selected from absent, or from 5-9 membered hetero cycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0058] In some embodiments of the present disclosure, ring E is selected from absent, or from 5-9 membered hetero cycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0059] In some embodiments of the present disclosure, ring E is selected from absent, or from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered hetero cycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl or oxazolyl.

[0060] In some embodiments of the present disclosure, ring E is selected from absent, or from cyclopentenyl, mono cyclohexenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepinyl, azaspirocyclooctenyl, azaspirocyclononenyl, phenyl, pyrrolyl, pyrazolyl, furyl, oxazolyl or dihydrooxazinyl.

[0061] In still other embodiments of the present disclosure, ring E is selected from absent, or from C 5-6cycloalkenyl, 5- to 9-membered heteroalkenyl, phenyl, or 5- to 6-membered heteroaryl.

[0062] In some other embodiments of the present disclosure, Ring E is selected from absent, or selected from C 5-6 cycloalkenyl, 5- to 9-membered heteroalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0063] In some other embodiments of the present disclosure, Ring E is selected from absent, or selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-, 6-, 7-, 8-, or 9-membered heteroalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0064] In some other embodiments of the present disclosure, Ring E is selected from absent, or selected from cyclopentenyl, mono-cyclohexenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepinyl, azaspirooctenyl, azaspirononenyl, phenyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, or dihydrooxazinyl.

[0065] In some specific embodiments of the present disclosure, Ring E is selected from C 5-12 membered cycloalkenyl or 5- to 12-membered heteroalkenyl.

[0066] In some embodiments of the present disclosure, Ring E is selected from 5- to 9-membered heteroalkenyl.

[0067] In some specific embodiments of the present disclosure, Ring E is selected from C 5-6 cycloalkenyl or 5- to 9-membered heteroalkenyl.

[0068] In some specific embodiments of the present disclosure, Ring E is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-, 6-, 7-, 8-, or 9-membered heteroalkenyl.

[0069] In some specific embodiments of the present disclosure, Ring E is selected from absent, or selected from phenyl or 5- to 6-membered heteroaryl.

[0070] In some specific embodiments of the present disclosure, Ring E is selected from absent, or selected from phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0071] In some specific embodiments, Ring E is selected from C 5-9 cycloalkenyl. In some specific embodiments, Ring E is selected from C 5-6 cycloalkenyl. In some specific embodiments, Ring E is selected from 5- to 9-membered heteroalkenyl.

[0072] In some specific embodiments, Ring E is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepinyl, azaspirononenyl, azaspirooctenyl, phenyl, pyrrolyl, or pyrazolyl.

[0073] In some more specific embodiments, ring E is selected from cyclopentenyl, pyrrolidinyl, piperidinyl, azepanyl, azaspiro[4.5]decenyl or azaspiro[4.4]nonenyl.

[0074] In some more specific embodiments, ring E is selected from cyclopentenyl, azepanyl, phenyl, pyrrolyl or pyrazolyl.

[0075] In some specific embodiments, ring E is selected from cyclopentenyl, pyrrolidinyl, piperidinyl, azepanyl, azaspiro[4.5]decenyl, azaspiro[4.4]nonenyl, phenyl, pyrrolyl or pyrazolyl. In some more specific embodiments, ring E is selected from cyclopentenyl, pyrrolidinyl, piperidinyl, azepanyl, azaspiro[4.5]decenyl or azaspiro[4.4]nonenyl. In some more specific embodiments, ring E is selected from cyclopentenyl, azepanyl, phenyl, pyrrolyl or pyrazolyl.

[0076] In some more specific embodiments, ring E is selected from phenyl, pyrrolyl or pyrazolyl.

[0077] In some specific embodiments of the present disclosure, ring E is selected from non-existence.

[0078] In some embodiments of the present disclosure, ring F is selected from phenyl ring or pyridine ring.

[0079] In some embodiments of the present disclosure, ring F is selected from phenyl.

[0080] In some embodiments of the present disclosure, ring G does not exist, or is selected from imidazolidinone, pyrrolidinedione, pyrrolidinone, oxazolyl or furyl.

[0081] In some embodiments of the present disclosure, ring G does not exist, or is selected from pyrrolidinedione, isoxazolyl or furyl.

[0082] In some embodiments of the present disclosure, ring G is selected from isoxazolyl or furyl.

[0083] In some embodiments of the present disclosure, ring G does not exist. In some embodiments of the present disclosure, ring G is selected from pyrrolidinedione.

[0084] In some embodiments of the present disclosure, ring G is selected from isoxazolyl. In some embodiments of the present disclosure, ring G is selected from furyl.

[0085] In some embodiments of the present disclosure, ring G is selected from non-existence, isoxazolyl or furyl.

[0086] In some embodiments of the present disclosure, ring G is selected from non-existence or isoxazolyl. In some embodiments of the present disclosure, ring G is selected from non-existence or furyl.

[0087] In some embodiments of the present disclosure, the structural fragment is selected from a benzene ring, pyridine,

[0088] In some embodiments of the present disclosure, the structural fragment is selected from a benzene ring, pyridine,

[0089] In some embodiments of the present disclosure, the structural fragment is selected from a benzene ring, pyridine, Or,

[0090] In some embodiments of the present disclosure, the structural fragment is selected from a benzene ring or pyridine.

[0091] In some embodiments of the present disclosure, the structural fragment is selected from

[0092] In some embodiments of the present disclosure, the structural fragment is selected from

[0093] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from

[0094] In some embodiments of the present disclosure, the structural fragment is selected from Or,

[0095] In some embodiments of the present disclosure, the structural fragment is selected from Or,

[0096] In some embodiments of the present disclosure, the structural fragment is selected from a benzene ring, pyridine,

[0097] In some embodiments of the present disclosure, the structural fragment is selected from a benzene ring, pyridine,

[0098] In some embodiments of the present disclosure, the structural fragment is selected from

[0099]

[0100] In some embodiments of the present disclosure, the structural fragment The left - hand bond is connected to ring E or ring F.

[0101] In some embodiments of the present disclosure, the structural fragment The right - hand bond is connected to ring G.

[0102] In some embodiments of the present disclosure, the structural fragment The left - hand bond and the right - hand bond are not simultaneously connected to ring E, ring F or ring G.

[0103] In some embodiments of the present disclosure, the structural fragment The left - hand bond is connected to ring E or ring F, and the right - hand bond is connected to ring G.

[0104] In some embodiments of the present disclosure, the structural fragment is selected from

[0105] In some embodiments of the present disclosure, the structural fragment is selected from and R 5 is selected from F; further, the structural fragment is selected from

[0106] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from halogen, - CN, or an optionally substituted one of the following groups: - OH, - NH2, - CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylOC(O)-, C 3-10 cycloalkyl or 3 - 10 - membered heteroalkyl.

[0107] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from halogen, - CN, or an optionally substituted one of the following groups: - OH, - NH2, - CHO, C 1-4 alkyl or C 1-4 alkoxy.

[0108] In some embodiments of the present disclosure, each R 5 or R6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 alkyl-OH, C 1-6 alkyl OC(O)-, or 3- to 12-membered heterocycloalkyl optionally substituted with C 1-6 alkyl COC(O)-.

[0109] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 alkyl-OH, C 1-4 alkyl OC(O)-, or 3- to 10-membered heterocycloalkyl optionally substituted with C 1-4 alkyl COC(O)-.

[0110] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl.

[0111] In some embodiments of the present disclosure, each R5 or R 6 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl or C 1-4 alkoxy group.

[0112] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from halogen, -CN, -OH, -NH2 or C 1-4 alkyl.

[0113] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from halogen, -CN, -OH or -NH2.

[0114] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from F, Cl, Br, I or C 1-3 alkyl. In some embodiments of the present disclosure, R 5 is selected from F or methyl.

[0115] In some embodiments of the present disclosure, q' and r are each independently selected from 0, 1 or 2. In some embodiments of the present disclosure, q' and r are each independently selected from 0 or 1. In some embodiments of the present disclosure, q' is selected from 0, 1 or 2. In some embodiments of the present disclosure, q' is selected from 0 or 2. In some embodiments of the present disclosure, r is selected from 0.

[0116] In some embodiments of the present disclosure, L a and L b are each independently selected from a bond, O, S, -CO-, -COO-, or the following optionally substituted groups: NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0117] In some embodiments of the present disclosure, L a and L b are each independently selected from a bond, O, S, -COO-, or the following optionally substituted groups: NH, C 1-3 alkyl, C 1-3 heteroalkyl or -CONH-.

[0118] In some embodiments of the present disclosure, L a and L bIndependently selected from a bond, NH, O, S, or the following optionally substituted groups: C 1-3 alkyl or -CONH-.

[0119] In some embodiments of the present disclosure, L a and L b are independently selected from a bond, NH, O, or the following optionally substituted groups: -CH2- or -CONH-.

[0120] In some embodiments of the present disclosure, L a and L b are independently selected from a bond, O, S, -CO-, -COO-, NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0121] In some embodiments of the present disclosure, L a and L b are independently selected from a bond, O, S, -COO-, NH, C 1-3 alkyl, C 1-3 heteroalkyl or -CONH-.

[0122] In some embodiments of the present disclosure, L a and L b are independently selected from a bond, NH, O, S, C 1-3 alkyl or -CONH-.

[0123] In some embodiments of the present disclosure, L a and L b are independently selected from a bond, NH, O, -CH2- or -CONH-.

[0124] In some specific embodiments of the present disclosure, L a and L b are selected from a bond.

[0125] In some embodiments of the present disclosure, the heteroatoms of the heteroalkyl are selected from NH, O or S. Optionally, the number of heteroatoms is selected from 1, 2, 3 or 4.

[0126] In some embodiments of the present disclosure, X is independently selected from C(R d ). In some embodiments of the present disclosure, X is independently selected from N.

[0127] In some embodiments of the present disclosure, X is independently selected from CH or N.

[0128] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, S, C(R d ), C(R d )2, or N.

[0129] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, C(R d ), or C(R d )2.

[0130] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, CH, or CH2.

[0131] In some embodiments of the present disclosure, X a1 and X a2 are each independently selected from O, S, C(R d ), C(R d )2, or N.

[0132] In some embodiments of the present disclosure, X a1 and X a2 are each independently selected from O, C(R d ), C(R d )2, or N.

[0133] In some embodiments of the present disclosure, X a1 and X a2 are each independently selected from C(R d ), or C(R d )2.

[0134] In some embodiments of the present disclosure, X a1 and X a2 are each independently selected from CH or CH2.

[0135] In some embodiments of the present disclosure, X 1 , X 2 , X a1 and X a2 are each independently selected from O, S, C(R d ), C(R d )2, or N.

[0136] In some embodiments of the present disclosure, X 1 , X 2 , X a1 and X a2 are each independently selected from O, C(R d ), or C(Rd ) 2。

[0137] In some embodiments of the present disclosure, X 1 , X 2 , X a1 and X a2 are each independently selected from O, CH or CH2.

[0138] In some embodiments of the present disclosure, X is connected to X 2 , or X is connected to X a2 to form a 7- to 10-membered bridged heterocycloalkyl group.

[0139] In some embodiments of the present disclosure, X is connected to X 2 , or X is connected to X a2 to form a 7- to 9-membered bridged heterocycloalkyl group. In some embodiments of the present disclosure, X is connected to X 2 , or X is connected to X a2 to form a 7- to 8-membered bridged heterocycloalkyl group.

[0140] In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, or the following optionally substituted groups: hydroxy, NH2, C 1-3 alkyl or C 1-3 alkoxy. In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, hydroxy, NH2, C 1-3 alkyl or C 1-3 alkoxy.

[0141] In some embodiments of the present disclosure, R d and R e are each independently selected from H or C 1-3 alkyl. In some embodiments of the present disclosure, R d and R e are selected from H.

[0142] In some embodiments of the present disclosure, X h and X k are each independently selected from C, CH or N.

[0143] In some embodiments of the present disclosure, X a is selected from N. In some embodiments of the present disclosure, X f is selected from C.

[0144] In some embodiments of the present disclosure, X g is selected from CH.

[0145] In some embodiments of the present disclosure, X h and X k are each independently selected from CH or N.

[0146] In some embodiments of the present disclosure, X a 、X f 、X h and X k are each independently selected from C, CH or N, and X g is selected from CH.

[0147] In some embodiments of the present disclosure, X a 、X h and X k are each independently selected from C, CH or N, X f is selected from C, and X g is selected from CH.

[0148] In some embodiments of the present disclosure, X h and X k are each independently selected from CH or N, X a is selected from N; X f is selected from C, and X g is selected from CH.

[0149] In some embodiments of the present disclosure, X b and X c are selected from CH2.

[0150] In some embodiments of the present disclosure, X e is selected from CH2.

[0151] In some embodiments of the present disclosure, X d is selected from O, S, CH2 or NH.

[0152] In some embodiments of the present disclosure, X d is selected from O, S or NH.

[0153] In some embodiments of the present disclosure, X d is selected from NH.

[0154] In some embodiments of the present disclosure, X b and X c are selected from CH2; X e is selected from CH2; X d is selected from NH.

[0155] In some embodiments of the present disclosure, the structural fragment is selected from

[0156] In some embodiments of the present disclosure, the structural fragment is selected from

[0157] In some embodiments of the present disclosure, the structural fragment is selected from and R 5 is independently selected from F; further, the structural fragment is selected from

[0158] In some embodiments of the present disclosure, the CLM is selected from:

[0159]

[0160]

[0161]

[0162]

[0163] In some embodiments of the present disclosure, the VHL E3 ubiquitin ligase binding moiety is selected from:

[0164]

[0165] In some embodiments of the present disclosure, the IAP E3 ubiquitin ligase binding moiety is selected from:

[0166]

[0167] In some embodiments of the present disclosure, the MDM2 E3 ubiquitin ligase binding moiety is selected from:

[0168]

[0169]

[0170] In some embodiments of the present disclosure, the CLM is selected from the following structural fragments:

[0171]

[0172]

[0173]

[0174] wherein, R a is independently selected from hydroxyl, halogen, amino, cyano or C 1-8 alkyl;

[0175] q is selected from 0, 1, 2 or 3;

[0176] X 4 is selected from N or optionally substituted CH.

[0177] In some embodiments of the present disclosure, wherein R a are each independently selected from hydroxy, halogen, amino, cyano or C 1-6 alkyl.

[0178] In some embodiments of the present disclosure, wherein R a are each independently selected from hydroxy, halogen, amino, cyano or C 1-4 alkyl.

[0179] In some embodiments of the present disclosure, wherein R a are each independently selected from hydroxy, halogen, amino, cyano or C 1-3 alkyl.

[0180] In some embodiments of the present disclosure, wherein R a are each independently selected from hydroxy, halogen, amino or cyano.

[0181] In some embodiments of the present disclosure, wherein R a are each independently selected from halogen or amino.

[0182] In some embodiments of the present disclosure, q is selected from 0, 1 or 2. In some embodiments of the present disclosure, q is selected from 0 or 1.

[0183] In some embodiments of the present disclosure, X 4 is selected from N or CH, wherein CH is optionally substituted with the following substituents: hydroxy, halogen, amino, cyano or C 1-4 alkyl.

[0184] In some embodiments of the present disclosure, X 4 is selected from N. In some embodiments of the present disclosure, X 4 is selected from CH.

[0185] In some embodiments of the present disclosure, CLM is selected from the following structural fragments:

[0186]

[0187]

[0188]

[0189] In some embodiments of the present disclosure, the L is selected from optionally substituted by one or more R b substituting the following groups: C 1-50alkyl, C 2-50 alkenyl or C 2-50 alkynyl, wherein one or more methylenes in said C 1-50 alkyl, C 2-50 alkenyl or C 2-50 alkynyl are optionally replaced by a group selected from: -NH-, -N(C 1-12 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heteroalkyl, 3-15 membered heteroalkenyl, C 6-12 aryl or 5-12 membered heteroaryl,

[0190] R b is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, -NH(C 1-6 alkyl), or -NH(C 1-6 alkyl)2.

[0191] In some embodiments of the present disclosure, said L is selected from those optionally substituted by one or more R b substituting the following groups: C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl, wherein one or more methylenes in said C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl are optionally replaced by a group selected from: -NH-, -N(C 1-12 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3-15 membered heteroalkyl, 3-15 membered heteroalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, R b is as defined in the present disclosure.

[0192] In some embodiments of the present disclosure, said L is selected from those optionally substituted by one or more R b substituting the following groups: C 1-15 alkyl, C 2-15 alkenyl or C 2-15 alkynyl, wherein one or more methylenes in said C 1-15 alkyl, C 2-15 alkenyl or C 2-15 alkynyl are optionally replaced by a group selected from: -NH-, -N(C1-12 -alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3- to 10-membered heteroalkyl, 3- to 10-membered heteroalkenyl, C 6-10 aryl or 5- to 10-membered heteroaryl, where R b is as defined in the present disclosure.

[0193] In some embodiments of the present disclosure, the L is selected from those optionally substituted with one or more R b substituting the following groups: C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl, where the C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl optionally has one or more methylenes replaced with a group selected from: -NH-, -N(C 1-10 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heteroalkyl, 3- to 12-membered heteroalkenyl, C 6-10 aryl or 5- to 10-membered heteroaryl, where R b is as defined in the present disclosure.

[0194] In some embodiments of the present disclosure, the L is selected from those optionally substituted with one or more R b substituting the following groups: C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, where the C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl optionally has one or more methylenes replaced with a group selected from: -NH-, -N(C 1-6 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3- to 12-membered heteroalkyl, or 3- to 12-membered heteroalkenyl, where R b is as defined in the present disclosure.

[0195] In some embodiments of the present disclosure, the L is selected from C b alkyl optionally substituted with one or more R 1-6 where the C 1-6The alkyl group is optionally substituted at one or more methylene groups with a group selected from: -NH-, -O-, -S-, -C(O)-, C 3-10 cycloalkyl or 3- to 12-membered heterocycloalkyl, R b is as defined in the present disclosure.

[0196] In some embodiments of the present disclosure, L is selected from C b alkyl optionally substituted with one or more R 1-6 wherein the C 1-6 alkyl is optionally substituted at one or more methylene groups with a group selected from: -NH-, -C(O)-, C 4-9 cycloalkyl or 4- to 11-membered heterocycloalkyl, R b is as defined in the present disclosure.

[0197] In some embodiments of the present disclosure, L is selected from -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -L 8 -;

[0198] wherein L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, 3- to 15-membered heterocycloalkyl, 3- to 15-membered heterocycloalkenyl, C 6-12 aryl or 5- to 12-membered heteroaryl;

[0199] R 11 is selected from H or C 1-12 alkyl;

[0200] Each R a2 is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6Alkoxy, halo C 1-6 alkyl, (C 1-6 alkyl)NH-, or (C 1-6 alkyl)2NH-.

[0201] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heteroalkenyl, 3-12 membered heteroalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0202] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heteroalkenyl, 3-12 membered heteroalkyl, C6 aryl or 5-8 membered heteroaryl.

[0203] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0204] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocycloalkenyl, or 3- to 12-membered heterocycloalkyl.

[0205] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocycloalkenyl, or 3- to 12-membered heterocycloalkyl.

[0206] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-11 cycloalkyl, C 3-11 cycloalkenyl, 3- to 11-membered heteroalkenyl or 3- to 11-membered heteroalkyl.

[0207] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or the following groups optionally substituted with one or more R a2 : C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 3-11 cycloalkenyl, 3- to 10-membered heteroalkenyl or 3- to 12-membered heteroalkyl.

[0208] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, or the following groups optionally substituted with one or more R a2 : C 1-6alkyl, C 3-12 cycloalkyl, 5-10 membered heteroalkenyl or 4-12 membered heteroalkyl.

[0209] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -N(R 11 )-, -C(O)-, -O-, -S-, C 1-6 alkyl, C 3-12 cycloalkyl, 5-10 membered heteroalkenyl or 4-12 membered heteroalkyl.

[0210] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, -O-, -S-, C 1-4 alkyl, C 3-9 cycloalkyl, 5-6 membered heteroalkenyl or 4-12 membered heteroalkyl.

[0211] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2-, C 4-6 cycloalkyl, C9 cycloalkyl, 6 membered heteroalkenyl, 4-11 membered heteroalkyl.

[0212] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2- or 4-12 membered heteroalkyl.

[0213] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2-, or 4-10 membered heterocycloalkyl.

[0214] In some specific embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2-, or 4-6 membered heterocycloalkyl.

[0215] In some specific embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, O, -CH2-, -CH2CH2-, C 4-6 cycloalkyl, or 4-6 membered heterocycloalkyl. In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are independently selected from absent, -CH2-, C 4-6 cycloalkyl, or 4-6 membered heterocycloalkyl containing 1 or 2 nitrogen atoms.

[0216] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8Independently selected from absent, -NH-, -N(CH3)-, -C(O)-, -S-, -O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, monoazabicyclohexane, diazaspironanyl, monoazabicyclononanyl, spironanyl, monoazaspironanyl, diazaspirononanyl, monoazaspironundecyl, monoazaspironundecyl, monoazaspiroheptane, diazabicyclooctanyl, octahydrocyclopentapyrrolyl, tetrahydropyridinyl or monoazaspirooctane.

[0217] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -N(CH3)-, -C(O)-, -S-, -O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-,

[0218] In some embodiments of the present disclosure, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are independently selected from absent, -NH-, -S-, -O-, -N(CH3)-, -C(O)-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-,

[0219] In some embodiments of the present disclosure, the L 4 , L 5 , L 6 , L 7 or L 8 Select from does not exist.

[0220] In some embodiments of the present disclosure, R 11 Select from H or C 1-10 In some embodiments of the present disclosure, R 11 Select from H or C 1-6 In some embodiments of the present disclosure, R 11Selected from H or C 1-4 alkyl. In some embodiments of the present disclosure, R 11 Selected from H or C 1-3 alkyl. In some embodiments of the present disclosure, R 11 Selected from H, methyl or ethyl. In some embodiments of the present disclosure, R 11 Selected from H.

[0221] In some embodiments of the present disclosure, each R b is independently selected from halogen, ═O, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -NH(C 1-3 alkyl), or -NH(C 1-3 alkyl)2.

[0222] In some embodiments of the present disclosure, each R b is independently selected from halogen, ═O, -OH, -NH2 or -CN.

[0223] In some embodiments of the present disclosure, each R a2 is independently selected from halogen, ═O, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -NH(C 1-3 alkyl), or -NH(C 1-3 alkyl)2.

[0224] In some embodiments of the present disclosure, each R a2 is independently selected from halogen, ═O, -OH, -NH2 or -CN.

[0225] In some embodiments of the present disclosure, the L is selected from a bond, -Cy 1 -, -LNK 1 -, -Cy 1 -LNK 1 -, -Cy 1 -Cy 2 -, -Cy 1 -LNK 1 -Cy 2 -, -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 2 -LNK 2 -, -Cy 1 -Cy 2-Cy 3 -,-Cy 1 -LNK 1 -Cy 2 -LNK 2 -,-LNK 1 -Cy 1 -Cy 2 -LNK 2 -,-Cy 1 -Cy 2 -Cy 3 -LNK 1 -,-Cy 1 -Cy 2 -LNK 1 -Cy 3 -,-Cy 1 -Cy 2 -Cy 3 -Cy 4 -,-LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -,-LNK 1 -Cy 1 -LNK 2 -Cy 2 -Cy 3 -,-LNK 1 -Cy 1 -Cy 2 -LNK 2 -Cy 3 -,-LNK 1 -Cy 1 -Cy 2 -Cy 3 -LNK 2 -,-Cy 1 -LNK 1 -Cy 2 -LNK 2 -Cy 3 -or-LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -,wherein,

[0226] Cy 1 、Cy 2 、Cy 3 orCy 4 isindependentlyselectedfromthefollowinggroupsoptionallysubstitutedbyoneormoreR ba :C 3-15Cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkenyl, 3-15 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0227] LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 1-12 heteroalkyl;

[0228] Each R ba and R bb Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 alkyl)NH-, or (C 1-6 Alkyl)2NH-.

[0229] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl.

[0230] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, C6 aryl or 5-8 membered heteroaryl.

[0231] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more Rba Substituted with the following groups: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heteroalkenyl, 3- to 12-membered heteroalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0232] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from the following groups optionally substituted with one or more R ba : C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heteroalkenyl, or 3- to 12-membered heteroalkyl.

[0233] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from the following groups optionally substituted with one or more R ba : C 3-11 cycloalkyl, C 3-11 cycloalkenyl, 3- to 11-membered heteroalkenyl, or 3- to 11-membered heteroalkyl.

[0234] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from the following groups optionally substituted with one or more R ba : C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3- to 10-membered heteroalkenyl, or 3- to 12-membered heteroalkyl.

[0235] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from C 3-12 cycloalkyl, 5- to 10-membered heteroalkenyl, or 4- to 12-membered heteroalkyl.

[0236] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from C 4-12 cycloalkyl, 5- to 10-membered heteroalkenyl, or 4- to 12-membered heteroalkyl.

[0237] In some embodiments of the present disclosure, the Cy1 , Cy 2 , Cy 3 or Cy 4 is independently selected from C 4-9 cycloalkyl, 5-6 membered heteroalkenyl or 4-12 membered heteroalkyl.

[0238] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from C 4-6 cycloalkyl, C9 cycloalkyl, 6 membered heteroalkenyl, 4-9 membered or 11 membered heteroalkyl.

[0239] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from 3-12 membered heteroalkyl.

[0240] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from 4-10 membered heteroalkyl.

[0241] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from 4-6 membered heteroalkyl.

[0242] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, diazaspiro[nonane], azabicyclo[nonane], spirononane, azaspiro[nonane], diazaspiro[undecane], azaspiro[undecane], azaspiro[heptane], diazabicyclo[octane], octahydrocyclopenta[pyrrole], tetrahydropyridyl or azaspiro[octane].

[0243] In some embodiments of the present disclosure, Cy 1 , Cy 2 , Cy 3 or Cy 4 is independently selected from

[0244] In some embodiments of the present disclosure, Cy 1 、Cy 2 、Cy 3 or Cy 4 is independently selected from

[0245] In some embodiments of the present disclosure, the LNK 1 、LNK 2 and LNK 3 are each independently selected from the following groups optionally substituted with one or more R bb substituents: -NH-, -S-, -O-, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 heteroalkyl.

[0246] In some embodiments of the present disclosure, the LNK 1 、LNK 2 and LNK 3 are each independently selected from the following groups optionally substituted with one or more R bb substituents: -NH-, -S-, -O-, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl or C 1-8 heteroalkyl.

[0247] In some embodiments of the present disclosure, the LNK 1 、LNK 2 and LNK 3 are each independently selected from the following groups optionally substituted with one or more R bb substituents: -NH-, -S-, -O-, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 heteroalkyl.

[0248] In some embodiments of the present disclosure, the LNK 1 、LNK 2 and LNK 3 are each independently selected from the following groups optionally substituted with one or more R bb substituents: -NH-, -S-, -O-, C 1-6 alkyl or C 1-6 heteroalkyl.

[0249] In some embodiments of the present disclosure, the LNK 1 、LNK 2 and LNK3 independently selected from the following groups optionally substituted with one or more R bb : -NH-, -S-, -O-, C 1-6 alkyl or C 1-6 heteroalkyl, C 1-6 The heteroatoms of the heteroalkyl are selected from N, O or S.

[0250] In some embodiments of the present disclosure, the LNK 1 , LNK 2 and LNK 3 are independently selected from the following groups optionally substituted with one or more R bb : -NH-, -S-, -O-, C 1-4 alkyl or C 1-4 heteroalkyl, C 1-4 The heteroatoms of the heteroalkyl are selected from N, O or S.

[0251] In some embodiments of the present disclosure, the LNK 1 , LNK 2 and LNK 3 are independently selected from the following groups optionally substituted with one or more R bb : -NH-, -S-, -O-, C 1-2 alkyl or C 1-2 heteroalkyl, C 1-4 The heteroatoms of the heteroalkyl are selected from N or O.

[0252] In some embodiments of the present disclosure, the LNK 1 , LNK 2 and LNK 3 are independently selected from the following groups optionally substituted with one or more R bb : C 1-3 alkyl. In some embodiments of the present disclosure, the LNK 1 , LNK 2 and LNK 3 are independently selected from the following groups optionally substituted with one or more R bb : C 1-2 alkyl.

[0253] In some embodiments of the present disclosure, each R ba and R bb is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, (C 1-4 alkyl)NH-, or (C 1-4 alkyl)2NH-.

[0254] In some embodiments of the present disclosure, each R ba and R bb is independently selected from halogen, =O, -OH, -NH2, or -CN.

[0255] In some embodiments of the present disclosure, each R ba and R bb is independently selected from =O.

[0256] In some embodiments of the present disclosure, the LNK 1 , LNK 2 and LNK 3 are each independently selected from -NH-, -S-, -O-, C(O), -NHCH2-, -CH2NHCH2-, -(CH2)2O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -C(O)CH2-.

[0257] In some embodiments of the present disclosure, the LNK 1 , LNK 2 and LNK 3 are each independently selected from -NH-, -S-, -O-, C(O), -CH2-, -CH2CH2-, -NHCH2-, -CH2NHCH2-, -(CH2)2O-, or -C(O)CH2-. In some embodiments of the present disclosure, the LNK 1 , LNK 2 and LNK 3 are each independently selected from C(O), -CH2-, or -C(O)CH2-.

[0258] In some embodiments of the present disclosure, the L is selected from -NHCH2-, -CH2NHCH2-, -CH2-, -(CH2)2O-,

[0259] or

[0260] In some embodiments of the present disclosure, the L is selected from or,

[0261] In some embodiments of the present disclosure, L is in the reading order from left to right.

[0262] In some embodiments of the present disclosure, L is in the reading order from right to left.

[0263] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups which are optionally substituted: halogen, OH, NH2, CN, -CHO, -COOH, -CONH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylNH-, (C 1-12 alkyl)2N-, C 1-12 alkylCOO-, C 1-12 alkylOCO-, C 1-12 alkylCONH-, C 1-12 alkylNHCO-, (C 1-12 alkyl)2NCO-, C 1-12 alkylS(O)2NH-, C 1-12 alkylNHS(O)2-, (C 1-12 alkyl)2NS(O)2-, C 3-12 cycloalkyl of 3-12 members, heterocycloalkyl of 3-12 members, C 3-12 cycloalkenyl of 3-12 members, heterocycloalkenyl of 3-12 members, C 6-12 aryl or heteroaryl of 5-12 members.

[0264] In some specific embodiments of the present disclosure, R is selected from hydrogen, or the following groups which are optionally substituted: C 1-12 alkyl, C 2-12 alkenyl, heterocycloalkyl of 3-12 members, C 6-12 aryl or heteroaryl of 5-12 members.

[0265] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups which are optionally substituted by one or more R”’: halogen, OH, NH2, CN, -CHO, -COOH, -CONH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylNH-, (C 1-12 alkyl)2N-, C 1-12 alkylCOO-, C 1-12 alkylOCO-, C 1-12 alkylCONH-, C 1-12 alkylNHCO-, (C 1-12 alkyl)2NCO-, C 1-12 alkylS(O)2NH-, C 1-12 alkylNHS(O)2-, (C1-12 (alkyl)2NS(O)2-, C 3-12 -membered cycloalkyl, 3-12-membered heterocycloalkyl, C 3-12 -membered cycloalkenyl, 3-12-membered heterocycloalkenyl, C 6-12 aryl or 5-12-membered heteroaryl, wherein,

[0266] R''' is selected from halogen, OH, NH2, CN, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 alkyl)2N-, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)OC 1-10 alkyl, -OC(O)C 1-10 alkyl, -C(O)NHC 1-10 alkyl, -C(O)N(C 1-10 alkyl)2, -NHC(O)C 1-10 alkyl, C 3-10 -membered cycloalkyl or 3-10-membered heterocycloalkyl, the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 alkyl)2N-, -C(O)NHC 1-10 alkyl, -C(O)N(C 1-10 alkyl)2, -NHC(O)C 1-10 alkyl, C 3-10 -membered cycloalkyl or 3-10-membered heterocycloalkyl is optionally substituted by one or more of the following groups: halogen, OH, NH2, CN, C 1-6 alkyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 alkyl)2N-, -C(O)OR c , -OC(O)R c , -C(O)NHR c , -NHC(O)R c , -S(O)NHR c , -NHS(O)R c , -S(O)2NHR c or -NHS(O)2R c ,

[0267] R c is selected from hydrogen or C 1-10 alkyl.

[0268] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl having from 3 to 10 members, heterocycloalkyl having from 3 to 10 members, heteroalkenyl having from 3 to 10 members, C 6-10 aryl or heteroaryl having from 5 to 10 members, where R''' is defined as described in the present disclosure.

[0269] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl having from 3 to 8 members, heterocycloalkyl having from 3 to 8 members, heteroalkenyl having from 3 to 8 members, C 6-8 aryl or heteroaryl having from 5 to 8 members, where R''' is defined as described in the present disclosure.

[0270] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl having from 3 to 6 members, heterocycloalkyl having from 3 to 6 members, heteroalkenyl having from 5 to 6 members, C6 aryl or heteroaryl having from 5 to 6 members, where R''' is defined as described in the present disclosure.

[0271] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, heterocycloalkyl having from 5 to 6 members, heteroalkenyl having from 6 members, C6 aryl or heteroaryl having from 5 to 6 members, where R''' is defined as described in the present disclosure.

[0272] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-4 alkyl, C 2-4 alkenyl, heterocycloalkyl having from 6 members, heteroalkenyl having from 6 members, C6 aryl or heteroaryl having from 6 members, where R''' is defined as described in the present disclosure.

[0273] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 2-3 alkyl, C 2-3 alkenyl, heterocycloalkyl having from 6 members, heteroalkenyl having from 6 members, C6 aryl or heteroaryl having from 6 members, where R''' is defined as described in the present disclosure.

[0274] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl, and the definition of R''' is as described in the present disclosure.

[0275] In some embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl or pyrimidinyl, and the definition of R''' is as described in the present disclosure.

[0276] In still other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl having [number of carbon atoms] carbon atoms, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, and the definition of R''' is as described in the present disclosure.

[0277] In still other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl having [number of carbon atoms] carbon atoms, 3-8 membered heterocycloalkyl, C 6-8 aryl or 5-8 membered heteroaryl, and the definition of R''' is as described in the present disclosure.

[0278] In still other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl having [number of carbon atoms] carbon atoms, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl, and the definition of R''' is as described in the present disclosure.

[0279] In still other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, 5-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl, and the definition of R''' is as described in the present disclosure.

[0280] In still other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-4 alkyl, C 2-4an alkenyl group, a 6-membered heteroalkyl group, a C6 aryl group or a 6-membered heteroaryl group, and the definition of R''' is as described in the present disclosure.

[0281] In some other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 2-3 alkyl, C 2-3 alkenyl, 6-membered heteroalkyl, C6 aryl or 6-membered heteroaryl, and the definition of R''' is as described in the present disclosure.

[0282] In some other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': ethyl, isopropyl, propenyl, piperidinyl, phenyl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl, and the definition of R''' is as described in the present disclosure.

[0283] In some other embodiments of the present disclosure, R is selected from hydrogen, or the following groups optionally substituted with one or more R''': ethyl, isopropyl, propenyl, piperidinyl, phenyl or pyrimidinyl, and the definition of R''' is as described in the present disclosure.

[0284] In some embodiments of the present disclosure, R''' is selected from halogen, OH, NH2, CN, ═O, C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 alkyl)2N-, -C(O)OH, -C(O)NH2, -C(O)NHC 1-10 alkyl, -C(O)N(C 1-10 alkyl)2 or 3- to 10-membered heteroalkyl, and the C 1-10 alkyl or 3- to 10-membered heteroalkyl is optionally substituted with one or more of the following groups: OH, C 1-6 alkyl, -NHC(O)R c or -C(O)NHR c .

[0285] In some embodiments of the present disclosure, R''' is selected from halogen, OH, NH2, CN, ═O, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, -C(O)OH, -C(O)NH2, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2 or 3- to 6-membered heteroalkyl, and the C 1-6 alkyl or 3- to 6-membered heteroalkyl is optionally substituted with one or more of the following groups: OH, C 1-4 alkyl, -NHC(O)Rc or -C(O)NHR c 。

[0286] In some embodiments of the present disclosure, R''' is selected from halogen, OH, NH2, CN, ═O, C 1-3 alkyl, C 1-3 alkoxy, (C 1-3 alkyl)2N-, -C(O)OH, -C(O)NH2, -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl)2 or 5- to 6-membered heteroalkyl, wherein the C 1-3 alkyl or 5- to 6-membered heteroalkyl is optionally substituted with one or more of the following groups: OH, C 1-3 alkyl, -NHC(O)R c or -C(O)NHR c 。

[0287] In some embodiments of the present disclosure, R''' is selected from OH, CN, ═O, methyl, methoxy, isopropyl O-, (CH3)2N-, -C(O)OH, -C(O)NH2, piperazinyl, -C(O)N(CH3)2 or -C(O)NHCH3, wherein the methyl or piperidyl is optionally substituted with one or more of the following groups: OH, methyl, -NHC(O)H, -NHC(O)CH3 or -C(O)NHCH3.

[0288] In some embodiments of the present disclosure, R''' is selected from OH, CN, methyl, methoxy, (CH3)2N-, -C(O)N(CH3)2, -C(O)NHCH3, -CH2NHC(O)H, -CH2NHC(O)CH3, -CH2C(O)NHCH3, -C(O)OH, -C(O)NH2, ═O, -CH2OH or -OCH(CH3)2. In some embodiments of the present disclosure, R c is selected from hydrogen or C 1-6 alkyl. In some embodiments of the present disclosure, R c is selected from hydrogen or C 1-3 alkyl. In some embodiments of the present disclosure, R c is selected from hydrogen or methyl.

[0289] In still other embodiments of the present disclosure, R''' is selected from halogen, OH, NH2, CN, ═O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10(alkyl)2N-, -C(O)NHC 1-10 alkyl, -C(O)N(C 1-10 alkyl)2, -NHC(O)C 1-10 alkyl, C 3-10 -membered cycloalkyl or 3-10-membered heterocycloalkyl, said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 (alkyl)2N-, -C(O)NHC 1-10 alkyl, -C(O)N(C 1-10 (alkyl)2, -NHC(O)C 1-10 alkyl, C 3-10 -membered cycloalkyl or 3-10-membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, OH, NH2, CN, C 1-6 alkyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 (alkyl)2N-, -C(O)OR c , -OC(O)R c , -C(O)NHR c , -NHC(O)R c , -S(O)NHR c , -NHS(O)R c , -S(O)2NHR c or -NHS(O)2R c .

[0290] In still other embodiments of the present disclosure, R''' is selected from halogen, OH, NH2, CN, =O, C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 (alkyl)2N-, -C(O)NHC 1-10 alkyl, -C(O)N(C 1-10 (alkyl)2 or 3-10-membered heterocycloalkyl, said C 1-10 alkyl or 3-10-membered heterocycloalkyl is optionally substituted with one or more of the following groups: C 1-6 alkyl or -NHC(O)R c .

[0291] In still other embodiments of the present disclosure, R''' is selected from halogen, OH, NH2, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6alkyl NH-, (C 1-6 alkyl)2N-, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2 or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 alkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with one or more of the following groups: C 1-4 alkyl or -NHC(O)R c .

[0292] In some further embodiments of the present disclosure, R''' is selected from halogen, OH, NH2, CN, C 1-3 alkyl, C 1-3 alkoxy, (C 1-3 alkyl)2N-, -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl)2 or 5- to 6-membered heterocycloalkyl, wherein the C 1-3 alkyl or 5- to 6-membered heterocycloalkyl is optionally substituted with one or more of the following groups: C 1-3 alkyl or -NHC(O)R c .

[0293] In some further embodiments of the present disclosure, R''' is selected from OH, CN, C 1-2 alkyl, C 1-2 alkoxy, (C 1-2 alkyl)2N-, -C(O)NHC 1-2 alkyl, -C(O)N(C 1-2 alkyl)2 or 6-membered heterocycloalkyl, wherein the C 1-2 alkyl or 6-membered heterocycloalkyl is optionally substituted with one or more of the following groups: C 1-2 alkyl, -NHC(O)H or -NHC(O)C 1-2 alkyl.

[0294] In some further embodiments of the present disclosure, R''' is selected from OH, CN, methyl, methoxy, (CH3)2N-, piperazinyl, -C(O)N(CH3)2 or -C(O)NHCH3, wherein the methyl or piperidyl is optionally substituted with one or more of the following groups: methyl, -NHC(O)H or -NHC(O)CH3.

[0295] In some further embodiments of the present disclosure, R''' is selected from OH, CN, methyl, methoxy, (CH3)2N-, -C(O)N(CH3)2, -C(O)NHCH3, -CH2NHC(O)H or -CH2NHC(O)CH3.

[0296] In some other embodiments of the present disclosure, R''' is selected from OH, (CH3)2N-, methyl, methoxy or -CH2NHC(O)H.

[0297] In some embodiments of the present disclosure, R is selected from hydrogen,

[0298] In some specific embodiments of the present disclosure, R is selected from hydrogen,

[0299] In some specific embodiments of the present disclosure, R is selected from hydrogen,

[0300] In some embodiments of the present disclosure, m is selected from 0, 1, 2 or 3. In some embodiments of the present disclosure, m is selected from 1 or 2.

[0301] In some embodiments of the present disclosure, R 1 is selected from the following groups which are optionally substituted: C 6-12 aryl, 5- to 12-membered heterocyclic group or 5- to 12-membered heteroaryl.

[0302] In some embodiments of the present disclosure, R 1 is selected from the following groups which are optionally substituted by one or more R': C 6-12 aryl, 5- to 12-membered heterocyclic group or 5- to 12-membered heteroaryl, wherein R' is selected from halogen, OH, NH2, CN, =O, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylNH- or (C 1-12 alkyl)2N-.

[0303] In some embodiments of the present disclosure, R 1 is selected from the following groups which are optionally substituted by one or more R': C 6-10 aryl, 5- to 10-membered heterocyclic group or 5- to 10-membered heteroaryl, where the definition of R' is as described in the present disclosure.

[0304] In some embodiments of the present disclosure, R 1 is selected from the following groups which are optionally substituted by one or more R': C6 aryl, 5- to 6-membered heterocyclic group or 5- to 6-membered heteroaryl, where the definition of R' is as described in the present disclosure.

[0305] In some embodiments of the present disclosure, R 1Selected from the following groups optionally substituted with one or more R': C6 aryl, 6-membered heterocyclic group or 6-membered heteroaryl, where the definition of R' is as described in the present disclosure.

[0306] In some embodiments of the present disclosure, R 1 Selected from the following groups optionally substituted with one or more R': phenyl or 6-membered N-containing heterocyclic group, where the definition of R' is as described in the present disclosure.

[0307] In some embodiments of the present disclosure, R 1 Selected from the following groups optionally substituted with one or more R': phenyl or 6-membered N-containing heteroalkenyl, where the definition of R' is as described in the present disclosure.

[0308] In some embodiments of the present disclosure, R 1 Selected from the following groups optionally substituted with one or more R': phenyl or dihydropyridyl, where the definition of R' is as described in the present disclosure.

[0309] In some embodiments of the present disclosure, the R' is selected from halogen, OH, NH2, CN, ═O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-.

[0310] In some embodiments of the present disclosure, R' is selected from halogen, OH, NH2, CN, ═O, C 1-6 alkyl or C 2-6 alkenyl, C 2-6 alkynyl.

[0311] In some embodiments of the present disclosure, R' is selected from halogen (such as fluorine, chlorine, bromine or iodine), OH, NH2, CN, ═O or C 1-6 alkyl.

[0312] In some embodiments of the present disclosure, R' is selected from fluorine, chlorine, bromine, iodine, ═O or C 1-3 alkyl.

[0313] In some embodiments of the present disclosure, R' is selected from chlorine, ═O or methyl.

[0314] In some embodiments of the present disclosure, R 1 is selected from

[0315] In some specific embodiments of the present disclosure, R 1 is selected from

[0316] In some specific embodiments of the present disclosure, R 1 is selected from

[0317] In some embodiments of the present disclosure, R 2 is selected from the following groups which are optionally substituted: 5- to 12-membered heterocyclic group, C 6-12 aryl or 5- to 12-membered heteroaryl.

[0318] In some embodiments of the present disclosure, R 2 is selected from the following groups which are optionally substituted by one or more R″: 5- to 12-membered heterocyclic group, C 6-12 aryl or 5- to 12-membered heteroaryl, wherein R″ is selected from halogen, OH, NH2, CN, ═O, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylNH- or (C 1-12 alkyl)2N-.

[0319] In some embodiments of the present disclosure, R 2 is selected from the following groups which are optionally substituted by one or more R″: 5- to 10-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the definition of R″ is as described in the present disclosure.

[0320] In some embodiments of the present disclosure, R 2 is selected from the following groups which are optionally substituted by one or more R″: 5- to 6-membered heterocyclic group, C6 aryl or 5- to 6-membered heteroaryl, wherein the definition of R″ is as described in the present disclosure.

[0321] In some embodiments of the present disclosure, R 2 is selected from the following groups which are optionally substituted by one or more R″: C6 aryl or 6-membered heteroaryl, wherein the definition of R″ is as described in the present disclosure.

[0322] In some embodiments of the present disclosure, R 2 is selected from phenyl which is optionally substituted by one or more R″, wherein the definition of R″ is as described in the present disclosure.

[0323] In some embodiments of the present disclosure, R″ is selected from halogen, OH, NH2, CN, ═O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-.

[0324] In some embodiments of the present disclosure, R” is selected from halogen, OH, NH2, CN, ═O, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl.

[0325] In some embodiments of the present disclosure, R” is selected from halogen, OH, NH2, CN, ═O or C 1-6 alkyl.

[0326] In some embodiments of the present disclosure, R” is selected from fluorine, chlorine, bromine, iodine, CN or C 1-3 alkyl.

[0327] In some embodiments of the present disclosure, R” is selected from fluorine, chlorine, CN or methyl.

[0328] In some specific embodiments of the present disclosure, R” is selected from chlorine, CN or methyl.

[0329] In some embodiments of the present disclosure, R 2 is selected from

[0330] In some specific embodiments of the present disclosure, R 2 is selected from

[0331] In some embodiments of the present disclosure, R 3 is selected from H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl.

[0332] In some embodiments of the present disclosure, R 3 is selected from H, halogen, OH, NH2, CN or C 1-3 alkyl. In some embodiments of the present disclosure, R 3 is selected from H or C 1-3 alkyl.

[0333] In some embodiments of the present disclosure, R 3 is selected from H.

[0334] In some embodiments of the present disclosure, ring K is selected from 5-10 membered heteroaryl or C 6-10 aryl.

[0335] In some embodiments of the present disclosure, ring K is selected from 5-6 membered heteroaryl or C6 aryl.

[0336] In some embodiments of the present disclosure, ring K is selected from 5-6 membered heteroaryl.

[0337] In some embodiments of the present disclosure, ring K is selected from 5-membered heteroaryl. In some embodiments of the present disclosure, ring K is selected from 5-membered N-containing heteroaryl. In some embodiments of the present disclosure, ring K is selected from pyrrolyl, imidazolyl or pyrazolyl. In some embodiments of the present disclosure, ring K is selected from pyrrolyl or pyrazolyl. In some embodiments of the present disclosure, ring K is selected from pyrrolyl. In some embodiments of the present disclosure, ring K is selected from pyrazolyl.

[0338] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from

[0339] In some embodiments of the present disclosure, the connecting position on one side of the L group is on the R 1 group or on ring K. In some embodiments of the present disclosure, the connecting position on one side of the L group is on the R 1 group.

[0340] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from wherein T 1 , T 2 and T 3 are each independently selected from CH, N, O, S or NH; or, T 1 , T 2 and T 3 are each independently selected from CH, N or NH; or, at least one of T 1 , T 2 and T 3 is selected from NH; T 3 is selected from NH, T 1 and T 2 are selected from CH; or T 3 is selected from CH, T 1 and T 2 are selected from NH or N; the definitions of R, m, R 1 and R 2 are as described in the present disclosure.

[0341] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from wherein R, m, R 1 , R'', T 1 , T 2 and T 3 As described in the present disclosure, u is selected from 0, 1, 2, 3 or 4; alternatively, u is selected from 1 or 2.

[0342] In some embodiments, the attachment position on one side of the group L is on R 1 or on the ring K.

[0343] In some embodiments, the attachment position on one side of the group L is on R 1 or T 2 . In some embodiments, the attachment position on one side of the group L is on T 2 .

[0344] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from wherein T 1 and T 2 are each independently selected from CH, N, O, S or NH; alternatively, T 1 and T 2 are each independently selected from N, O, S or NH; alternatively, T 1 and T 2 are each independently selected from N or NH; alternatively, one of T 1 and T 2 is selected from NH and the other is selected from N. Wherein, the definitions of R, m, R 1 and R 2 are as described in the present disclosure.

[0345] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from T 1 and T 2 are as described in the present disclosure. Wherein, the definitions of L, R, m, R 1 and R 2 are as described in the present disclosure.

[0346] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from wherein the definitions of R, m, R 1 and R 2 are as described in the present disclosure.

[0347] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from wherein R f and R g are defined as the definition of group R in the present disclosure. In some embodiments of the present disclosure, the structural fragment is selected from wherein R f and R g are defined as the definition of group R in the present disclosure. Wherein, R 1 and R 2 are as described in the present disclosure.

[0348] In some embodiments of the present disclosure, the structural fragment is selected from In some embodiments of the present disclosure, the structural fragment is selected from wherein the definitions of R, m, R 1 and R 2 are as described in the present disclosure.

[0349] In some embodiments of the present disclosure, the structural fragment is selected from wherein R f and R g are defined as the definition of group R in the present disclosure; In some embodiments of the present disclosure, the structural fragment is selected from wherein R f and R g are defined as the definition of group R in the present disclosure; In some embodiments of the present disclosure, the structural fragment is selected from wherein R f and R g are defined as the definition of group R in the present disclosure. Wherein, R 1 and R 2 are as described in the present disclosure.

[0350] In some embodiments of the present disclosure, R f is selected from hydrogen, or the following groups optionally substituted by one or more R''': C1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the definition of R''' is as described in the present disclosure. In some embodiments of the present disclosure, R f is selected from the following groups optionally substituted with one or more R''': C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, wherein the definition of R''' is as described in the present disclosure. In some embodiments of the present disclosure, R f is selected from C 1-4 alkyl optionally substituted with one or more substituents selected from halogen, OH, NH2 or CN. In some embodiments of the present disclosure, R f is selected from C 2-3 alkyl optionally substituted with one or more OH groups. In some embodiments of the present disclosure, R f is selected from

[0351] In some embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the definition of R''' is as described in the present disclosure.

[0352] In some embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkenyl, C 6-8 aryl or 5- to 8-membered heteroaryl, wherein the definition of R''' is as described in the present disclosure.

[0353] In some embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, C6 aryl or 5- to 6-membered heteroaryl, wherein the definition of R''' is as described in the present disclosure.

[0354] In some embodiments of the present disclosure, Rg Selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-6 alkyl, C 2-6 alkenyl, 5-6 membered heterocycloalkyl, 6 membered heteroalkenyl, C6 aryl or 5-6 membered heteroaryl, wherein the definition of R''' is as described in the present disclosure.

[0355] In some embodiments of the present disclosure, R g Selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-4 alkyl, C 2-4 alkenyl, 6 membered heterocycloalkyl, 6 membered heteroalkenyl, C6 aryl or 6 membered heteroaryl, wherein the definition of R''' is as described in the present disclosure.

[0356] In some embodiments of the present disclosure, R g Selected from hydrogen, or the following groups optionally substituted with one or more R''': C 2-3 alkyl, C 2-3 alkenyl, 6 membered heterocycloalkyl, 6 membered heteroalkenyl, C6 aryl or 6 membered heteroaryl, wherein the definition of R''' is as described in the present disclosure.

[0357] In some embodiments of the present disclosure, R g Selected from hydrogen, or the following groups optionally substituted with one or more R''': ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl, wherein the definition of R''' is as described in the present disclosure.

[0358] In some embodiments of the present disclosure, R g Selected from hydrogen, or the following groups optionally substituted with one or more R''': ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl or pyrimidinyl, wherein the definition of R''' is as described in the present disclosure.

[0359] In some embodiments of the present disclosure, R g Selected from hydrogen,

[0360] In some specific embodiments of the present disclosure, R g Selected from hydrogen, or the following groups optionally substituted with one or more R''': C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the definition of R''' is as described in the present disclosure.

[0361] In some specific embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted by one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl having [number of carbon atoms] carbon atoms, 3-8 membered heterocycloalkyl, C 6-8 aryl or 5-8 membered heteroaryl, where the definition of R''' is as described in the present disclosure.

[0362] In some specific embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted by one or more R''': C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl having [number of carbon atoms] carbon atoms, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl, where the definition of R''' is as described in the present disclosure.

[0363] In some specific embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted by one or more R''': C 1-6 alkyl, C 2-6 alkenyl, 5-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl, where the definition of R''' is as described in the present disclosure.

[0364] In some specific embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted by one or more R''': C 1-4 alkyl, C 2-4 alkenyl, 6 membered heterocycloalkyl, C6 aryl or 6 membered heteroaryl, where the definition of R''' is as described in the present disclosure.

[0365] In some specific embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted by one or more R''': C 2-3 alkyl, C 2-3 alkenyl, 6 membered heterocycloalkyl, C6 aryl or 6 membered heteroaryl, where the definition of R''' is as described in the present disclosure.

[0366] In some specific embodiments of the present disclosure, R g is selected from hydrogen, or the following groups optionally substituted by one or more R''': ethyl, isopropyl, propenyl, piperidinyl, phenyl, pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, where the definition of R''' is as described in the present disclosure.

[0367] In some specific embodiments of the present disclosure, R gSelected from hydrogen, or the following groups optionally substituted by one or more R''': ethyl, isopropyl, propenyl, piperidinyl, phenyl or pyrimidinyl, where the definition of R''' is as described in the present disclosure.

[0368] In some specific embodiments of the present disclosure, R g is selected from hydrogen,

[0369] In some embodiments of the present disclosure, the structural fragment is selected from where the definitions of R', R'', R, m and u are as described in the present disclosure, and v is selected from 0, 1, 2, 3 or 4; or v is selected from 2 or 3.

[0370] In some embodiments of the present disclosure, the structural fragment is selected from

[0371] In some embodiments of the present disclosure, the structural fragment is selected from

[0372]

[0373] In some embodiments of the present disclosure, the structural fragment is selected from

[0374] In some embodiments of the present disclosure, the structural fragment is selected from

[0375] In some embodiments of the present disclosure, the structural fragment is selected from

[0376] In some embodiments of the present disclosure, the structural fragment is selected from

[0377]

[0378] In some embodiments of the present disclosure, the structural fragment is selected from

[0379]

[0380] The compound of formula I, its stereoisomers or its pharmaceutically acceptable salts according to the present disclosure are selected from formula IIA, formula IIA-1, formula IIA-2, formula IIB, formula IIB-1, formula IIB-2, formula IIIA, formula IIIA-1, formula IIIA-2, formula IIIB, formula IIIB-1, formula IIIB-2, formula IVA, formula IVA-1, formula IVA-2, formula IVB, formula IVB-1, formula IVB-2, formula VA, formula VA-1, formula VA-2, formula VB, formula VB-1, formula VB-2, formula VI, formula VII, formula VIII, formula VIII-1, formula VIII-2, formula VIII-3, their stereoisomers or their pharmaceutically acceptable salts,

[0381]

[0382]

[0383]

[0384]

[0385] wherein,

[0386] L, CLM, T 1 , T 2 , R’, R”, R 1 , R 2 , R, m, L, ring E, ring F, ring G, R 5 , q’, L a , X, X 1 , X 2 , X g and X f are as defined in the present disclosure;

[0387] X 5 is selected from N or CH;

[0388] Ring A and ring B are each independently selected from optionally substituted 3- to 12-membered rings;

[0389] j and t are each independently selected from 0, 1, 2, 3, 4 or 5.

[0390] In some embodiments, R 1 is selected from the fragment The definitions of R’, ring A and j are as defined in the present disclosure. In some embodiments, R 2 is selected from the fragment The definitions of R”, ring B and t are as defined in the present disclosure.

[0391] In some embodiments of the present disclosure, ring A is selected from C 6-12 aryl, 5- to 12-membered heterocyclic group, or 5- to 12-membered heteroaryl. In some embodiments of the present disclosure, ring A is selected from C 6-10 aryl, 5- to 10-membered heterocyclic group, or 5- to 10-membered heteroaryl. In some embodiments of the present disclosure, ring A is selected from C6 aryl, 5- to 6-membered heterocyclic group, or 5- to 6-membered heteroaryl. In some embodiments of the present disclosure, ring A is selected from C6 aryl, 6-membered heterocyclic group, or 6-membered heteroaryl. In some embodiments of the present disclosure, ring A is selected from phenyl or 6-membered N-containing heterocyclic group. In some embodiments of the present disclosure, ring A is selected from phenyl or 6-membered N-containing heterocyclic enyl group. In some embodiments of the present disclosure, ring A is selected from phenyl or dihydropyridyl.

[0392] In some embodiments of the present disclosure, ring B is selected from 5- to 12-membered heterocyclic group, C 6-12 aryl, or 5- to 12-membered heteroaryl. In some embodiments of the present disclosure, ring B is selected from 5- to 10-membered heterocyclic group, C 6-10 aryl, or 5- to 10-membered heteroaryl. In some embodiments of the present disclosure, ring B is selected from 5- to 6-membered heterocyclic group, C6 aryl, or 5- to 6-membered heteroaryl. In some embodiments of the present disclosure, ring B is selected from C6 aryl or 6-membered heteroaryl. In some embodiments of the present disclosure, ring B is selected from phenyl.

[0393] In some embodiments of the present disclosure, j and t are each independently selected from 0, 1, 2, 3, or 4. In some embodiments of the present disclosure, j and t are each independently selected from 1, 2, or 3.

[0394] In some embodiments of the present disclosure, the structural fragment is as defined in the present disclosure.

[0395] The present disclosure relates to the following compounds, their stereoisomers, or their pharmaceutically acceptable salts:

[0396] On the other hand, the present disclosure relates to compounds of formula II', moieties, their stereoisomers, their derivatives (such as PROTACs), or their pharmaceutically acceptable salts:

[0397]

[0398] wherein, represents a single bond or a double bond;

[0399] ring E is selected from C 5-15 cycloalkenyl, 5- to 15-membered heterocycloalkenyl, phenyl, or 5- to 6-membered heteroaryl;

[0400] ring F is selected from phenyl ring group, pyridine ring group, pyridazine ring group, or pyrazine ring group;

[0401] Ring G is selected from oxazolyl, isoxazolyl or furyl;

[0402] Each R 5 is selected from halogen, -CN, or an optionally substituted group selected from: -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylOC(O)-, C 3-12 cycloalkyl or 3-12 membered heteroalkyl;

[0403] q’ is selected from 0, 1, 2, 3 or 4;

[0404] L a is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group selected from: NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-;

[0405] X is independently selected from C(R d ) or N;

[0406] X 1 and X 2 are independently selected from O, S, C(R d )), C(R d )2, N or N(R e );

[0407] Alternatively, X and X 2 are joined to form a 7-12 membered bridged heteroalkyl;

[0408] R d and R e are independently selected from H, halogen, CN, hydroxy, NH2, C 1-6 alkyl or C 1-6 alkoxy.

[0409] In some embodiments of the present disclosure, L a is selected from a bond, O, S, -CO-, -COO-, NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0410] In some embodiments of the present disclosure, ring E is selected from C 5-15 cycloalkenyl or 5-15 membered heteroalkenyl. Optionally, ring E is defined as described in the present disclosure.

[0411] In some embodiments of the present disclosure, ring F is selected from phenyl.

[0412] In some embodiments of the present disclosure, ring G is selected from isoxazolyl or furyl.

[0413] In some embodiments of the present disclosure, optionally, R 5 , q’, L a , X, X 1 , X 2 , R d and R e are defined as described in the present disclosure;

[0414] Optionally, the structural fragment is defined as described in the present disclosure.

[0415] On the other hand, the present disclosure relates to a compound of formula II’-A, a moiety, its stereoisomers, its derivatives (such as PROTAC), or a pharmaceutically acceptable salt thereof:

[0416]

[0417] Wherein, ring E, ring F, ring G, R 5 , q’, X, L a , X 1 , X 2 are defined as described in the present disclosure;

[0418] L is selected from linking groups.

[0419] On the other hand, the present disclosure relates to a compound of formula II’-B, its stereoisomers, or a pharmaceutically acceptable salt thereof:

[0420]

[0421] Wherein, ring E, ring F, ring G, R 5 , q’, X, L a , X 1 , X 2 are defined as described in the present disclosure;

[0422] L is selected from linking groups;

[0423] PTM is selected from target protein molecules.

[0424] On the other hand, the present disclosure relates to a compound of formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9 or II-10, a moiety, its stereoisomers, its derivatives (such as PROTAC), or a pharmaceutically acceptable salt thereof:

[0425]

[0426] Wherein, represents a single bond or a double bond;

[0427] Ring E is selected from a C 5-15 cycloalkenyl group having 3 to 15 carbon atoms, a hetero-cycloalkenyl group having 5 to 15 carbon atoms, or a heteroaryl group having 5 to 6 carbon atoms;

[0428] Ring F is selected from a phenyl group, a pyridyl group, a pyridazinyl group, or a pyrazinyl group;

[0429] Each R 5 is independently selected from a halogen, -CN, or an optionally substituted group selected from the following: -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl, or a hetero-cycloalkyl group having 3 to 12 carbon atoms;

[0430] q' is selected from 0, 1, 2, 3, or 4;

[0431] X is independently selected from C(R d ) or N;

[0432] L a is selected from O, S, -CO-, -COO-, or an optionally substituted group selected from the following: NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-;

[0433] X 1 and X 2 are independently selected from O, S, C(R d )), C(R d )2, N, or N(R e );

[0434] Alternatively, X and X 2 are connected to each other to form a 7- to 12-membered bridged hetero-cycloalkyl group;

[0435] L aa is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group selected from the following: NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-;

[0436] X b1 and X b2One selected from C(R d ) or C(R d )2, and the other selected from O, S, N or N(R e );

[0437] X 11 and X 22 are each independently selected from C(R d ) or N;

[0438] R d and R e are each independently selected from H, halogen, CN, or optionally substituted groups: hydroxy, NH2, C 1-6 alkyl or C 1-6 alkoxy.

[0439] In some embodiments of the present disclosure, ring E is selected from C 5-12 cycloalkenyl, 5-12 membered hetero cycloalkenyl or 5-6 membered heteroaryl.

[0440] In some embodiments of the present disclosure, ring E is selected from C 5-10 cycloalkenyl, 5-10 membered hetero cycloalkenyl or 5-6 membered heteroaryl.

[0441] In some embodiments of the present disclosure, ring E is selected from C 5-8 cycloalkenyl, 5-10 membered hetero cycloalkenyl or 5-6 membered heteroaryl.

[0442] In some embodiments of the present disclosure, ring E is selected from C 5-6 cycloalkenyl, 5-9 membered hetero cycloalkenyl or 5-6 membered heteroaryl.

[0443] In some embodiments of the present disclosure, ring E is selected from absent, C 5-6 cycloalkenyl, 5-9 membered hetero cycloalkenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0444] In some embodiments of the present disclosure, ring E is selected from absent, C5 cycloalkenyl, C6 cycloalkenyl, 5 membered, 6 membered, 7 membered, 8 membered or 9 membered hetero cycloalkenyl, pyrrolyl, pyrazolyl, furyl or oxazolyl.

[0445] In some embodiments of the present disclosure, ring E is selected from absent, cyclopentenyl, mono cyclohexenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepinyl, azaspirooctenyl, azaspirononenyl, pyrrolyl, pyrazolyl, furyl, oxazolyl or dihydrooxazinyl.

[0446] In some embodiments of the present disclosure, ring E is selected from C 5-12 cycloalkenyl or 5-12 membered hetero cycloalkenyl.

[0447] In some embodiments of the present disclosure, ring E is selected from C 5-6 cycloalkenyl or 5- to 9-membered hetero cycloalkenyl.

[0448] In some embodiments of the present disclosure, ring E is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered hetero cycloalkenyl.

[0449] In some embodiments of the present disclosure, ring E is selected from 5- to 6-membered heteroaryl.

[0450] In some embodiments of the present disclosure, ring E is selected from pyrrolyl, pyrazolyl, furyl or oxazolyl.

[0451] In some specific embodiments, ring E is selected from C 5-9 cycloalkenyl. In some specific embodiments, ring E is selected from C 5-6 cycloalkenyl. In some specific embodiments, ring E is selected from 5- to 9-membered hetero cycloalkenyl.

[0452] In some specific embodiments, ring E is selected from cyclopentenyl, pyrrolidinyl, piperidinyl, azepanyl, azaspiro nonenyl, azaspiro octenyl, pyrrolyl or pyrazolyl.

[0453] In some more specific embodiments, ring E is selected from cyclopentenyl, pyrrolidinyl, piperidinyl, azepanyl, azaspiro nonenyl or azaspiro octenyl.

[0454] In some more specific embodiments, ring E is selected from pyrrolyl or pyrazolyl.

[0455] In some embodiments of the present disclosure, ring F is selected from phenyl.

[0456] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, or an optionally substituted group selected from: -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl.

[0457] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, or an optionally substituted group selected from: -OH, -NH2, -CHO, C 1-4 alkyl or C 1-4 alkoxy.

[0458] In some embodiments of the present disclosure, each R 5Independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 alkyl-OH, C 1-6 alkyl OC(O)-, or 3- to 12-membered heterocycloalkyl optionally substituted with C 1-6 alkyl COC(O)-substituted 3- to 12-membered heterocycloalkyl.

[0459] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 alkyl-OH, C 1-4 alkyl OC(O)-, or 3- to 10-membered heterocycloalkyl optionally substituted with C 1-4 alkyl COC(O)-substituted 3- to 10-membered heterocycloalkyl.

[0460] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl.

[0461] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C1-4 alkyl or C 1-4 alkoxy group.

[0462] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, -OH or -NH2.

[0463] In some embodiments of the present disclosure, q' is selected from 0, 1 or 2. In some embodiments of the present disclosure, q' is selected from 0 or 1.

[0464] In some embodiments of the present disclosure, X is independently selected from C(R d ). In some embodiments of the present disclosure, X is independently selected from N.

[0465] In some embodiments of the present disclosure, X is independently selected from CH or N.

[0466] In some embodiments of the present disclosure, L a is selected from O, S, -CO-, -COO-, or an optionally substituted group: NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0467] In some embodiments of the present disclosure, L a is selected from O, S, -CO-, -COO-, NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0468] In some embodiments of the present disclosure, L a is selected from O, S, -CO-, -COO-, NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0469] In some embodiments of the present disclosure, L a is selected from NH, O, S, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH- or -COO-.

[0470] In some embodiments of the present disclosure, L a is selected from NH, O, S, C 1-3 alkyl or -CONH-.

[0471] In some embodiments of the present disclosure, L a is selected from NH, O, -CH2-, or -CONH-.

[0472] In some embodiments of the present disclosure, the heteroatom of the heteroalkyl is selected from NH, O, or S. Optionally, the number of heteroatoms is selected from 1, 2, 3, or 4.

[0473] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, S, C(R d ), C(R d )2, or N.

[0474] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, C(R d ), or C(R d )2.

[0475] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, CH, or CH2.

[0476] In some embodiments of the present disclosure, X and X 2 are connected to each other to form a 7- to 10-membered bridged heteroalkyl ring.

[0477] In some embodiments of the present disclosure, X and X 2 are connected to each other to form a 7- to 9-membered bridged heteroalkyl ring. In some embodiments of the present disclosure, X and X 2 are connected to each other to form a 7- to 8-membered bridged heteroalkyl ring.

[0478] In some embodiments of the present disclosure, L aa is selected from a bond, O, S, -CO-, -COO-, or optionally substituted groups: NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-.

[0479] In some embodiments of the present disclosure, L aa is selected from a bond, O, S, -CO-, -COO-, NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-.

[0480] In some embodiments of the present disclosure, L aa is selected from a bond, O, S, -CO-, -COO-, NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0481] In some embodiments of the present disclosure, L aa is selected from a bond, NH, O, S, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH- or -COO-.

[0482] In some embodiments of the present disclosure, L aa is selected from a bond, NH, O, S, C 1-3 alkyl or -CONH-.

[0483] In some embodiments of the present disclosure, L aa is selected from a bond, NH, O, -CH2- or -CONH-.

[0484] In some embodiments of the present disclosure, the heteroatoms of the heteroalkyl are selected from NH, O or S. Optionally, the number of heteroatoms is selected from 1, 2, 3 or 4.

[0485] In some embodiments of the present disclosure, one of X b1 and X b2 is selected from C(R d )2, and the other is selected from O, S, N or N(R e ).

[0486] In some embodiments of the present disclosure, one of X b1 and X b2 is selected from CH2, and the other is selected from O, S or NH.

[0487] In some embodiments of the present disclosure, one of X b1 and X b2 is selected from CH2, and the other is selected from O.

[0488] In some embodiments of the present disclosure, X 11 and X 22 are selected from C(R d ). In some embodiments of the present disclosure, X 11 and X 22 are each independently selected from CH.

[0489] In some embodiments of the present disclosure, R d and R eIndependently selected from H, halogen, CN, or the following optionally substituted groups: hydroxy, NH2, C 1-3 alkyl or C 1-3 alkoxy.

[0490] In some embodiments of the present disclosure, R d and R e are independently selected from H, halogen, CN, hydroxy, NH2, C 1-6 alkyl or C 1-6 alkoxy.

[0491] In some embodiments of the present disclosure, R d and R e are independently selected from H, halogen, CN, hydroxy, NH2, C 1-3 alkyl or C 1-3 alkoxy.

[0492] In some embodiments of the present disclosure, R d and R e are independently selected from H or C 1-3 alkyl. In some embodiments of the present disclosure, R d and R e are selected from H.

[0493] In some embodiments of the present disclosure, the structural fragment is selected from

[0494] In some embodiments of the present disclosure, the structural fragment is selected from

[0495] In some embodiments of the present disclosure, the structural fragment is selected from

[0496] In some embodiments of the present disclosure, the structural fragment is selected from Or,

[0497] In some embodiments of the present disclosure, the structural fragment is selected from Or,

[0498] In some embodiments of the present disclosure, the structural fragment is selected from

[0499] In some embodiments of the present disclosure, the structural fragment is selected from and R 5 is selected from F; further, the structural fragment is selected from

[0500] In some embodiments of the present disclosure, the structural fragment is selected from

[0501] In some embodiments of the present disclosure, the structural fragment is selected from

[0502] In some embodiments of the present disclosure, the structural fragment is selected from

[0503] In some embodiments of the present disclosure, the structural fragment is selected from and R 5 is selected from F; further, the structural fragment is selected from

[0504] In some embodiments of the present disclosure, the structural fragment is selected from Or

[0505] In some embodiments of the present disclosure, the structural fragment is selected from Or

[0506] In some embodiments of the present disclosure, the structural fragment is selected from

[0507] In some embodiments of the present disclosure, the structural fragment is selected from and R 5 is selected from F; further, the structural fragment is selected from

[0508] In some embodiments of the present disclosure, the structural fragment is selected from

[0509] In some embodiments of the present disclosure, the structural fragment is selected from

[0510] In some embodiments of the present disclosure, the structural fragment is selected from

[0511] In some embodiments of the present disclosure, the structural fragment is selected from and R 5 is selected from F; further, the structural fragment is selected from

[0512] On the other hand, the present disclosure relates to compounds, moieties, their stereoisomers, their derivatives (such as PROTACs), or pharmaceutically acceptable salts thereof of formula II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A or II-10A:

[0513]

[0514]

[0515] Ring E, Ring F, R 5 , q’, X, L a , X 1 , X 2 , L aa , X b1 , X b2 , X 11 or X 22 are defined as in compounds of formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9 or II-10, their stereoisomers, their derivatives (such as PROTACs), or pharmaceutically acceptable salts thereof;

[0516] L is selected from linking groups.

[0517] In some embodiments of the present disclosure, the structural fragment is defined as described in the present disclosure.

[0518] On the other hand, the present disclosure relates to compounds of formula II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B or II-10B, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0519]

[0520]

[0521] Ring E, Ring F, R 5 , q’, X, L a , X 1 , X 2 , L aa , X b1 , X b2 , X 11 or X 22 is as defined in compounds of formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9 or II-10, their stereoisomers, their derivatives (such as PROTAC), or pharmaceutically acceptable salts thereof;

[0522] L is selected from linking groups;

[0523] PTM is selected from target protein molecules.

[0524] On the other hand, the present disclosure relates to compounds of formula III-1, moieties, their stereoisomers, their derivatives (such as PROTAC), or pharmaceutically acceptable salts thereof:

[0525]

[0526] Wherein,

[0527] represents a single bond or a double bond;

[0528] Ring E is selected from C 5-15 -membered cycloalkenyl or 5-15-membered hetero cycloalkenyl;

[0529] Ring F is selected from phenyl, pyridyl, pyridazinyl or pyrazinyl;

[0530] X 3 is selected from CH or N;

[0531] Each R 5 is independently selected from halogen, -CN, or the following optionally substituted groups: -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6Alkyl OC(O)-, C 3-12 Cycloalkyl or 3- to 12-membered heteroalkyl;

[0532] q’ is selected from 0, 1, 2, 3, or 4;

[0533] X is independently selected from C(R d ) or N;

[0534] L a is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group: NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-;

[0535] X 1 and X 2 are independently selected from O, S, C(R d )), C(R d )2, N, or N(R e );

[0536] Alternatively, X and X 2 are connected to each other to form a 7- to 12-membered bridged heteroalkyl;

[0537] R d and R e are independently selected from H, halogen, CN, or an optionally substituted group: hydroxyl, NH2, C 1-6 alkyl, or C 1-6 alkoxy.

[0538] In some embodiments of the present disclosure, the compound of Formula III-1 is not selected from the following compounds:

[0539]

[0540]

[0541]

[0542]

[0543]

[0544] In some embodiments of the present disclosure, when L a is selected from a bond, it is not selected from In some embodiments of the present disclosure, ring E is selected from C 5-12 cycloalkenyl or 5- to 12-membered heterocycloalkenyl.

[0545] In some embodiments of the present disclosure, ring E is selected from C 5-6 cycloalkenyl or 5- to 9-membered hetero cycloalkenyl.

[0546] In some embodiments of the present disclosure, ring E is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered hetero cycloalkenyl.

[0547] In some embodiments of the present disclosure, ring E is selected from C 5-9 cycloalkenyl. In some specific embodiments, ring E is selected from C 5-6 cycloalkenyl. In some specific embodiments, ring E is selected from 5- to 9-membered hetero cycloalkenyl.

[0548] In some embodiments of the present disclosure, ring E is selected from cyclopentenyl, pyrrolidinyl, tetrahydropyridinyl, tetrahydroazepinyl, azaspiro nonenyl or azaspiro octenyl.

[0549] In some embodiments of the present disclosure, ring F is selected from phenyl.

[0550] In some embodiments of the present disclosure, X 3 is selected from CH. In some embodiments of the present disclosure, X 3 is selected from N.

[0551] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, or an optionally substituted group selected from: -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl.

[0552] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, or an optionally substituted group selected from: -OH, -NH2, -CHO, C 1-4 alkyl or C 1-4 alkoxy.

[0553] In some embodiments of the present disclosure, each R 5 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heteroalkyl optionally substituted with one or more of the following groups: halogen, ═O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 alkyl-OH, C 1-6 alkyl OC(O)-, or 3- to 12-membered heteroalkyl optionally substituted with C 1-6 alkyl COC(O)-.

[0554] In some embodiments of the present disclosure, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heteroalkyl, wherein the -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heteroalkyl optionally substituted with one or more of the following groups: halogen, ═O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 alkyl-OH, C 1-4 alkyl OC(O)-, or 3- to 10-membered heteroalkyl optionally substituted with C 1-4 alkyl COC(O)-.

[0555] In some embodiments of the present disclosure, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heteroalkyl.

[0556] In some embodiments of the present disclosure, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl or C 1-4 alkoxy.

[0557] In some embodiments of the present disclosure, each R 5 independently selected from halogen, -CN, -OH or -NH2.

[0558] In some embodiments of the present disclosure, q' is selected from 0, 1, or 2. In some embodiments of the present disclosure, q' is selected from 0 or 1.

[0559] In some embodiments of the present disclosure, X is independently selected from C(R d ). In some embodiments of the present disclosure, X is independently selected from N.

[0560] In some embodiments of the present disclosure, X is independently selected from CH or N.

[0561] In some embodiments of the present disclosure, L a is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group: NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-.

[0562] In some embodiments of the present disclosure, L a is selected from a bond, O, S, -CO-, -COO-, NH, -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-.

[0563] In some embodiments of the present disclosure, L a is selected from a bond, O, S, -CO-, -COO-, NH, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-. In some embodiments of the present disclosure, L a is selected from a bond, NH, O, S, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, or -COO-.

[0564] In some embodiments of the present disclosure, L a is selected from a bond, NH, O, S, C 1-3 alkyl, or -CONH-.

[0565] In some embodiments of the present disclosure, L a is selected from a bond, NH, O, -CH2-, or -CONH-.

[0566] In some embodiments of the present disclosure, the heteroatom of the heteroalkyl is selected from NH, O, or S. Optionally, the number of heteroatoms is selected from 1, 2, 3, or 4.

[0567] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, S, C(R d ), C(R d )2, or N.

[0568] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, C(R d ), or C(R d )2.

[0569] In some embodiments of the present disclosure, X 1 and X 2 are each independently selected from O, CH, or CH2.

[0570] In some embodiments of the present disclosure, X and X 2 are connected to each other to form a 7- to 10-membered bridged heterocycloalkyl group.

[0571] In some embodiments of the present disclosure, X and X 2 are connected to each other to form a 7- to 9-membered bridged heterocycloalkyl group. In some embodiments of the present disclosure, X and X 2 are connected to each other to form a 7- to 8-membered bridged heterocycloalkyl group.

[0572] In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, or an optionally substituted group selected from: hydroxyl, NH2, C 1-3 alkyl, or C 1-3 alkoxy.

[0573] In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, hydroxyl, NH2, C 1-6 alkyl, or C 1-6 alkoxy.

[0574] In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, hydroxyl, NH2, C 1-3 alkyl, or C 1-3 alkoxy.

[0575] In some embodiments of the present disclosure, R d and R e are each independently selected from H or C 1-3 alkyl. In some embodiments of the present disclosure, R dand R e selected from H.

[0576] In some embodiments of the present disclosure, the structural fragment is selected from

[0577] In some embodiments of the present disclosure, the structural fragment is selected from

[0578]

[0579] In some embodiments of the present disclosure, the structural fragment is selected from

[0580] In some embodiments of the present disclosure, the structural fragment is selected from

[0581] In some other embodiments of the present disclosure, the structural fragment is selected from

[0582] In some other embodiments of the present disclosure, the structural fragment is selected from and R 5 is selected from F; further, the structural fragment is selected from

[0583] In some other embodiments of the present disclosure, the structural fragment is selected from

[0584] In some other embodiments of the present disclosure, the structural fragment is selected from

[0585] In some other embodiments of the present disclosure, the structural fragment is selected from

[0586] In some other embodiments of the present disclosure, the structural fragment is selected from In some other embodiments of the present disclosure, the structural fragment is selected from and R5 Selected from F; further, the structural fragment Selected from

[0587] On the other hand, the present disclosure relates to a compound of formula III-1A, a moiety, a stereoisomer thereof, a derivative thereof (such as a PROTAC), or a pharmaceutically acceptable salt thereof:

[0588]

[0589] Ring E, Ring F, X 3 , R 5 , q’, X, X 1 , X 2 or L a are defined as in the compound of formula III-1, a stereoisomer thereof, a derivative thereof (such as a PROTAC), or a pharmaceutically acceptable salt thereof, respectively;

[0590] L is selected from linking groups.

[0591] In some embodiments of the present disclosure, the definition of the structural fragment is as described in the present disclosure.

[0592] On the other hand, the present disclosure relates to a compound of formula III-1B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0593]

[0594] Ring E, Ring F, X 3 , R 5 , q’, X, X 1 , X 2 or L a are defined as in the compound of formula III-1, a stereoisomer thereof, a derivative thereof (such as a PROTAC), or a pharmaceutically acceptable salt thereof, respectively;

[0595] L is selected from linking groups;

[0596] PTM is selected from target protein molecules.

[0597] In some embodiments of the present disclosure, the definition of the structural fragment is as described in the present disclosure.

[0598] On the other hand, the present disclosure relates to a compound of formula IV-1, a moiety, a stereoisomer thereof, a derivative thereof (such as a PROTAC), or a pharmaceutically acceptable salt thereof:

[0599]

[0600] represents a single bond or a double bond;

[0601] Each R 6 is independently selected from halogen, -CN, or an optionally substituted group selected from the following: -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 4-12 membered heteroalkyl;

[0602] r is selected from 0, 1, 2, 3, or 4;

[0603] L b is selected from a bond, S, -CO-, -COO-, or an optionally substituted group selected from the following: -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-;

[0604] X is independently selected from C(R d ) or N;

[0605] X a1 and X a2 are independently selected from O, S, C(R d )), C(R d )2, N or N(R e );

[0606] Alternatively, X and X a2 are joined to each other to form a 7-12 membered bridged heteroalkyl;

[0607] R d and R e are independently selected from H, halogen, CN, or an optionally substituted group selected from the following: hydroxy, NH2, C 1-6 alkyl or C 1-6 alkoxy; X h and X k are independently selected from CH or N;

[0608] X b X c and X e are independently selected from O, S, CH2 or NH. In some embodiments of the present disclosure, each R 6 is independently selected from halogen, -CN, or an optionally substituted group selected from the following: -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4Alkyl OC(O)-, C 3-10 Cycloalkyl or 3- to 10-membered heterocycloalkyl.

[0609] In some embodiments of the present disclosure, each R 6 is independently selected from halogen, -CN, or an optionally substituted group selected from: -OH, -NH2, -CHO, C 1-4 alkyl or C 1-4 alkoxy.

[0610] In some embodiments of the present disclosure, each R 6 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the -OH, -NH2, -CHO, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl OC(O)-, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 alkyl-OH, C 1-6 alkyl OC(O)-, or 3- to 12-membered heterocycloalkyl optionally substituted with C 1-6 alkyl COC(O)-.

[0611] In some embodiments of the present disclosure, each R 6 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 alkyl-OH, C 1-4 alkyl OC(O)-, or 3- to 10-membered heterocycloalkyl optionally substituted with C 1-4 alkyl COC(O)-.

[0612] In some embodiments of the present disclosure, each R 6 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl OC(O)-, C 3-10 cycloalkyl or 3-10 membered heteroalkyl.

[0613] In some embodiments of the present disclosure, each R 6 is independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 alkyl or C 1-4 alkoxy.

[0614] In some embodiments of the present disclosure, each R 5 or R 6 is independently selected from halogen, -CN, -OH or -NH2.

[0615] In some embodiments of the present disclosure, r is selected from 0, 1 or 2. In some embodiments of the present disclosure, r is selected from 0 or 1.

[0616] In some embodiments of the present disclosure, L b is selected from a bond, S, -CO-, -COO-, or an optionally substituted group: -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0617] In some embodiments of the present disclosure, L b is selected from a bond, S, -CO-, -COO-, or an optionally substituted group: -N(C 1-6 alkyl)-, C 1-6 alkyl, C 1-6 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-.

[0618] In some embodiments of the present disclosure, L b is selected from a bond, S, -CO-, -COO-, -N(C 1-3 alkyl)-, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-. In some embodiments of the present disclosure, L b is selected from a bond, S, C 1-3 alkyl, C 1-3 heteroalkyl, -CONH- or -COO-.

[0619] In some embodiments of the present disclosure, L b is selected from a bond, S, C 1-3 alkyl or -CONH-.

[0620] In some embodiments of the present disclosure, L b is selected from a bond, -CH2- or -CONH-.

[0621] In some embodiments of the present disclosure, L b is selected from a bond.

[0622] In some embodiments of the present disclosure, X is independently selected from C(R d ). In some embodiments of the present disclosure, X is independently selected from N. In some embodiments of the present disclosure, X is independently selected from CH or N.

[0623] In some embodiments of the present disclosure, X a1 and X a2 are independently selected from O, S, C(R d ), C(R d )2 or N.

[0624] In some embodiments of the present disclosure, X a1 and X a2 are independently selected from O, C(R d ), C(R d )2 or N.

[0625] In some embodiments of the present disclosure, X a1 and X a2 are independently selected from O, C(R d ), C(R d )2.

[0626] In some embodiments of the present disclosure, X a1 and X a2 are independently selected from C(R d ), C(R d )2.

[0627] In some embodiments of the present disclosure, X a1 and X a2 are independently selected from CH or CH2.

[0628] In some embodiments of the present disclosure, X a1 and X a2 are independently selected from O, CH or CH2.

[0629] In some embodiments of the present disclosure, X and X a2Connect to each other to form a 7- to 10-membered bridged heterocycloalkyl group.

[0630] In some embodiments of the present disclosure, X and X a2 Connect to each other to form a 7- to 9-membered bridged heterocycloalkyl group. In some embodiments of the present disclosure, X and X a2 Connect to each other to form a 7- to 8-membered bridged heterocycloalkyl group.

[0631] In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, or the following optionally substituted groups: hydroxyl, NH2, C 1-3 alkyl or C 1-3 alkoxy.

[0632] In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, or the following optionally substituted groups: hydroxyl, NH2, C 1-6 alkyl or C 1-6 alkoxy.

[0633] In some embodiments of the present disclosure, R d and R e are each independently selected from H, halogen, CN, hydroxyl, NH2, C 1-3 alkyl or C 1-3 alkoxy.

[0634] In some embodiments of the present disclosure, R d and R e are each independently selected from H or C 1-3 alkyl. In some embodiments of the present disclosure, R d and R e are selected from H.

[0635] In some embodiments of the present disclosure, X b and X c are selected from CH2.

[0636] In some embodiments of the present disclosure, X e is selected from CH2.

[0637] In some embodiments of the present disclosure, X b and X c are selected from CH2; X e is selected from CH2.

[0638] In some embodiments of the present disclosure, the structural fragment is selected from

[0639] In some other embodiments of the present disclosure, the structural fragment is selected from and R 6 is selected from F; further, the structural fragment is selected from

[0640] In some embodiments of the present disclosure, the structural fragment is selected from and R 5 is selected from F; further, the structural fragment is selected from

[0641] On the other hand, the present disclosure relates to a compound of formula IV-1A, a moiety, a stereoisomer thereof, a derivative thereof (such as a PROTAC), or a pharmaceutically acceptable salt thereof:

[0642]

[0643] L is selected from linking groups;

[0644] R 6 , r, L b , X, X a1 , X a2 , R d , R e , X h , X k , X b , X c and X e are defined as described in the compound of formula III-1, its stereoisomer, its derivative (such as a PROTAC), or its pharmaceutically acceptable salt.

[0645] On the other hand, the present disclosure relates to a compound of formula IV-1B, its stereoisomer, its derivative (such as a PROTAC), or a pharmaceutically acceptable salt thereof:

[0646]

[0647] wherein,

[0648] L is selected from linking groups;

[0649] PTM is selected from target protein molecules;

[0650] R 6 , r, L b , X, X a1 , X a2 , R d , R e , Xh , X k , X b , X c and X e are defined as described in the compound of formula III-1, its stereoisomers, its derivatives (such as PROTAC), or its pharmaceutically acceptable salts.

[0651] In some embodiments of the present disclosure, the "optionally substituted" as described in the present disclosure is selected from "optionally substituted by one or more substituents".

[0652] In some embodiments of the present disclosure, the "optionally substituted" as described in the present disclosure is selected from "optionally substituted by 1, 2 or more than 3 substituents".

[0653] In some embodiments of the present disclosure, the "optionally substituted" as described in the present disclosure is selected from "optionally substituted by 1, 2 or 3 substituents".

[0654] In some embodiments of the present disclosure, the substituents in the "optionally substituted by one or more substituents", "optionally substituted by 1, 2 or more than 3 substituents" or "optionally substituted by 1, 2 or 3 substituents" are selected from the following substituents: -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, cycloalkyl group, halo-cycloalkyl group, alkenyl group, halo-alkenyl group, cycloalkenyl group, halo-cycloalkenyl group, alkynyl group, halo-alkynyl group, cycloalkynyl group, halo-cycloalkynyl group, heteroalkyl group, halo-heteroalkyl group, alkoxy group, alkylthio group, aryl group, aryloxy group, arylthio group, aralkyl group, arylalkoxy group, arylalkylthio group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroaralkyl group, heteroarylalkoxy group, heteroarylalkylthio group, heterocyclic group, heterocyclicoxy group, heterocyclicthio group, heterocyclicalkyl group, heterocyclicalkoxy group, heterocyclicalkylthio group, acyl group, acyloxy group, carbamate group, amide group, urea group, epoxy group and ester group, etc.

[0655] In some embodiments of the present disclosure, each of the "hetero" is independently selected from heteroatoms of oxygen, sulfur and nitrogen, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), the sulfur atom is optionally oxidized to S(O) or S(O)2, and other variables are as defined in the present disclosure.

[0656] In some embodiments of the present disclosure, each of the "hetero" is independently selected from heteroatoms of oxygen, sulfur and nitrogen, wherein the sulfur heteroatom is optionally oxidized to S(O) or S(O)2, and other variables are as defined in the present disclosure.

[0657] In some embodiments of the present disclosure, the PTM group is a group that binds to a target protein. The target species of the PTM group are numerous and are selected from proteins that are expressed in a cell such that at least a portion of the sequence is found in the cell and can bind to the PTM group. The term "protein" encompasses oligopeptides and polypeptide sequences that are long enough such that they can bind to the PTM groups of the present disclosure. As described elsewhere herein, any protein in a eukaryotic or microbial system, including viruses, bacteria, or fungi, is a target for ubiquitination mediated by a compound according to the present disclosure. Preferably, the target protein is a eukaryotic protein.

[0658] The PTM group according to the present disclosure includes, for example, any moiety that specifically binds to a protein (binds to the target protein), and includes the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, androgen receptor inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), etc. These binding moieties are preferably linked to the ubiquitin ligase binding moiety via a linker group so as to present the target protein (bind to the protein target moiety) in the vicinity of the ubiquitin ligase for ubiquitination and degradation.

[0659] Any protein that can bind to the protein target moiety or the PTM group and act on or be degraded by the ubiquitin ligase is the target protein according to the present disclosure. Generally, the target protein can include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins related to the integrative functions of the cell (including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (metabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins having kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid, carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli), behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular tissue and biogenesis activity, translational regulator activity). The proteins of interest can include proteins from eukaryotes and prokaryotes (including humans as targets for drug therapy), other animals (including domesticated animals), microorganisms for determining the targets of antibiotics and other antimicrobial agents and plants, and even viruses, etc.

[0660] The term "target protein" is used to describe a protein or polypeptide that is a target that binds to a compound according to the present disclosure and is degraded by a ubiquitin ligase according to the present disclosure. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target a protein of interest. These binding moieties are linked to the CLM group by a linking group L.

[0661] Target proteins that can bind to a protein target moiety and be degraded by a ligase that binds a ubiquitin ligase binding moiety include any protein or peptide, including fragments, analogs, and / or homologs thereof. Target proteins include proteins and peptides having any biological function or activity (including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transport, and signal transduction). In certain embodiments, the target protein includes structural proteins, receptors, enzymes, cell surface proteins, proteins related to the integrative functions of the cell (including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins having kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli), behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular tissue and biogenesis activity, translational regulator activity). The protein of interest can include proteins from eukaryotes and prokaryotes (including microorganisms, viruses, fungi, and parasites, including humans, microorganisms, viruses, fungi, and parasites, etc. that are targets of drug therapies), other animals (including domesticated animals), microorganisms for determining targets of antibiotics and other antimicrobial agents and plants, and even viruses, etc.

[0662] More specifically, many drug targets for human therapeutics represent protein targets that can bind to the protein target moiety and be incorporated into the compounds according to the present disclosure. These include proteins that can be used to restore function in many polygenic diseases, including, for example, B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza, ceramidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neuropeptide and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin 1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus 1 (HSV-1), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, estrogen receptor, androgen receptor (AR), adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferase, geranylgeranyl transferase, TrkA a receptor for NGF, β-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neutrophil, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase. Other protein targets include, for example, ecdysone 20-monooxygenase, ion channels of GABA-gated chloride channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channels and chloride channels.Still other target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and phosphoenolpyruvate shikimate phosphate synthase.

[0663] Optionally, the target protein is selected from: AR, BTK, ER, IRAK4, EGFR, BRD9, IKZF1, IKZF3, BET, BRD4, KRAS-G12D\G12C\G12V, STAT3, SWI / SNF, SMARCA2, SMARCA4, MDM2, Bcl-xl, c-Myc, GSPT1, CK1α, BCL6, Mcl-1, Trk, BRAF, HER2, KDM1A, MYB, CDK12, CCNK, CDK13, ARv7, PRMT5, Bcr-Abl, EZH2, ALK, Tau, CDK6, CBP / EP300, Akt, MEK, JAK, PARP1, CDK2, Bcl-2, β-cat, HPK1, HDAC3, CDK4, SHP2, STAT5, FAK, SOS1, NSD2, IKZF2, CDK9, HSF1, EED, HBV, FRα, HTT, WDR5, CDK8, GSK-3, α-synuclein, PDE4, MALT1, FER, WEE1, GSPT2, c-Met, IRAK3, LRRK2, FGFR1, FGFR2, RNA, Flt3, HDAC8, ADRM1, H-PGDS, NR4A2, BRD7, SARS-CoV-2 3Clpro, CDC20, MLLT1, PA protein, NCL, RPA, TYR, LDHB, GRK2, TRIM24, ERK2, ERK1, SUMO1, ERK5, ZFP91, GCCR, HPV E7, LXR, PDL1, SMAD3, NF1, DAPK1, TEAD, activin receptor-like kinase, PARP14, p38 MAPK, USP7, nicotine, Lck, USP1, axin, SGK3, TBK1, LDHA, MNK2, MNK1, CCNE1, ADAR, MDMX, RIPK1, EEF1A2, CCND1, SF3B1, FKBP12, WRN, DcpS, USP30, CD33, Cbl-b, CFB, cyclin-T1, MIF, SIRT2, PIKfyve, PIP4K2C, cyclin-C, PLK4, C4B, PLK1, CDK5, CDK7, Hsp90, STING, NSD3, TRIB1, IRAK1, COP1, pirin, SALL4, ERRα, HDAC1, c-Kit, HDAC2, Aurora A or GPX4.

[0664] Optionally, the target protein is selected from: AR, BTK, ER, IRAK4, EGFR, BRD9, IKZF1, IKZF3, BET, BRD4, KRAS-G12D\G12C\G12V, STAT3, SWI / SNF, SMARCA2, SMARCA4, MDM2, Bcl-xl, c-Myc, GSPT1, CK1α, BCL6, Mcl-1, Trk, BRAF, HER2, KDM1A, MYB, CDK12, CCNK or CDK13.

[0665] The term "protein target moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and positions / presents the protein or polypeptide near a ubiquitin ligase such that the protein or polypeptide is degraded by the ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), etc.

[0666] In some embodiments of the present disclosure, the PTM is selected from molecular structures having anti-cancer, anti-neurodegenerative, anti-microbial, anti-viral, anti-HIV or anti-fungal effects.

[0667] In some embodiments of the present disclosure, the PTM is selected from drugs or their derivatives that act on AR, ER, kinases (such as tyrosine kinases, threonine / serine kinases), phosphatases, MDM2, proteins of the human BET bromodomain, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular growth factor, immunosuppression-related receptors or proteins, aryl hydrocarbon receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease, or acyl protein thioesterase 1 and / or acyl protein thioesterase 2.

[0668] In some embodiments of the present disclosure, the PTM is selected from molecules or compounds (including small molecules, polypeptides, proteins, nucleic acids, antibodies, etc.) that act on FLT-3, VEGFR, EGFR TK, aurora kinase, PIK-1, Bcl-2, HDAC, c-MET, PARP, Cdk, IGFR-TK, anti-HGF antibody, PI3K kinase, BRAF, BCL6, SMARCA2 (BRM), SMARCA4, AR-V7, Map kinase kinase (mek), or VEGF trap antibody.

[0669] In some embodiments of the present disclosure, the PTM described in the present disclosure is selected from drugs acting on ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDAC, Akt, PI3K, mTOR, AR, ER, PDEδ, SRC, MDM2, RAF, IRAK4, STAT3, and c-Myc or derivatives thereof.

[0670] In some embodiments of the present disclosure, the PTM described in the present disclosure is selected from drugs acting on ALK, BRD4, CDK4 / 6, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, KRAS, EGFR, BTK, AR, ER, PDEδ, JAK, MDM2, or RAF or derivatives thereof.

[0671] In some embodiments of the present disclosure, the PTM described in the present disclosure is selected from drugs acting on MDM2 or WEE1 or derivatives thereof.

[0672] In some embodiments of the present disclosure, the PTM described in the present disclosure is selected from drugs acting on MDM2 or derivatives thereof.

[0673] The present disclosure relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691] On the other hand, the present disclosure relates to the compound (e.g., a compound of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B, or a specific compound), moiety, its stereoisomers, its derivatives, or its pharmaceutically acceptable salts, and the structural fragment involved The NH of the fragment may be optionally substituted.

[0692] In some embodiments of the present disclosure, the above-mentioned compound, moiety, its stereoisomers, its derivatives (such as PROTAC), or its pharmaceutically acceptable salts can be used to bind and / or inhibit cerebellin.

[0693] On the other hand, the present disclosure relates to the use of the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts in Protac molecules. On the other hand, the present disclosure relates to the use of the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts for use as part of a Protac molecule. On the other hand, the present disclosure relates to the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts existing in the form of Protac molecules.On the other hand, the present disclosure relates to the use of the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts for degrading a protein, for example, the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts degrade the protein in the form of a Protac molecule. On the other hand, the present disclosure relates to the use of the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts in the form of a Protac molecule for degrading a protein.The present disclosure relates to the use of the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts (such as as preparation intermediates) in the preparation of Protac molecules. The present disclosure relates to the use of the compounds (such as compounds of formula II’, II’-A, II’-B, II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-1A, II-2A, II-3A, II-4A, II-5A, II-6A, II-7A, II-8A, II-9A, II-10A, II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B, II-10B, III-1, III-1A, III-1B, IV-1, IV-1A or IV-1B or specific compounds), moieties, their stereoisomers, their derivatives, or their pharmaceutically acceptable salts (such as as preparation intermediates) in the preparation of proteolysis agents.

[0694] On the other hand, the present disclosure relates to a pharmaceutical composition, which contains the compounds, their stereoisomers or their pharmaceutically acceptable salts as described above in the present disclosure, and the pharmaceutical composition of the present disclosure further includes pharmaceutically acceptable excipients.

[0695] On the other hand, the present disclosure relates to the use of the above-mentioned compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs for preventing or treating diseases treated by degrading target proteins (such as MDM2) that bind to target ligands.

[0696] On the other hand, the present disclosure relates to the use of the above-mentioned compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs for preventing or treating diseases treated by binding to cerebellar proteins in vivo.

[0697] On the other hand, the present disclosure relates to the use of the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of a medicament for preventing or treating a disease (such as an MDM2-related disease).

[0698] The present disclosure relates to a method for treating or preventing a disorder in a mammal that is treated by degrading a target protein (such as MDM2) bound to a targeting ligand, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions of the present disclosure.

[0699] The present disclosure relates to a method for treating or preventing a disorder that is treated by binding to a cerebellar protein in vivo, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions of the present disclosure.

[0700] On the other hand, the present disclosure relates to a method for treating a mammalian disease (such as an MDM2-related disease), comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions of the present disclosure.

[0701] On the other hand, the present disclosure relates to the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating a disorder that is treated by degrading a target protein (such as MDM2) bound to a targeting ligand.

[0702] On the other hand, the present disclosure relates to the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating a disorder that is treated by binding to a cerebellar protein in vivo.

[0703] On the other hand, the present disclosure relates to the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating a disease (such as an MDM2-related disease).

[0704] On the other hand, the present disclosure relates to the use of the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in preventing or treating a disorder that is treated by degrading a target protein (such as MDM2) bound to a targeting ligand.

[0705] On the other hand, the present disclosure relates to the use of the above compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in preventing or treating a disorder that is treated by binding to a cerebellar protein in vivo.

[0706] On the other hand, the present disclosure relates to the use of the above-mentioned compounds, their stereoisomers, or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the prevention or treatment of diseases (such as MDM2-related diseases).

[0707] In some specific embodiments, the above-mentioned MDM2-related diseases are selected from the conditions treated by degrading and / or inhibiting proteins that bind to the ligand of the MDM2 target protein; in some specific embodiments, the above-mentioned MDM2-related diseases are selected from the conditions treated by binding to cerebellar proteins in vivo; in some embodiments of the present disclosure, the above-mentioned diseases or conditions are selected from cancers.

[0708] In some specific embodiments, the conditions treated by binding to cerebellar proteins in vivo and / or the conditions treated by binding to cerebellar proteins in vivo are selected from MDM2-related diseases; in some specific embodiments, the conditions treated by degrading target proteins (such as MDM2) that bind to the target ligand are selected from MDM2-related diseases; in some specific embodiments, the above-mentioned MDM2-related diseases are selected from cancers.

[0709] In some embodiments of the present disclosure, the "one or more" are selected from one, two, three, four, five, or six. In some embodiments of the present disclosure, the "one or more" are selected from one, two, or three. In some embodiments of the present disclosure, the "one or more" are selected from one or two.

[0710] In some embodiments of the present disclosure, the present disclosure includes the variables and their embodiments defined above, and any combination thereof.

[0711] Technical effects

[0712] The compounds of the present disclosure (such as the compounds formed in the form of Protac molecules) have in vitro cell proliferation inhibitory activity (such as against RS4; 11 or MV-4-11 cells); they have MDM2 binding ability. In addition, the compounds of the present disclosure (such as the compounds formed in the form of Protac molecules) also have good in vitro liver microsome stability (human, monkey, dog, rat, or mouse), and good in vivo (such as human or mouse, etc.) pharmacokinetic properties, and can inhibit tumor growth in vivo, showing the prospect of becoming a drug.

[0713] Definitions

[0714] Unless otherwise specified, the following terms used in the present disclosure have the following meanings. A specific term should not be considered indeterminate or unclear without a special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding product or its active ingredient.

[0715] represents a single bond or a double bond, that is, the connecting bond is correspondingly selected from a single bond according to specific connecting group options and valence bond rules or a double bond

[0716] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0717] The term "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and the description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally" substituted by a halogen for ethyl means that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.) or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0718] As used herein, the "substituent" includes, but is not limited to, the terms "alkyl", "alkoxy", "cycloalkyl", "heterocycloalkyl", "heteroaryl", "alkenyl", "alkynyl", "cycloalkenyl", "heterocycloalkenyl", "heteroaromatic ring", etc. mentioned in the context, and the corresponding non-limiting or exemplary groups. Some non-limiting examples of the "substituent" include deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, cycloalkenyl, halocycloalkenyl, alkynyl, haloalkynyl, cycloalkynyl, halocycloalkynyl, heteroalkyl, haloheteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, aralkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroaralkoxy, heteroaralkylthio, heterocyclic group, heterocyclic oxy group, heterocyclic thio group, heterocyclic alkyl group, heterocyclic alkoxy group, heterocyclic alkylthio group, acyl group, acyloxy group, carbamate group, amide group, urea group, epoxy group, ester group, etc. The groups are optionally substituted with one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic group, heterocyclic alkyl group, heterocyclic oxy group, heterocycloalkyl group, heterocycloalkylalkyl group, heterocycloalkyloxy group, heteroaryl group, heteroarylalkyl group, heteroaryloxy group, aryl group, arylalkyl group or aryloxy group.

[0719] In some embodiments herein, the "substituent" is selected from deuterium, tritium, hydroxy, mercapto, halogen, amino, nitro, nitroso, cyano, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, aldehyde group, imine group, C 1-12 alkyl, halo-C 1-12 alkyl, 3- to 12-membered cycloalkyl, halocycloalkyl having 3 to 12 members, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3- to 12-membered cycloalkenyl, halocycloalkenyl having 3 to 12 members, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8- to 12-membered cycloalkynyl, halocycloalkynyl having 8 to 12 members, C 1-12 heteroalkyl, halo-C 1-12Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10-membered aryl, 6-10-membered aryloxy, 6-10-membered arylthio, 6-10-membered arylC 1-12 Alkylene, 6-10-membered arylC 1-12 Alkoxy, 6-10-membered arylC 1-12 Alkylthio, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, 5-10-membered heteroarylthio, 5-10-membered heteroarylene, 5-10-membered heteroarylalkoxy, 5-10-membered heteroarylalkylthio, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic thio group, 3-12-membered heterocyclic C 1-12 Alkylene, 3-12-membered heterocyclic C 1-12 Alkoxy, 3-12-membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acetyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, and the substituents are optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halo C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halo C 1-12 Alkylamino, halo diC 1-12 Alkylamino, carboxyl, -C(O)O-C 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 Alkyl)2, 3-12-membered cycloalkyl, 3-12-membered cycloalkyl C 1-12 Alkylene, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclic group, 3-12-membered heterocyclic C 1-12Alkylene, 3- to 12-membered heterocyclic group oxy, 3- to 12-membered heterocyclic alkyl, 3- to 12-membered heterocyclic alkyl C 1-12 Alkylene, 3- to 12-membered heterocyclic alkyl oxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl C 1-12 Alkylene, 5- to 10-membered heteroaryl oxy, 6- to 10-membered aryl, 6- to 10-membered aryl C 1-12 Alkylene or 6- to 10-membered aryl oxy.

[0720] C in this article m-n , means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that this group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, "C 1-3 " means that this group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.

[0721] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group contains 2 R's, each R has independent options.

[0722] When a bond cross-links to two atoms of a ring (including a monocyclic, fused-ring or spiro ring), this bond can be bonded to any atom on the ring (including a monocyclic, fused-ring or spiro ring). For example, the structural unit means that the bonds on both sides can be connected to any two different atoms on ring E, ring F or ring G; for another example means that the bonds on both sides can be connected to any two different atoms on ring E, the middle benzene ring or ring G; for a further example means that the bonds on both sides can be connected to any two different atoms of the four rings in this system.

[0723] The term "halogen" or "halogen element" refers to fluorine, chlorine, bromine and iodine.

[0724] The term "hydroxyl" refers to the -OH group.

[0725] The term "amino" refers to the -NH2 group.

[0726] Unless otherwise specified, the term "hetero" means a heteroatom or a heteroatomic group (i.e., a group containing a heteroatom), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms. For example, heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, germanium, aluminum, boron; specific heteroatoms or heteroatomic groups such as: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-. Preferably, the term "hetero" means a heteroatom or a heteroatomic group (i.e., a group containing a heteroatom) selected from oxygen, nitrogen or sulfur.

[0727] In each group containing a "heteroatom" in the present disclosure, the "heteroatom" includes an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), the sulfur atom is optionally oxidized to S(O) or S(O)2, and the phosphorus atom is optionally oxidized to P(O) or P(O)2.

[0728] The term "alkyl" refers to a hydrocarbon group of the general formula C n H 2n+1 . The alkyl group can be straight-chain or branched-chain. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moieties of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups (i.e., alkyl) have the same definition as above.

[0729] The term "heteroalkyl" is a straight-chain or branched-chain heteroalkyl composed of a certain number of carbon atoms and at least one heteroatom. It preferably has 1 to 14 carbons, more preferably 1 to 10 carbons, further more preferably 1 to 6 carbons, and most preferably 1 to 3 carbons in the chain, wherein the heteroatoms are preferably selected from S, O and N heteroatoms, and the number is preferably selected from 1, 2 or 3. Among them, the nitrogen atom and the sulfur atom are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatomic group can be located at any internal position of the heteroalkyl group, including the position where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyls include alkyl ethers, secondary alkylamines, tertiary alkylamines, amides, thioethers, etc., including alkoxy, alkylthio, alkamino; unless otherwise specified, C 1-6 heteroalkyl includes C1, C2, C3, C4, C5 and C6 heteroalkyls, such as C 1-6alkoxy, C 1-6 alkylthio, C 1-6 alkylamino.

[0730] The term "heteroalkylene" refers to a divalent group formed by removing one hydrogen from any position of a heteroalkyl group.

[0731] The term "alkoxy" refers to -O-alkyl.

[0732] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0733] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C-C≡CH), etc.

[0734] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring that can exist as a monocyclic, bicyclic bridged or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 4- to 16-membered ring, a 4- to 12-membered ring, a 4- to 10-membered ring or a 4- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc. Specifically, for example

[0735] The term "ring" refers to a cyclic group, which can be fully saturated, partially saturated or aromatic.

[0736] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 16-membered ring (e.g., a 3- to 10-membered ring, or a 5- to 8-membered ring). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0737] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle is usually a 3- to 20-membered ring, 3- to 15-membered ring, 3- to 10-membered ring or 3- to 7-membered ring containing 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, sulfur, silicon and / or phosphorus (preferably heteroatoms of sulfur, oxygen and / or nitrogen, preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.

[0738] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle is usually a 3- to 16-membered ring, 3- to 11-membered ring, 3- to 10-membered ring, 3- to 7-membered ring, 3- to 6-membered ring or 3- to 5-membered ring containing 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, sulfur, silicon and / or phosphorus (preferably heteroatoms of sulfur, oxygen and / or nitrogen, preferably 1 or 2 heteroatoms). Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, aziridinyl; non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl; examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl; examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Preferred is a monocyclic heterocycloalkyl having 5 or 6 ring atoms.

[0739] The term "bridged heterocycloalkyl" refers to a cyclic group that is fully saturated and exists as a bridged ring. Unless otherwise indicated, the heterocycle is usually a 5- to 16-membered bridged heterocycle, 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7-12 membered bridged heterocycle, 7- to 10-membered bridged heterocycle, or 7- to 8-membered bridged heterocycle containing 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, sulfur, silicon and / or phosphorus (preferably heteroatoms of sulfur, oxygen and / or nitrogen, preferably 1 or 2 heteroatoms). Specifically, for example

[0740] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic system in which a single carbon atom (referred to as the spiro atom) is shared between monocyclic rings, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the spirocycle is 5 to 20 membered, preferably 6 to 14 membered, more preferably 8 to 12 membered. When the spirocycle is a heterocycle, one or more ring atoms in the polycycle are selected from heteroatoms of N, O, S(O) n , P(O) n (where n is 0, 1 or 2) (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0741] The term "spiroalkyl" refers to a fully saturated all-carbon polycycle in which a single carbon atom (referred to as the spiro atom) is shared between monocyclic rings. Unless otherwise indicated, the spiroalkyl is 5 to 20 membered, preferably 6 to 14 membered, more preferably 8 to 12 membered. Spiroalkyls are classified into monospiroalkyls, dispiroalkyls or polyspiroalkyls according to the number of spiro atoms shared between rings, preferably monospiroalkyls and dispiroalkyls, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5 or 5 / 6 monospiroalkyls. Non-limiting examples of spiroalkyls include

[0742] The term "spiroheteroalkyl" refers to a fully saturated polycycle in which a single carbon atom (referred to as the spiro atom) is shared between monocyclic rings, and one or more ring atoms in the polycycle are selected from heteroatoms of N, O, S(O) n , P(O) n (where n is 0, 1 or 2) (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiroheteroalkyl is 5 to 20 membered, preferably 6 to 14 membered, more preferably 6 to 10 membered. Spiroheterocycles are classified into monospiroheterocycles, dispiroheterocycles or polyspiroheterocycles according to the number of spiro atoms shared between rings, preferably monospiroheterocycles or dispiroheterocycles, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5 or 5 / 6 monospiroheterocycles. Non-limiting examples of spiroheteroalkyls include etc.

[0743] The term "heterocycloalkenyl" includes a cycloalkenyl group in which one or more carbon atoms are replaced by heteroatoms, specifically, for example, a cycloalkenyl group in which up to 3 carbon atoms, in one embodiment up to 2 carbon atoms, and in another embodiment 1 carbon atom are each independently replaced by B, O, S, S(O), S(O)2, N, Si, P, P(O), provided that at least one carbon-carbon double bond of the cycloalkenyl group is retained. The cyclic group can be a monocyclic, bridged or spiro ring, and can be a 3- to 16-membered ring (e.g., 3- to 12-membered, 5- to 8-membered rings, specifically 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered rings). Examples of heterocycloalkenyl include, but are not limited to, pyrrolidinyl, tetrahydropyridyl, tetrahydroazepinyl or azaspirooctene. Specifically, for example

[0744] Unless otherwise indicated, the carbocyclic ring is usually a 4- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptadienyl, etc.

[0745] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, and anthracenyl, etc.

[0746] The term "heteroaryl" refers to a monocyclic or fused polycyclic system that contains at least one ring atom selected from N, O, S, the remaining ring atoms are C, and has at least one aromatic ring. Preferred heteroaryl has a single 4- to 8-membered ring, especially a 5- to 8-membered ring (e.g., 5-membered, 6-membered, 7-membered or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9 or 10) ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.

[0747] The term "derivative" refers to one or a group of new compounds produced by undergoing one or more chemical reactions; or structural evolution, while retaining the basic structure of the parent compound, with changes and modifications only occurring in the side chains, functional groups or substituents.

[0748] In the present disclosure, a wavy line represents one of the absolute configurations of a stereocenter (e.g., one of them, specifically represents ), or one of the relative configurations (e.g., represents ) or one of the absolute configurations of axial chirality (e.g., represents an atropisomer ). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, they include E and Z geometric isomers. Similarly, all tautomeric forms are included within the scope of the present disclosure.

[0749] Groups or structural moieties in the present disclosure such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -LNK 2 -, LNK, Cy 1 , Cy 2 , -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK- or -LNK-Cy 2 - etc. and their specific options, optionally can adopt the reading order from left to right, corresponding to be connected with the left and right groups of the group or fragment in the general formula respectively. For example, when L is selected from -Cy 1 -LNK-Cy 2 -, when Cy 1 is selected from According to the reading order from left to right, the left side of Cy 1 is connected with the corresponding left fragment in the general formula and the right side is connected with the right fragment to form a fragment which is Optionally, groups or structural moieties in the present disclosure such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -LNK 2 -, LNK, Cy 1 , Cy 2 , -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK- or -LNK-Cy 2 - and their specific options can adopt the reading order from right to left, corresponding to be connected with the left and right groups of the group or fragment in the general formula respectively. For example, when L is selected from -Cy 1 -LNK-Cy 2 -, when Cy 1 is selected from In the reading order from right to left, Cy 1 The fragment on the right is connected to the corresponding left fragment in the general formula and the fragment on the left is connected to the corresponding right fragment in the general formula to form a fragment that is Other groups are as described above.

[0750] The term "Protac (proteolysis targeting chimera) molecule" refers to a class of bifunctional compounds that can simultaneously bind to a target protein and an E3 ubiquitin ligase. Such compounds can induce the target protein to be recognized by the cell's proteasome, leading to the degradation of the target protein and effectively reducing the content of the target protein in the cell.

[0751] The term "derivative" refers to one or more hydrogen atoms in the basic structure of the parent compound being substituted or replaced by other groups or structural moieties, thereby generating one or a group of new compounds. The derivatives in this application refer to derivative compounds that retain the parent structure. For example, when the parent compound is derivatized into a Protac molecule, specifically it refers to a PTM-linker-ULM molecule, where PTM is the protein target moiety that binds to the target protein and target polypeptide; linker is the linking group, and ULM refers to the moiety that binds to the ubiquitin ligase.

[0752] The term "PTM group" refers to a drug or its derivative that binds to a target protein. There are many types of targets for the PTM group, and they are selected from proteins that are expressed in cells such that at least a part of the sequence is present in the cells, and the protein can bind to the PTM group. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length that can bind to the PTM group according to this application. Any protein in a eukaryotic system or a microbial system (including viruses, bacteria, or fungi) as described elsewhere herein is a target for ubiquitination mediated by the compounds according to this application. The target protein is preferably a eukaryotic protein.

[0753] The "target protein" is used hereinafter to describe a protein or polypeptide that is a target that binds to the compounds according to this application and is degraded by the ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. These binding moieties are connected to the group through a linker group L and are connected.

[0754] Unless otherwise specified, used to represent the hydrogen atom at any site within the group can be replaced by a group connected by "—".

[0755] The term "treatment" means administering a compound or preparation as described in the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0756] (i) inhibiting a disease or disease state, i.e., curbing its development;

[0757] (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to subside.

[0758] The term "prevention" means administering a compound or preparation as described in the present disclosure to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in a mammal, especially when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0759] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0760] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0761] As pharmaceutically acceptable salts, for example, mention may be made of metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, etc.

[0762] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present disclosure to an organism.

[0763] The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation to an organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0764] The term "comprise" or "comprises" or its English variants such as "comprises" or "comprising" shall be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0765] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via proton migration, such as keto-enol and imine-enamine isomerization. Specific examples of proton tautomers are imidazole moieties where the proton can migrate between two ring nitrogens. Valence tautomers involve interconversion through the reorganization of some bonding electrons. Specifically, for example, any compound of the present disclosure having pyrazole alone or as part of a heterocyclic group can exist in either of two tautomers or as a mixture of any number of the two tautomers, i.e., or or The present disclosure includes all possible tautomers of the compounds of the present disclosure, as a single tautomer or any mixture of the tautomers in any proportion.

[0766] The present disclosure also includes isotopically labeled compounds of the present disclosure that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. For example, it should be understood that a compound in which one or more hydrogen atoms in the compound of formula I of the present disclosure are replaced by deuterium atoms is still within the scope of the compound of formula I of the present disclosure.

[0767] Certain isotopically labeled compounds of the present disclosure (e.g., with 3 H and 14Those labeled with C can be used in the analysis of the tissue distribution of compounds and / or substrates. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an unlabeled reagent with an isotopically labeled reagent by procedures similar to those described in the protocols and / or examples disclosed below.

[0768] In addition, substitution with a heavier isotope (such as deuterium (i.e., 2 H)) can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may therefore be preferred in certain cases, where deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

[0769] Compounds of the present disclosure can be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. This occurs when rotation around a single bond in the molecule is prevented or greatly slowed down due to steric interactions with other parts of the molecule. Compounds of the present disclosure can include all atropisomers, can be pure individual atropisomers, or can be enriched in one of the atropisomers, or can be non-specific mixtures of each. If the rotational potential energy around the single bond is high enough and the interconversion between conformations is slow enough, separation of the isomers can be allowed. The bond indicates that the steric orientation on this side is outward. For example there is atropisomer 1 and atropisomer 2 Compounds of the present disclosure containing an asymmetric carbon atom can be isolated in optically pure form or as a racemate. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0770] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0771] The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art.

[0772] In all methods of administration of the compounds of general formula I described herein, the daily dose administered is from 0.001 to 1000 mg / kg body weight, in single or divided doses.

[0773] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0774] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required therefor. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction processes on the basis of the existing embodiments.

[0775] An important consideration in the synthesis route planning in the art is to select a suitable protecting group for the reactive functional groups (such as the amino group in the present disclosure). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0776] In some embodiments of the present disclosure, the compounds of formula I of the present disclosure can be prepared by those skilled in the art of organic synthesis through the following route:

[0777] The compound of general formula I-1 and the compound of general formula I-2 are subjected to a condensation reaction to obtain the compound of general formula I-3, that is, the compound of general formula I:

[0778]

[0779] wherein, R 1 、R 2 、R 3 、ring K, R, m, L and CLM are as defined in the present disclosure.

[0780] The present disclosure uses the following abbreviations:

[0781] Et represents ethyl; THF represents tetrahydrofuran; DMSO represents dimethyl sulfoxide; DCM represents dichloromethane; EtOH represents ethanol; Me represents methyl; Boc represents tert-butoxycarbonyl; LDA represents lithium diisopropylamide; IBX represents 2-iodoxybenzoic acid; DIPEA represents N,N-diisopropylethylamine; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EA represents ethyl acetate; DMF represents dimethylformamide; DMAP represents 4-dimethylaminopyridine; TFA represents trifluoroacetic acid; DCE represents 1,2-dichloroethane; MeOH represents methanol; PMB represents p-methoxybenzyl; DAST represents diethylaminosulfur trifluoride; RuPhos Pd G3 represents palladium(II) (2-dicyclohexylphosphino-

[0782] 2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl). Detailed implementation mode

[0783] For clarity, the present invention is further illustrated by examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0784] Preparation example

[0785] Synthesis of compounds z8 and z9 in Preparation Examples 8 and 9

[0786]

[0787] Step 1: Preparation of intermediates z8o-1 and z8o-2

[0788] Preparation and resolution: Dissolve 43 g of intermediate z8n in 430 mL of a dichloromethane-ethanol solution at a concentration of about 100.0 mg / mL, and filter the filtrate with a 0.45 μm organic filter membrane. Instrument: YMC high-pressure preparative chromatograph, chromatographic column: CHIRALPAK IG (Innovation 036#, 30*250 mm, S-10 μm), mobile phase A: ethanol, mobile phase B: n-hexane. The intermediate z8o-1 (9.057 g) was obtained from the front peak, and the intermediate z8o-2 (8.833 g) was obtained from the rear peak.

[0789] z8o-1: MS(ESI,[M+H] + ) m / z: 276.1.

[0790] z8o-2: MS(ESI,[M+H] + ) m / z: 276.1.

[0791] Step 2: Preparation of compound z8

[0792] In a reaction flask, under N2 protection, z8o-1 (11.93 g), THF (200 mL), and acrylamide (3.39 g) were successively added. After cooling to 0 °C, a solution of potassium tert-butoxide in THF (1 M, 34.7 mL) was added, and the mixture was reacted at 0 °C. After the reaction was completed, the reaction solution was added dropwise to a saturated aqueous ammonium chloride solution on ice, and ethyl acetate was added for extraction. After the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by distillation under reduced pressure, followed by filtration. The filter cake was collected to obtain 6.77 g of compound z8.

[0793] 1 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.74 (td, J = 5.3, 2.2 Hz, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 3.43 (dd, J = 6.8, 5.3 Hz, 2H), 3.22–3.09 (m, 2H), 2.94–2.83 (m, 2H), 2.76 (dq, J = 16.9, 6.3 Hz, 2H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.50–2.44 (m, 1H), 2.23–2.13 (m, 1H). Step 3 Synthesis of compound z9

[0794] Referring to the preparation process of z8, using intermediate z8o-2 to replace z8o-1, compound z9 (7.454 g) was obtained.

[0795] 1 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.74 (td, J = 5.3, 2.2 Hz, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 3.43 (dd, J = 6.8, 5.2 Hz, 2H), 3.21–3.09 (m, 2H), 2.94–2.83 (m, 2H), 2.80–2.71 (m, 2H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.46 (dd, J = 12.1, 4.5 Hz, 1H), 2.23–2.15 (m, 1H). Preparation Example z36-1, z36-2 Preparation of compounds z36-1 and z36-2

[0796]

[0797] Step 1: Preparation of intermediate z36b

[0798] Add z36a (3.04 g) and DCM (50 mL) successively into the reaction flask. Cool down the temperature to 0 °C. After adding liquid bromine (2.17 g), react at room temperature for 0.5 h, and the reaction ends. Rotavaporize the solvent. Add ethanol (20 mL) and potassium hydroxide (2.24 g) to the residue, heat up to 70 °C and react for 0.5 h, and the reaction ends. Pour the reaction solution into water, stir vigorously, extract with ethyl acetate, wash with saturated brine and then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate the crude product by column chromatography to obtain intermediate z36b (0.92 g).

[0799] Step 2: Preparation of intermediate z36c

[0800] Add z36b (0.86 g), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.71 g), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.18 g), copper(I) iodide (0.24 g), cesium carbonate (1.95 g) and dioxane (20 ml) into the reaction flask successively, and react at 120 °C. After the reaction ends, concentrate the reaction solution, add water and ethyl acetate, extract and separate the layers. Wash the organic phase with saturated brine and then dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate the crude product by column chromatography to obtain intermediate z36c (0.86 g).

[0801] MS(ESI,[M+H] + ) m / z: 421.11

[0802] Step 3: Preparation of intermediate z36d

[0803] Add z36c (0.86 g) and trifluoromethanesulfonic acid (10 mL) successively into the reaction flask, and react at room temperature for 0.5 h, and the reaction ends. Slowly add the reaction solution into water, adjust the pH to 7 - 8 with sodium bicarbonate, extract with ethyl acetate, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and purify the filtrate through a silica gel column to obtain intermediate z36d (0.48 g).

[0804] MS(ESI,[M+H] + ) m / z: 301.1

[0805] 11H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.69 (s, 1H), 4.68 (t, J = 5.3 Hz, 1H), 3.97 (t, J = 6.7 Hz, 2H), 3.40 (ddd, J = 7.5, 5.3, 2.4 Hz, 2H), 3.08 (ddd, J = 29.2, 16.0, 8.2 Hz, 2H), 2.85 (dd, J = 16.1, 5.5 Hz, 1H), 2.80–2.74 (m, 3H), 2.71–2.63 (m, 1H).

[0806] Step 4: Preparation of Compounds z36-1 and z36-2

[0807] Intermediate 36d was separated by high-pressure preparation (instrument: YMC high-pressure preparation chromatograph; chromatographic column: CHIRALART Cellulose SC, 4.6 x 250 mm, 5 μm; mobile phase: ethanol / n-hexane) to obtain Intermediate z36-1 (260 mg) and z36-2 (255 mg) successively.

[0808] Compound z36-1: MS (ESI, [M+H] + ) m / z: 301.1

[0809] Compound z36-2: MS (ESI, [M+H] + ) m / z: 301.1

[0810] Example 30: Synthesis of Compound 30

[0811]

[0812] Step 1: Preparation of Intermediate 30b

[0813] Under N2 protection, triethyl phosphonoacetate (105 g) and THF (450 mL) were successively added to a reaction flask, cooled to 0 °C, NaH (18.75 g) was added, and after stirring at 0 °C for 1 h, a solution of 30a (50 g) in THF (200 mL) was slowly added dropwise. The mixture was reacted at room temperature for 3.5 h. After the reaction was completed, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain Intermediate 30b (98 g).

[0814] Step 2: Preparation of Intermediate 30c

[0815] Under N₂ protection at 0 °C, a solution of NaH (19.20 g) in THF (300 mL) was slowly added dropwise to a mixture of 30b (68 g) and tosylmethyl isocyanide (49.2 g) in THF (300 mL). After the addition was complete, the mixture was stirred at 0 °C for 2 h. After the reaction was complete, ethyl acetate and water were added to the reaction mixture for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. Filtration gave the intermediate 30c (80 g).

[0816] 1 H NMR (500 MHz, DMSO-d₆) δ 11.18 (s, 1H), 7.31 (dd, J = 3.2, 2.1 Hz, 1H), 6.64–6.59 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.09–3.98 (m, 2H), 3.05 (tt, J = 11.9, 3.3 Hz, 1H), 2.75 (s, 2H), 1.87–1.80 (m, 2H), 1.40 (s, 9H), 1.32 (td, J = 12.5, 4.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).

[0817] MS (ESI, [M+H]⁺) m / z: 323.07

[0818] Step 3: Preparation of intermediate 30d

[0819] To a reaction flask were added successively 30c (40 g), CCl₄ (700 mL), and N-bromosuccinimide (20.98 g). The mixture was reacted at room temperature for 20 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography to give the intermediate 30d (18 g).

[0820] 1 H NMR (500 MHz, DMSO-d₆) δ 7.62 (s, 1H), 4.44 (hept, J = 6.6 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.03 (td, J = 7.1, 3.4 Hz, 2H), 3.18 (tt, J = 12.4, 3.6 Hz, 1H), 2.73 (s, 2H), 2.11 (qd, J = 12.6, 4.3 Hz, 2H), 1.45–1.42 (m, 2H), 1.42 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).

[0821] MS (ESI, [M+H]⁺) m / z: 402.86

[0822] Step 4: Preparation of intermediate 30e

[0823] At 0 °C under N2 protection, 30d (18 g), N,N-dimethylformamide (100 mL), and NaH (2.69 g) were successively added to the reaction flask. After stirring at 0 °C for 1 h, 2-iodopropane (15.25 g) was added, and the mixture was reacted at room temperature for 5 h. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain intermediate 30e (20 g).

[0824] 1 1H NMR (500 MHz, DMSO-d6) δ 7.62 (s, 1H), 4.15 (q, J = 7.0 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.16 (d, J = 12.6 Hz, 1H), 2.71 (s, 2H), 2.11 (qd, J = 12.7, 4.2 Hz, 2H), 1.43 (s, 1H), 1.42 (s, 9H), 1.38 (s, 3H), 1.36 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0825] MS (ESI, [M+H] + ) m / z: 444.96

[0826] Step 5: Preparation of intermediate 30f

[0827] At -78 °C under N2 protection, LDA (2.215 g, 10.15 ml) was slowly added dropwise to a stirred solution of 30e (3 g) in THF (50 mL). After the addition was complete, the reaction was carried out at -78 °C for 1 h, then a solution of p-chlorobenzaldehyde (2.85 g) in THF (2 mL) was added dropwise. After the addition was complete, the mixture was stirred for 30 min and then gradually warmed to -20 °C and reacted for 1 h. After the reaction was completed, the reaction solution was poured into ice water, and ethyl acetate and water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain intermediate 30f (3.89 g).

[0828] 11H NMR (500 MHz, DMSO-d6) δ 7.43–7.40 (m, 2H), 7.30–7.23 (m, 2H), 6.49 (t, J = 3.5 Hz, 2H), 4.72 (hept, J = 7.1 Hz, 1H), 4.25–4.16 (m, 2H), 4.11–4.03 (m, 2H), 3.06 (tt, J = 12.4, 3.7 Hz, 1H), 2.72 (s, 2H), 2.12 (qd, J = 12.6, 4.4 Hz, 1H), 1.94 (td, J = 12.5, 4.4 Hz, 1H), 1.51 (d, J = 13.3 Hz, 1H), 1.45 (d, J = 6.9 Hz, 3H), 1.41 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H).

[0829] MS (ESI, [M+H] + ) m / z: 584.9

[0830] Step 6: Preparation of Intermediate 30g

[0831] Under N2 protection, 30f (10 g), dichloromethane (500 mL), and triethylamine (8.66 g, 11.87 mL) were successively added to the reaction flask. The temperature was lowered to -30 °C, and methanesulfonic anhydride (5.97 g) was added. After stirring for 10 min, 3-amino-5-chloro-1-methyl-2(1H)-pyridone (3.12 g) was added. Under N2 protection, the temperature was raised to -10 °C and the reaction was carried out for 30 min. After the reaction was completed, water was added to dilute the reaction solution, and dichloromethane was added for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain Intermediate 30g (5.41 g).

[0832] 1 1H NMR (500 MHz, DMSO-d6) δ 7.44 (s, 2H), 7.24 (d, J = 2.3 Hz, 1H), 7.16 (s, 2H), 6.42 (s, 1H), 6.28 (s, 1H), 6.06 (s, 1H), 4.63 (s, 1H), 4.03 (d, J = 7.1 Hz, 2H), 3.46 (s, 3H), 3.35 (s, 1H), 2.99 (s, 1H), 2.70 (s, 2H), 1.99 (s, 2H), 1.89 (d, J = 36.1 Hz, 1H), 1.44 (d, J = 7.1 Hz, 6H), 1.40 (s, 9H), 1.22 (d, J = 7.8 Hz, 2H), 1.17 (d, J = 7.1 Hz, 3H).

[0833] MS (ESI, [M+H] +)m / z: 723.1

[0834] Step 7: Preparation of Intermediate 30h

[0835] An aqueous solution of sodium hydroxide (5.30 g) in water (20 mL) was added to a solution of 30 g (4.8 g) of THF / CH3OH = 1:1 (200 mL). The mixture was heated to 80 °C and reacted for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature. After neutralizing the reaction with 10% aqueous citric acid solution, ethyl acetate was added for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain Intermediate 30h (4.2 g).

[0836] 1 H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.48–7.41 (m, 2H), 7.41–7.37 (m, 1H), 7.23 (s, 1H), 7.17–7.12 (m, 1H), 6.30 (s, 1H), 6.17 (s, 1H), 4.58 (s, 1H), 4.04–3.99 (m, 2H), 3.46 (s, 3H), 3.44 (s, 1H), 3.14 (s, 1H), 2.69 (s, 2H), 2.08 (s, 2H), 1.45 (d, J = 6.6 Hz, 6H), 1.42 (s, 2H), 1.40 (s, 9H).

[0837] MS (ESI, [M+H] + )m / z: 697.4

[0838] Step 8: Preparation of Intermediate 30i

[0839] Under N2 protection, Intermediate 30h (4.2 g), N,N-dimethylformamide (100 mL), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 2.90 g), and DIEA (2.338 g, 3.16 mL) were successively added to the reaction flask and heated to 80 °C for reaction for 6 h. After the reaction was completed, the reaction solution was poured into a mixed solution of ethyl acetate and water for extraction. The organic phase was purified by column chromatography to obtain Intermediate 30i (4.05 g).

[0840] 11H NMR (500 MHz, DMSO-d6) δ 7.89 (d, J = 2.8 Hz, 1H), 7.42–7.36 (m, 3H), 7.13 (d, J = 8.1 Hz, 2H), 6.63 (s, 1H), 4.44 (hept, J = 6.8 Hz, 1H), 4.09–4.05 (m, 1H), 3.44 (s, 3H), 2.71 (d, J = 20.9 Hz, 4H), 2.12 (s, 1H), 1.88 (d, J = 25.8 Hz, 1H), 1.67 (d, J = 12.7 Hz, 1H), 1.60–1.53 (m, 1H), 1.42 (s, 9H), 1.30 (d, J = 6.9 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H).

[0841] MS (ESI, [M+H] + ) m / z: 679.4

[0842] Step 9: Preparation of intermediates 30j and 30k

[0843] For preparative resolution: Column: (R,R) Whelk-O1 (30 * 250 mm, 10 um) Mobile phase: B: Ethanol: Dichloromethane (1:1) D: n-Hexane. Flow rate: 1.0 mL / min Column temperature: 25 °C Detection wavelength: 254 nm

[0844] The front peak was prepared to obtain intermediate 30j (2 g).

[0845] MS (ESI, [M+H] + ) m / z: 679.4

[0846] The rear peak was prepared to obtain intermediate 30k (1.75 g).

[0847] MS (ESI, [M+H] + ) m / z: 679.4

[0848] Step 10: Preparation of intermediate 30l

[0849] Under N2 protection, 30k (2 g), N,N-dimethylformamide (50 ml), 2,4-dimethoxypyrimidine-5-boronic acid (1.085 g), potassium phosphate (2.503 g), and bis(triphenylphosphine)palladium(II) dichloride (0.207 g) were successively added to the reaction flask, and the mixture was heated to 100 °C for reaction for 3 h. The reaction solution was cooled to room temperature, and ethyl acetate and water were added to the reaction solution for extraction. The organic phase was purified by column chromatography to obtain intermediate 30l (0.305 g).

[0850] MS (ESI, [M+H] + ) m / z: 737.2

[0851] 1 1H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 9.3 Hz, 1H), 7.88 (dd, J = 5.6, 2.8 Hz, 1H), 7.41 (td, J = 4.8, 2.5 Hz, 3H), 7.24–7.18 (m, 2H), 6.61 (d, J = 15.0 Hz, 1H), 3.97 (d, J = 1.2 Hz, 3H), 3.90 (d, J = 22.0 Hz, 3H), 3.83 (dq, J = 13.7, 6.9 Hz, 1H), 3.44 (d, J = 2.6 Hz, 3H), 3.33 (d, J = 1.8 Hz, 2H), 2.22 (t, J = 12.0 Hz, 1H), 2.05 (s, 2H), 1.71 (d, J = 12.5 Hz, 1H), 1.56 (d, J = 11.9 Hz, 1H), 1.40 (d, J = 1.3 Hz, 9H), 1.28–1.19 (m, 3H), 0.47 (dd, J = 41.8, 6.7 Hz, 3H).

[0852] Step 11: Preparation of Intermediate 30m

[0853] 30l (120 mg), dichloromethane (6 mL) and hydrochloric acid (237 mg, 1.625 mL) were successively added to a reaction flask, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain Intermediate 30m (120 mg).

[0854] MS (ESI, [M+H] + ) m / z: 637.2

[0855] Step 12: Preparation of Intermediate 30n

[0856] Intermediate z8 (5 g), IBX (9.32 g) and DMSO (10 mL) were successively added to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, the extract was concentrated, Intermediate 1h (7.35 g), methanol (100 mL), sodium acetate (5.46 g) and sodium cyanoborohydride (2.62 g) were added, and the reaction was carried out at room temperature. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the extract was concentrated and purified by column chromatography to obtain Intermediate 30n (4.98 g).

[0857] MS (ESI, [M+H] + ) m / z: 467.17

[0858] 11H NMR (500 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 4.55 (dd, J = 11.8, 5.0 Hz, 1H), 3.42 (t, J = 5.7 Hz, 2H), 3.14 (ddd, J = 35.8, 16.3, 8.0 Hz, 3H), 2.86–2.71 (m, 6H), 2.61 (d, J = 4.7 Hz, 4H), 2.50–2.41 (m, 3H), 2.16 (ttd, J = 13.3, 9.8, 7.3 Hz, 2H), 1.77 (d, J = 12.1 Hz, 4H), 1.55–1.44 (m, 2H).

[0859] Step 13: Preparation of Compound 30

[0860] 30m (0.1 g), N,N-dimethylformamide (6 mL), DIPEA (126 mg, 0.170 mL), 30n (93 mg), and HATU (96 mg) were successively added to a reaction flask and reacted at room temperature for 2 h. After the reaction was completed, water was added to the reaction solution to precipitate a solid, which was filtered by suction. The filter cake was purified by column chromatography to obtain Compound 30 (93 mg).

[0861] 1 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.29 (d, J = 10.0 Hz, 1H), 7.89 (dd, J = 5.9, 2.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.6, 3.8 Hz, 3H), 7.26–7.16 (m, 3H), 6.58 (dd, J = 16.3, 11.2 Hz, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 4.51–4.36 (m, 1H), 3.97 (d, J = 1.3 Hz, 3H), 3.90 (d, J = 22.1 Hz, 3H), 3.83 (dq, J = 13.7, 6.9 Hz, 1H), 3.44 (d, J = 2.8 Hz, 3H), 3.15 (ddd, J = 37.3, 17.4, 7.7 Hz, 2H), 2.98–2.90 (m, 1H), 2.90–2.65 (m, 8H), 2.60 (dt, J = 17.2, 4.2 Hz, 4H), 2.48–2.26 (m, 4H), 2.21–2.04 (m, 2H), 1.98 (t, J = 14.7 Hz, 1H), 1.80 (s, 3H), 1.57 (s, 6H), 1.26 (dd, J = 13.8, 7.0 Hz, 3H), 1.21 (d, J = 6.8 Hz, 1H), 0.47 (dd, J = 42.7, 6.8 Hz, 3H).

[0862] MS(ESI,[M+H] + ) m / z: 1085.4178

[0863] Example 31: Preparation of Compound 31

[0864]

[0865] Step 1: Preparation of Intermediate 31a

[0866] Under an ice bath, intermediate 1f (1.2 g), tetrahydrofuran (20 mL) and lithium aluminum hydride (0.22 g) were successively added to a reaction flask, and the reaction was carried out at 10 °C. After the reaction was completed, the reaction was quenched with water, concentrated, and the residue was purified by column chromatography to obtain intermediate 31a (0.8 g).

[0867] Step 2: Preparation of Intermediate 31b

[0868] Intermediate 31a (0.61 g), IBX (1.9 g) and DMSO (10 mL) were successively added to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was concentrated, and intermediate 30m (0.36 g), dichloroethane (20 mL) and sodium triacetoxyborohydride (0.30 g) were added, and the reaction was carried out at room temperature. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted with dichloromethane. The extract was concentrated and then purified by column chromatography to obtain intermediate 31b (0.19 g).

[0869] MS(ESI,[M+H] + ) m / z: 889.39

[0870] Step 3: Preparation of Intermediate 31c

[0871] Intermediate 31b (180 mg), trifluoroacetic acid (1 mL) and DCM (10 mL) were successively added to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was directly concentrated to obtain intermediate 31c (300 mg).

[0872] Step 4: Preparation of Compound 31

[0873] Intermediate z8 (82 mg), IBX (153 mg) and DMSO (1 mL) were successively added to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was concentrated, and intermediate 31c (0.3 g), methanol (60 mL), sodium acetate (41 mg) and sodium cyanoborohydride (35 mg) were added, and the reaction was carried out at room temperature. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted with dichloromethane. The extract was concentrated and then purified by column chromatography to obtain compound 31 (108 mg).

[0874] MS (ESI, [M+H] + ) m / z:: 1071.43

[0875] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.27 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45–7.39 (m, 3H), 7.26–7.19 (m, 3H), 6.62 (s, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 3.97 (s, 3H), 3.89 (d, J = 22.7 Hz, 4H), 3.44 (d, J = 2.7 Hz, 4H), 3.15 (ddd, J = 36.5, 16.3, 7.7 Hz, 3H), 2.93–2.53 (m, 14H), 2.22–1.98 (m, 6H), 1.66 (s, 6H), 1.57–1.33 (m, 3H), 1.28–1.20 (m, 4H), 1.07 (t, J = 12.0 Hz, 2H), 0.47 (dd, J = 45.1, 6.7 Hz, 3H).

[0876] Example 32: Preparation of Compound 32

[0877]

[0878] Step 1: Preparation of Intermediate 32a

[0879] To a reaction flask were successively added tert-butyl 4-oxocyclohexanecarboxylate (5.00 g), 3-(methylhydroxy)azetidine hydrochloride (3.12 g), sodium acetate (2.07 g), sodium triacetoxyborohydride (10.69 g), and dichloroethane (150 mL), and the reaction was carried out at room temperature. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by column chromatography to obtain Intermediate 32a (6.36 g).

[0880] 1 H NMR (500 MHz, DMSO-d6) δ 3.46 (dd, J = 6.5, 2.2 Hz, 2H), 3.27–3.17 (m, 2H), 2.97–2.73 (m, 2H), 2.46–2.36 (m, J = 6.6, 6.2 Hz, 1H), 2.32–1.94 (m, 2H), 1.87–1.64 (m, 3H), 1.38 (d, J = 4.0 Hz, 14H), 1.03–0.81 (m, 1H).

[0881] Step 2: Preparation of Intermediate 32b and Intermediate 32c

[0882] To the reaction flask, add intermediate 32a (1.75 g), IBX (4.5 g) and DMSO (5 mL) in sequence, and react at room temperature. After the reaction is completed, quench with saturated sodium bicarbonate solution, extract with ethyl acetate, concentrate the extract, add intermediate z1 (1 g), dichloroethane (120 mL), isopropanol (40 mL), sodium acetate (0.26 g) and sodium cyanoborohydride (0.51 g), and react at room temperature. After the reaction is completed, quench with water, extract with dichloromethane, concentrate the extract and purify by column chromatography, and perform HPLC chiral resolution (instrument: YMC high-pressure preparative chromatograph; chromatographic column: Xtimate C18, 21x250 mm, 5 μm; mobile phase: water / acetonitrile) to obtain intermediate 32b (327 mg) and intermediate 32c (645 mg) successively. Intermediate 32b:

[0883] MS(ESI,[M+H] + )m / z: 523.28

[0884] 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.71(d,J = 8.1Hz,1H),7.29(d,J = 8.1Hz,1H),4.59(dd,J = 11.9,5.0Hz,1H),4.11(d,J = 2.4Hz,2H),4.01(d,J = 2.4Hz,2H),3.49(s,2H),2.92(d,J = 7.3Hz,3H),2.82–2.53(m,4H),2.23–2.17(m,1H),2.08(ddt,J = 11.9,8.4,3.5Hz,1H),1.85(d,J = 13.0Hz,2H),1.82–1.73(m,2H),1.38(s,10H),1.35–1.20(m,3H),0.97(s,2H). Intermediate 32c:

[0885] MS(ESI,[M+H] + )m / z: 523.28

[0886] 11H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 4.59 (dd, J = 11.9, 5.0 Hz, 1H), 4.11 (s, 2H), 4.01 (s, 2H), 2.94–2.86 (m, 2H), 2.77 (ddd, J = 17.2, 12.0, 5.4 Hz, 2H), 2.51 (s, 4H), 2.49 (s, 1H), 2.41–2.09 (m, 3H), 1.77 (s, 2H), 1.40 (s, 16H).

[0887] Step 3: Preparation of Compound 32

[0888] To the reaction flask were successively added intermediate 32b (184 mg), trifluoroacetic acid (1 mL) and DCM (10 mL), and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was directly concentrated, and the residue was added with intermediate 30m (150 mg), HATU (134 mg), N,N-diisopropylethylamine (547 mg) and DMF (5 mL), and the reaction was carried out at 25 °C. After the reaction was completed, water and EA were added to the reaction solution for dilution. The organic phase was concentrated and purified by column chromatography. Maleic acid (6.3 mg) and methanol (5 mL) were added to the obtained concentrate. After dissolution and clarification, the solution was concentrated to obtain Compound 32 (68 mg).

[0889] MS (ESI, [M+H] + ) m / z: 1085.41

[0890] 11H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.12 (s, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.49–7.33 (m, 4H), 7.24–7.17 (m, 2H), 6.64–6.56 (m, 1H), 6.06 (s, 2H), 4.63 (dd, J = 12.0, 5.0 Hz, 1H), 4.46 (dd, J = 33.2, 12.9 Hz, 2H), 4.20 (s, 2H), 3.95 (d, J = 22.2 Hz, 7H), 3.88 (s, 3H), 3.44 (d, J = 2.7 Hz, 2H), 3.05–2.83 (m, 2H), 2.78 (ddd, J = 17.2, 12.0, 5.4 Hz, 2H), 2.65–2.52 (m, 2H), 2.41–2.28 (m, 2H), 2.27–2.07 (m, 2H), 2.07–1.88 (m, 2H), 1.72 (s, 8H), 1.48 (s, 3H), 1.24 (s, 7H), 0.48 (dd, J = 43.7, 6.8 Hz, 3H).

[0891] Example 33: Preparation of Compound 33

[0892]

[0893] Step 1: Preparation of Compound 33

[0894] Referring to the preparation of Compound 32 in Example 32, Intermediate 32c was replaced with 32b to obtain Compound 33 (33 mg).

[0895] MS (ESI, [M+H] + ) m / z: 1085.41

[0896] 11H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.70 (s, 1H), 8.33–8.27 (m, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.45–7.32 (m, 4H), 7.21 (d, J = 7.8 Hz, 2H), 6.66–6.53 (m, 1H), 6.10 (s, 2H), 4.62 (dd, J = 11.9, 5.0 Hz, 1H), 4.35 (dd, J = 105.5, 48.4 Hz, 7H), 3.97 (s, 10H), 3.44 (s, 2H), 3.17 (s, 4H), 2.96 (d, J = 12.2 Hz, 1H), 2.81–2.73 (m, 1H), 2.64–2.54 (m, 2H), 2.44–2.31 (m, 2H), 2.20 (d, J = 12.7 Hz, 1H), 1.94 (d, J = 26.3 Hz, 3H), 1.78 (d, J = 33.3 Hz, 3H), 1.52–1.12 (m, 10H), 0.48 (dd, J = 42.1, 6.8 Hz, 3H).

[0897] Example 34: Synthesis of Compound 34

[0898]

[0899] Step 1: Preparation of Intermediate 34a

[0900] Referring to the method described in Step 12 of Example 30, using tert-butyl 4-piperidinecarboxylate as the intermediate instead of Intermediate 1h, Intermediate 34a (122 mg) was synthesized.

[0901] MS (ESI, [M+H] + ) m / z: 468.0

[0902] Step 2: Preparation of Intermediate 34b

[0903] In a reaction flask, 34a (50 mg), dichloromethane (2 mL), and trifluoroacetic acid (2 mL) were added successively. Under N2 protection, the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent to obtain Intermediate 34b (0.038 g).

[0904] MS (ESI, [M+H] + ) m / z: 412.1

[0905] Step 3: Preparation of Compound 34

[0906] In a reaction flask, 30 m (45 mg), N,N-dimethylformamide (6 mL), DIPEA (52.6 mg) and 34b (38.7 mg) were added successively, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, water was added to the reaction solution to precipitate a solid, which was filtered by suction. The filter cake was purified by column chromatography to obtain compound 34 (37 mg).

[0907] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.29 (d, J = 9.9 Hz, 1H), 7.88 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.46–7.35 (m, 3H), 7.26 (d, J = 8.1 Hz, 1H), 7.24–7.16 (m, 2H), 6.59 (dd, J = 16.1, 11.6 Hz, 1H), 4.56 (dd, J = 11.7, 5.0 Hz, 1H), 3.97 (s, 3H), 3.91 (d, J = 22.2 Hz, 3H), 3.84 (dd, J = 14.1, 6.9 Hz, 1H), 3.43 (d, J = 2.8 Hz, 3H), 3.18 (s, 2H), 2.87 (d, J = 23.6 Hz, 5H), 2.77 (ddd, J = 22.6, 11.0, 5.0 Hz, 2H), 2.60 (d, J = 17.8 Hz, 2H), 2.32 (s, 3H), 2.19 (d, J = 10.2 Hz, 2H), 2.05–1.91 (m, 3H), 1.61 (s, 4H), 1.24 (td, J = 14.2, 6.9 Hz, 5H), 0.48 (dd, J = 42.7, 6.8 Hz, 3H).

[0908] MS (ESI, [M+H] + ) m / z: 1030.3

[0909] Example 35, 36: Synthesis of Compounds 35, 36

[0910]

[0911] Step 1: Preparation of Intermediate 35a

[0912] Referring to the method described in Step 3 of Example 37, using intermediate z1 instead of intermediate z5, intermediate 35a (700 mg) was synthesized. MS (ESI, [M+H] + ) m / z: 468.2

[0913] Step 2: Preparation of Intermediate 35b, Intermediate 36a

[0914] Intermediate 35a was prepared and separated by high pressure (instrument: YMC high pressure preparative chromatograph; chromatographic column: COSMOSIL Cholester, 20 * 250 mm, 5 μm; mobile phase: water (10 mmol ammonium acetate + 0.1% ammonia water) / acetonitrile, successively obtaining intermediate 35b (260 mg) and 36a (255 mg)

[0915] Intermediate 35b: MS(ESI, [M+H] + ) m / z: 468.2

[0916] Intermediate 36a: MS(ESI, [M+H] + ) m / z: 468.2

[0917] Step 3: Preparation of Compound 35 and Compound 36

[0918] Referring to the method described in Step 3 of Example 32, using intermediate 35b instead of intermediate 32b, Compound 35 (200 mg) was synthesized.

[0919] MS(ESI, [M+H] + ) m / z: 1030.3

[0920] 1 1H NMR(500 MHz, DMSO) δ 11.12(s, 1H), 10.48(s, 1H), 8.30(d, J = 8.5 Hz, 1H), 7.89(dd, J = 14.9, 7.2 Hz, 2H), 7.53–7.35(m, 4H), 7.24–7.13(m, 2H), 6.57(dd, J = 16.2, 11.9 Hz, 1H), 6.14(s, 3H), 4.85(s, 4H), 4.66(dd, J = 12.2, 5.0 Hz, 1H), 4.57–4.41(m, 1H), 3.97(s, 3H), 3.91(d, J = 22.2 Hz, 4H), 3.83(dt, J = 13.8, 7.1 Hz, 1H), 3.43(d, J = 2.7 Hz, 8H), 3.02–2.68(m, 4H), 2.67–2.52(m, 2H), 2.44–2.28(m, 2H), 2.26–2.05(m, 3H), 1.66(s, 6H), 1.50(s, 3H), 1.35–1.16(m, 5H), 0.48(dd, J = 43.0, 6.8 Hz, 3H).

[0921] Referring to the method described in Step 5 of Example 37, using intermediate 36a instead of intermediate 37e, Compound 36 (200 mg) was synthesized.

[0922] MS(ESI, [M+H]+ )m / z: 1030.3

[0923] 1 H NMR (500 MHz, DMSO) δ 11.12 (s, 1H), 8.30 (d, J = 9.2 Hz, 1H), 7.90 (dd, J = 9.3, 6.0 Hz, 2H), 7.50–7.28 (m, 4H), 7.26–7.14 (m, 2H), 6.58 (t, J = 15.0 Hz, 1H), 6.17 (s, 4H), 4.84 (s, 3H), 4.66 (dd, J = 12.2, 5.0 Hz, 1H), 4.55–4.42 (m, 1H), 3.97 (s, 3H), 3.91 (d, J = 22.0 Hz, 3H), 3.84 (dd, J = 13.9, 6.9 Hz, 1H), 3.44 (d, J = 2.7 Hz, 4H), 3.02–2.89 (m, 2H), 2.79 (ddd, J = 17.4, 12.2, 5.4 Hz, 1H), 2.67–2.53 (m, 3H), 2.33 (s, 2H), 2.20 (td, J = 14.4, 6.1 Hz, 2H), 1.88 (t, J = 18.4 Hz, 5H), 1.77–1.58 (m, 3H), 1.52–1.42 (m, 2H), 1.28–1.21 (m, 5H), 1.12 (s, 2H), 0.48 (dd, J = 43.2, 6.7 Hz, 3H).

[0924] Examples 37, 38: Synthesis of Compounds 37, 38

[0925]

[0926] Step 1: Preparation of Intermediate 37b

[0927] Under nitrogen protection at 0 °C, a THF solution of potassium tert-butoxide (1 M, 70.9 mL) was slowly added dropwise to a THF (200 ml) solution of (methoxymethyl)triphenylphosphonium chloride (20.75 g). After the addition was complete, the mixture was stirred at room temperature for 1 h, and Intermediate 37a (10 g) was added, followed by reaction at room temperature. After the reaction was complete, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain Intermediate 37b (11.58 g).

[0928] 11H NMR (500 MHz, DMSO-d6) δ 5.87–5.82 (m, 1H), 3.46 (s, 3H), 2.58–2.52 (m, 1H), 2.33–2.25 (m, 1H), 2.08–1.98 (m, 1H), 1.90–1.75 (m, 3H), 1.73–1.65 (m, 1H), 1.38 (s, 9H), 1.33–1.23 (m, 2H).

[0929] Step 2: Preparation of Intermediate 37c

[0930] To the reaction flask, add Intermediate 37b (3 g), water (30 ml) and acetic acid (30 ml) in sequence, and react at 70 °C. After the reaction is completed, add water, extract with petroleum ether, wash successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate, and obtain Intermediate 37c (2.65 g).

[0931] 1 1H NMR (500 MHz, DMSO-d6) δ 12.11–9.50 (m, 1H), 2.41–2.28 (m, 1H), 2.18–2.08 (m, 1H), 1.93–1.77 (m, 2H), 1.76–1.63 (m, 2H), 1.63–1.52 (m, 2H), 1.42–1.36 (m, 9H), 1.36–1.22 (m, 2H).

[0932] Step 3: Preparation of Intermediate 37d

[0933] To the reaction flask, add Intermediate 37c (379 mg), Intermediate z5 (500 mg), sodium acetate (122 mg), 1,2-dichloroethane (20 ml), isopropanol (5 ml) and sodium triacetoxyborohydride (631 mg) in sequence, and react at room temperature. After the reaction is completed, add saturated sodium bicarbonate solution, extract with dichloromethane, concentrate the extract and purify by silica gel column chromatography to obtain Intermediate 37d (750 mg).

[0934] MS (ESI, [M+H] + ) m / z: 496.2

[0935] Step 4: Preparation of Intermediate 37e and 38a

[0936] Intermediate 37d was separated by high-pressure preparation (instrument: YMC high-pressure preparation chromatograph; chromatographic column: COSMOSIL Cholester, 20 * 250 mm, 5 μm; mobile phase: water (10 mmol ammonium acetate + 0.1% ammonia) / acetonitrile), and Intermediate 37e (260 mg) and 38a (255 mg) were obtained successively

[0937] Intermediate 37e: MS(ESI, [M+H] + ) m / z: 496.2

[0938] Intermediate 38a: MS(ESI, [M+H] + ) m / z: 496.2

[0939] Step 5: Preparation of Compound 37

[0940] Add Intermediate 37e (110 mg), dichloromethane (6 ml) and trifluoroacetic acid (3 ml) to the reaction flask in sequence, and react at room temperature. After the reaction is completed, concentrate under reduced pressure to dryness. Add DMF (6 ml), DIPEA (0.236 ml), and HATU (0.169 g) to the above concentrate, stir for 2 minutes, then add Intermediate 30m (0.15 g), and react at room temperature. After the reaction is completed, add water, extract with ethyl acetate, concentrate the extract, and purify by column chromatography to obtain Compound 37 (45 mg).

[0941] MS(ESI, [M+H] + ) m / z: 1058.3

[0942] 1 1H NMR(500 MHz, DMSO) δ 11.07 (s, 1H), 8.29 (d, J = 10.0 Hz, 1H), 7.92–7.85 (m, 1H), 7.59–7.50 (m, 1H), 7.44–7.36 (m, 3H), 7.24–7.19 (m, 2H), 6.67–6.54 (m, 1H), 4.58–4.40 (m, 2H), 3.97 (s, 3H), 3.94–3.88 (m, 3H), 3.87–3.79 (m, 1H), 3.43 (s, 3H), 3.18–3.11 (m, 2H), 3.08–3.00 (m, 2H), 2.99–2.87 (m, 1H), 2.80–2.72 (m, 1H), 2.71–2.57 (m, 6H), 2.44–2.28 (m, 4H), 2.21–2.14 (m, 1H), 2.05–1.91 (m, 1H), 1.88–1.72 (m, 2H), 1.71–1.36 (m, 11H), 1.32–1.18 (m, 5H), 0.54–0.42 (m, 3H)

[0943] Step 6: Preparation of Compound 38

[0944] Refer to the method described in Step 5 of Example 37, use Intermediate 38a instead of Intermediate 37e, and synthesize to obtain Compound 38 (45 mg).

[0945] MS(ESI,[M+H] + ) m / z: 1058.3

[0946] 1 H NMR(500 MHz, DMSO) δ 11.07 (s, 1H), 8.29 (d, J = 9.8 Hz, 1H), 7.92–7.86 (m, 1H), 7.55–7.50 (m, 1H), 7.45–7.37 (m, 3H), 7.24–7.14 (m, 3H), 6.63–6.54 (m, 1H), 4.59–4.39 (m, 2H), 3.97 (s, 3H), 3.94–3.88 (m, 3H), 3.87–3.79 (m, 1H), 3.48–3.40 (m, 3H), 3.18–3.09 (m, 2H), 3.08–2.99 (m, 2H), 2.98–2.87 (m, 1H), 2.82–2.71 (m, 1H), 2.67–2.55 (m, 5H), 2.42–2.29 (m, 2H), 2.28–2.12 (m, 3H), 2.04–1.93 (m, 1H), 1.89–1.79 (m, 2H), 1.76–1.61 (m, 3H), 1.56–1.47 (m, 1H), 1.46–1.35 (m, 2H), 1.29–1.20 (m, 5H), 1.06–0.88 (m, 2H), 0.56–0.41 (m, 3H).

[0947] Example 39, 40: Synthesis of Compounds 39, 40

[0948]

[0949] Step 1: Preparation of Intermediate 39a

[0950] To the reaction flask were successively added Intermediate 37c (1 g), DMF (20 ml) and potassium peroxymonosulfate (2.90 g), and the reaction was carried out at room temperature. After the reaction was completed, water was added, and the pH was adjusted to ~2 with dilute hydrochloric acid. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a DMF solution containing Intermediate 39a. It was directly used for the next step.

[0951] Step 2: Preparation of Intermediate 39b

[0952] To the reaction flask were successively added the DMF solution of Intermediate 39a, HATU (1112 mg), DIPEA (1.703 ml), DMF (20 ml) and Intermediate z1 (500 mg), and the reaction was carried out at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The extract was purified by column chromatography to obtain Intermediate 39b (850 mg).

[0953] MS(ESI, [M+H] + ) m / z: 482.2

[0954] Step 3: Preparation of intermediates 39c and 40a

[0955] Intermediate 39b was separated by high-pressure preparation (instrument: YMC high-pressure preparative chromatograph; chromatographic column: Ultimate XB-C18, 30*250 mm, 5 μm; mobile phase: water / acetonitrile), and intermediates 39c (300 mg) and 40a (290 mg) were obtained successively

[0956] Intermediate 39c: MS(ESI, [M+H] + ) m / z: 482.2

[0957] Intermediate 40a: MS(ESI, [M+H] + ) m / z: 482.2

[0958] Step 3: Preparation of compound 39

[0959] Referring to the preparation of compound 32 in Reference Example 32, intermediate 39c was used to replace 32b. After the reaction was completed, it was purified by column chromatography to obtain intermediate 39 (55 mg, not salted with maleic acid).

[0960] MS(ESI, [M+H] + ) m / z: 1044.3

[0961] 1 H NMR(500 MHz, DMSO) δ 11.10 (s, 1H), 8.33–8.27 (m, 1H), 7.91–7.86 (m, 1H), 7.84–7.79 (m, 1H), 7.45–7.35 (m, 4H), 7.26–7.18 (m, 2H), 6.63–6.53 (m, 1H), 5.22 (s, 1H), 5.09 (s, 1H), 4.88 (s, 1H), 4.78 (s, 1H), 4.63 (dd, J = 12.0, 4.9 Hz, 1H), 4.57–4.40 (m, 1H), 4.11–4.00 (m, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.87–3.78 (m, 1H), 3.44 (s, 3H), 3.01–2.87 (m, 1H), 2.83–2.74 (m, 1H), 2.69–2.53 (m, 4H), 2.45–2.28 (m, 2H), 2.25–2.18 (m, 1H), 2.06–1.93 (m, 1H), 1.91–1.63 (m, 6H), 1.52 (s, 5H), 1.32–1.18 (m, 3H), 0.55–0.41 (m, 3H).

[0962] Step 4: Preparation of Compound 40

[0963] Referring to the preparation of Compound 39, Intermediate 40a was replaced with 39c to obtain Intermediate 40 (65 mg).

[0964] MS (ESI, [M+H] + ) m / z: 1044.3

[0965] 1 H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 8.34–8.26 (m, 1H), 7.88–7.84 (m, 1H), 7.83–7.79 (m, 1H), 7.44–7.33 (m, 4H), 7.24–7.18 (m, 2H), 6.62–6.56 (m, 1H), 5.17 (s, 1H), 5.05 (s, 1H), 4.89 (s, 1H), 4.79 (s, 1H), 4.67–4.60 (m, 1H), 4.58–4.40 (m, 1H), 3.97 (s, 3H), 3.94–3.88 (m, 3H), 3.88–3.78 (m, 1H), 3.45–3.40 (m, 3H), 3.02–2.88 (m, 1H), 2.83–2.68 (m, 3H), 2.66–2.58 (m, 1H), 2.25–2.18 (m, 1H), 2.03–1.84 (m, 5H), 1.82–1.71 (m, 1H), 1.69–1.39 (m, 6H), 1.30–1.19 (m, 4H), 0.54–0.41 (m, 3H).

[0966] Example 41: Preparation of Compound 41

[0967]

[0968] Step 1: Preparation of Intermediate 41a

[0969] To the reaction flask were successively added Intermediate z6 (280 mg), tert-butyl bromoacetate (257 mg), potassium carbonate (364 mg) and acetonitrile (20 mL), and the reaction was carried out at room temperature. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by column chromatography to obtain Intermediate 41a (146 mg). MS (ESI, [M+H] + ) m / z: 426.20

[0970] Step 2: Preparation of Compound 41

[0971] Referring to the preparation steps of Compound 32 in Reference Example 32, Intermediate 41a was used to replace 32b. After the reaction was completed, it was purified by column chromatography to obtain Compound 41 (26 mg, without salt formation with maleic acid).

[0972] MS(ESI,[M+H] + )m / z: 988.32

[0973] 1 H NMR(500MHz,DMSO-d6)δ11.17–11.01(m,1H),8.30(dd,J=11.3,6.3Hz,1H),7.82(q,J=4.1Hz,1H),7.66–7.52(m,1H),7.21(s,6H),6.64(dd,J=13.6,2.6Hz,1H),4.55(dd,J=11.8,4.9Hz,1H),4.39(dt,J=

[0974] 32.0,14.1Hz,1H),4.02–3.78(m,8H),3.42(d,J=3.9Hz,6H),3.25(s,2H),2.97–2.86(m,1H),2.76(td,J=12.1,5.8Hz,1H),2.66–2.52(m,2H),2.48–2.28(m,3H),2.09(dt,J=85.7,7.8Hz,3H),1.88–1.55(m,2H),

[0975] 1.45(dd,J=27.6,13.0Hz,1H),1.32–1.18(m,6H),0.44(s,3H).

[0976] Example 42: Synthesis of Compound 42

[0977]

[0978] Step 1: Preparation of Intermediate 42a

[0979] Z1 (200 mg), potassium carbonate (359 mg), acetonitrile (10 mL) and tert-butyl bromoacetate (254 mg) were successively added to a reaction flask and reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain Intermediate 42a (0.220 g).

[0980] 11H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.60 (dt, J = 12.0, 6.1 Hz, 1H), 4.34 (t, J = 2.6 Hz, 2H), 4.23 (t, J = 2.7 Hz, 2H), 3.60 (s, 2H), 2.77 (td, J = 12.0, 5.9 Hz, 1H), 2.61 (dt, J = 17.2, 4.2 Hz, 1H), 2.53 (d, J = 1.4 Hz, 1H), 2.23–2.17 (m, 1H), 1.43 (s, 9H).

[0981] MS (ESI, [M+H] + ) m / z: 386.1

[0982] Step 2: Preparation of Intermediate 42b

[0983] Referring to the method described in Step 2 of Example 34, using Intermediate 42a instead of Intermediate 34a, Intermediate 42b (200 mg) was synthesized.

[0984] Step 3: Preparation of Compound 42

[0985] Referring to the method described in Step 3 of Example 34, using Intermediate 42b instead of Intermediate 34b, Compound 42 (87 mg) was synthesized.

[0986] 11H NMR (500 MHz, DMSO) δ 11.09 (d, J = 3.2 Hz, 1H), 8.32–8.24 (m, 1H), 7.91 (dq, J = 5.3, 2.8 Hz, 1H), 7.73–7.57 (m, 1H), 7.47–7.28 (m, 3H), 7.23–7.15 (m, 2H), 6.67–6.59 (m, 1H), 4.59 (ddd, J = 18.4, 11.8, 5.2 Hz, 1H), 4.46 (dt, J = 31.2, 13.4 Hz, 1H), 4.38–4.22 (m, 3H), 4.11 (t, J = 16.1 Hz, 1H), 3.97 (d, J = 1.6 Hz, 3H), 3.94–3.86 (m, 3H), 3.86–3.68 (m, 2H), 3.57 (q, J = 14.7 Hz, 1H), 3.45 (t, J = 2.7 Hz, 3H), 3.03–2.87 (m, 1H), 2.82–2.72 (m, 1H), 2.61 (d, J = 17.7 Hz, 1H), 2.31 (d, J = 12.5 Hz, 2H), 2.03–1.88 (m, 1H), 1.78 (s, 1H), 1.62 (d, J = 13.3 Hz, 1H), 1.43 (t, J = 11.5 Hz, 1H), 1.32–1.17 (m, 5H), 0.47 (dd, J = 43.0, 6.6 Hz, 3H).

[0987] MS (ESI, [M+H] + ) m / z: 948.3

[0988] Example 43: Synthesis of Compound 43

[0989]

[0990] Referring to the methods described in Steps 10-11 and 13 of Example 30, Compound 43 (5.5 g) was synthesized by using Intermediate 48d to replace Intermediate 30k, 43a to replace 30l, Intermediate 44e to replace Intermediate 30n, and 43b to replace 30m, respectively.

[0991] MS (ESI, [M+H] + ) m / z: 1068.3

[0992] 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.30 (d, J = 11.0 Hz, 1H), 7.76 (d, J = 19.1 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.46–7.35 (m, 2H), 7.26–7.07 (m, 5H), 6.43 (s, 1H), 4.57 (dd, J = 11.8, 5.0 Hz, 1H), 4.53–4.38 (m, 1H), 3.98 (s, 3H), 3.92 (d, J = 18.5 Hz, 3H), 3.88–3.79 (m, 1H), 3.24–3.09 (m, 3H), 3.01–2.67 (m, 9H), 2.64–2.54 (m, 3H), 2.47–2.29 (m, 3H), 2.22–2.09 (m, 2H), 2.05–1.96 (m, 1H), 1.95–1.88 (m, 2H), 1.86–

[0993] 1.72 (m, 3H), 1.69–1.42 (m, 6H), 1.30–1.19 (m, 5H), 0.57–0.44 (m, 3H).

[0994] Example 44: Preparation of Compound 44

[0995]

[0996] Step 1: Preparation of Intermediate 44a

[0997] 3-Bromo-4-methoxyphenylacetic acid (8 g), methylamine hydrochloride (2.64 g), HATU (18.62 g), N,N-diisopropylethylamine (25.30 g) and DMF (100 mL) were successively added to a reaction flask. The reaction was carried out at 25 °C. After monitoring the completion of the reaction, water and EA were added to dilute the reaction solution, and the layers were separated. The organic phase was concentrated and purified by column chromatography to obtain Intermediate 44a (4.69 g).

[0998] MS (ESI, [M+H] + ) m / z: 258.01

[0999] 1 1H NMR (500 MHz, DMSO-d6) δ 7.89 (d, J = 6.1 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 8.5, 2.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.32 (s, 2H), 2.56 (d, J = 4.6 Hz, 3H).

[1000] Step 2: Preparation of Intermediate 44b

[1001] To the reaction flask were successively added intermediate 44a (4.1 g), neopentyl glycol diborate (10.76 g), bis(triphenylphosphine)palladium(II) dichloride (2.23 g), potassium acetate (4.68 g) and 1,4-dioxane (150 mL), and the reaction was carried out at 100 °C. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain intermediate 44b (2.06 g).

[1002] MS(ESI,[M+H] + ) m / z: 224.10

[1003] Step 3: Preparation of intermediates 44c and 44d

[1004] To the reaction flask were successively added intermediate 44b (202 mg), intermediate 30k (300 mg), bis(triphenylphosphine)palladium(II) dichloride (63 mg), potassium phosphate (578 mg) and DMF (50 mL), and the reaction was carried out at 100 °C. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography (instrument: YMC high-pressure preparative chromatograph; chromatographic column: XB-C18, 30x250 mm, 5 μm; mobile phase: water / acetonitrile) to obtain intermediate 44c (65 mg) and intermediate 44d (63 mg) successively.

[1005] Intermediate 44c: MS(ESI,[M+H] + ) m / z: 759.30

[1006] Intermediate 44d: MS(ESI,[M+H] + ) m / z: 759.30

[1007] Step 4: Preparation of intermediate 44e

[1008] Referring to the preparation of intermediate 30n in Step 12 of Example 30, using intermediate z9 to replace z8, intermediate 44e (4.98 g) was obtained.

[1009] MS(ESI,[M+H] - ) m / z: 467.17

[1010] 11H NMR (500 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 4.55 (dd, J = 11.8, 5.0 Hz, 1H), 3.42 (t, J = 5.7 Hz, 2H), 3.14 (ddd, J = 35.8, 16.3, 8.0 Hz, 3H), 2.86–2.71 (m, 6H), 2.61 (d, J = 4.7 Hz, 4H), 2.50–2.41 (m, 3H), 2.16 (ttd, J = 13.3, 9.8, 7.3 Hz, 2H), 1.77 (d, J = 12.1 Hz, 4H), 1.55–1.44 (m, 2H).

[1011] Step 5: Preparation of Compound 44

[1012] Referring to the preparation steps of Compound 32 in Reference Example 32, Intermediate 44c was replaced with 32b, Intermediate 44e was replaced with 30m. After the reaction was completed, it was purified by column chromatography to obtain Compound 44 (44 mg, without salt formation with maleic acid).

[1013] MS (ESI, [M+H] + ) m / z: 1107.46

[1014] 1 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.89 (d, J = 5.1 Hz, 1H), 7.78 (s, 1H), 7.60 (d, J = 8.0 Hz,

[1015] 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.5, 2.3 Hz, 1H), 7.22 (dd, J = 17.3, 8.0 Hz, 3H), 7.14 (s, 2H), 7.09 (t, J = 9.5 Hz, 2H), 6.40 (s, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 4.46 (dd, J = 45.9, 13.1 Hz, 1H), 3.94 (dd, J = 50.5,

[1016] (10.8 Hz, 1H), 3.82 (q, J = 6.9 Hz, 1H), 3.76 (s, 3H), 3.54–3.45 (m, 1H), 3.36 (s, 2H), 3.15 (dd, J = 37.1, 15.2 Hz, 3H), 2.88–2.65 (m, 8H), 2.55 (d, J = 4.6 Hz, 7H), 2.48–2.42 (m, 1H), 2.32 (dq, J = 26.5, 13.7, 12.9 Hz, 3H), 2.17 (td, J = 9.6, 8.7, 4.7 Hz, 2H), 1.91 (s, 2H), 1.78 (s, 4H), 1.54 (s, 6H), 1.27 (d, J = 7.1 Hz, 3H), 1.24 (s, 1H), 0.41 (s, 3H).

[1017] Example 45: Preparation of Compound 45

[1018]

[1019] Step 1: Preparation of Compound 45

[1020] Referring to Step 5 of Example 44 for the preparation of Compound 44, replace 44c with Intermediate 44d to obtain Compound 45 (44 mg).

[1021] MS (ESI, [M+H] + ) m / z: 1107.46

[1022] 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 7.7 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 15.3, 8.1 Hz, 3H), 7.17–7.04 (m, 4H), 6.41 (s, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.48 (d, J = 12.9 Hz, 1H), 3.94 (s, 1H), 3.84 (q, J = 7.0 Hz, 1H), 3.70 (s, 4H), 3.38 (s, 2H), 3.24–3.10 (m, 3H), 2.93–2.71 (m, 8H), 2.58 (d, J = 4.5 Hz, 7H), 2.33 (t, J = 13.6 Hz, 3H), 2.21–2.13 (m, 2H), 1.86 (dd, J = 37.9, 8.1 Hz, 7H), 1.59 (d, J = 35.2 Hz, 6H), 1.24 (s, 1H), 1.19 (d, J = 6.9 Hz, 3H), 0.53 (d, J = 6.8 Hz, 3H).

[1023] Examples 46 and 47: Synthesis of Compounds 46 and 47

[1024]

[1025] Step 1: Preparation of Intermediate 46b

[1026] At 0 °C and under nitrogen protection, methyl iodide (42.3 g) was added to a stirred solution of Intermediate 46a (40 g) and potassium carbonate (63.3 g) in DMF (300 ml), and the reaction was carried out at room temperature. After completion of the reaction, the reaction mixture was poured into ice water, filtered by suction, and the filter cake was dried to obtain Intermediate 46b (39 g).

[1027] MS (ESI, [M+H] + ) m / z: 189.0

[1028] Step 2: Preparation of Intermediate 46c

[1029] Raney nickel (15 g), Intermediate 46b (13.5 g) and methanol (200 ml) were successively added to a reaction flask, and the reaction was carried out at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered by suction, and the filtrate was purified by column chromatography to obtain Intermediate 46c (9.5 g).

[1030] MS (ESI, [M+H] + ) m / z: 159.0

[1031] Step 3-5: Preparation of Intermediate 46h

[1032] Referring to the method described in Steps 6-8 of Example 30, using Intermediate 46c instead of 3-amino-5-chloro-1-methyl-2(1H)-pyridone, Intermediate 46h (5.5 g) was synthesized.

[1033] MS(ESI,[M+H] + ) m / z: 677.1

[1034] Step 6: Preparation of Intermediate 46i

[1035] Intermediate 46h was separated by high-pressure preparation (instrument: YMC high-pressure preparation chromatograph; chromatographic column: CHIRALART Cellulose-SB, 30*250 mm, 5 um; mobile phase: ethanol / dichloromethane), and Intermediate 46i (2.50 g) and 46j (2.48 g) were obtained successively.

[1036] Intermediate 46i: MS(ESI,[M+H] + ) m / z: 677.1

[1037] Intermediate 46j: MS(ESI,[M+H] + ) m / z: 677.1

[1038] Step 7: Preparation of Intermediates 46l and 47a

[1039] To the reaction flask were successively added Intermediate 46i (250 mg), DMF (15 ml), Intermediate 46k (308 mg), potassium phosphate (469 mg), and bis(triphenylphosphine)palladium dichloride (51.7 mg). The reaction was carried out at 100 °C under nitrogen protection. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography (DCM / MeOH system) to obtain Intermediate 46l (120 mg) and Intermediate 47a (120 mg) successively.

[1040] Intermediate 46l: MS(ESI,[M+H] + ) m / z: 762.2

[1041] Intermediate 47a: MS(ESI,[M+H] + ) m / z: 762.2

[1042] Step 8: Preparation of Intermediate 46m

[1043] Referring to the method described in Step 11 of Example 30, using Intermediate 46l instead of Intermediate 30l, Intermediate 46m (105 mg) was synthesized.

[1044] MS(ESI,[M+H]+ ) m / z: 662.2

[1045] Step 9: Preparation of Compound 46

[1046] Referring to the method described in Step 13 of Example 30, using Intermediate 46m instead of Intermediate 30m and Intermediate 44e instead of Intermediate 30n, Compound 46 (95 mg) was synthesized.

[1047] MS (ESI, [M+H] + ) m / z: 1110.4

[1048] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.43–8.38 (m, 1H), 8.02 (dd, J = 8.7, 2.3 Hz, 1H), 7.97–7.86 (m, 2H), 7.75 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.25–7.20 (m, 2H), 6.30 (d, J = 16.9 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.45 (dd, J = 41.2, 12.7 Hz, 1H), 3.93 (dd, J = 45.6, 13.2 Hz, 1H), 3.82 (s, 3H), 3.78–3.71 (m, 1H), 3.45 (s, 3H), 3.24–3.05 (m, 3H), 2.87–2.66 (m, 12H), 2.64–2.54 (m, 3H), 2.47–2.43 (m, 1H), 2.39–2.12 (m, 4H), 2.03–1.90 (m, 1H), 1.89–1.67 (m, 4H), 1.66–1.38 (m, 6H), 1.30 (d, J = 6.9 Hz, 3H), 1.26–1.22 (m, 1H), 0.38 (d, J = 6.8 Hz, 3H).

[1049] Steps 10 and 11: Preparation of Compound 47

[1050] Referring to the preparation methods of Compounds 46m and 46 in Steps 8 - 9, using Intermediate 47a instead of Intermediate 46l, Compound 47 (105 mg) was synthesized.

[1051] MS (ESI, [M+H] + ) m / z: 1110.4

[1052] 11H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.44–8.37 (m, 1H), 8.05–7.97 (m, 1H), 7.96–7.85 (m, 2H), 7.73–7.69 (m, 1H), 7.63–7.56 (m, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.23 (dd, J = 10.6, 8.4 Hz, 2H), 6.36–6.28 (m, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 4.51–4.38 (m, 1H), 3.94 (d, J = 12.2 Hz, 1H), 3.85–3.74 (m, 4H), 3.49–3.40 (m, 4H), 3.29–3.06 (m, 3H), 2.91–2.66 (m, 11H), 2.64–2.53 (m, 3H), 2.48–2.43 (m, 1H), 2.38–2.23 (m, 2H), 2.21–2.14 (m, 1H), 1.85–1.73 (m, 2H), 1.69–1.43 (m, 6H), 1.28–1.18 (m, 5H), 0.53–0.35 (m, 3H).

[1053] Example 48: Synthesis of Compound 48

[1054]

[1055] Step 1: Preparation of Intermediate 48a

[1056] Referring to the method described in Step 6 of Example 30, using Intermediate 5-chloro-o-toluidine instead of Intermediate 3-amino-5-chloro-1-methyl-2(1H)-pyridone, Intermediate 48a (6.70 g) was synthesized.

[1057] MS (ESI, [M+H] + ) m / z: 706.1

[1058] Step 2: Preparation of Intermediate 48b

[1059] Referring to the method described in Step 7 of Example 30, using Intermediate 48a instead of Intermediate 30g, Intermediate 48b (5 g) was synthesized.

[1060] MS (ESI, [M+H] + ) m / z: 678.1

[1061] Step 3: Preparation of Intermediate 48c

[1062] Referring to the method described in step 8 of Example 30, intermediate 48c (5 g) was synthesized by using intermediate 48b instead of intermediate 30h.

[1063] MS(ESI,[M+H] + ) m / z: 660.1

[1064] Step 4: Preparation of intermediates 48d and 48e

[1065] For preparative resolution: Column: CHIRALART Cellulose SC (Innovation 035, 5 μm, 30 * 250 mm) Mobile phase: A: Ethanol:dichloromethane (1:1) B: n-Hexane. Flow rate: 1.0 mL / min Column temperature: 25 °C Detection wavelength: 254 nm

[1066] The front peak was prepared to obtain intermediate 48d (1.8 g).

[1067] MS(ESI,[M+H] + ) m / z: 660.1

[1068] The rear peak was prepared to obtain intermediate 48e (2 g).

[1069] MS(ESI,[M+H] + ) m / z: 660.1

[1070] Step 5: Preparation of intermediate 48f

[1071] In a reaction flask, 3-bromo-4-methoxybenzoic acid (5 g), tert-butanol (200 mL), di-tert-butyl dicarbonate (4.72 g), and 4-dimethylaminopyridine (0.793 g) were successively added. Under N2 protection, the mixture was heated to 85 °C and reacted for 9 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to obtain intermediate 48f (3.2 g).

[1072] MS(ESI,[M+H] + ) m / z: 287.2

[1073] Step 6: Preparation of intermediate 48g

[1074] In a reaction flask, under N2 protection, 48f (1.5 g), bis(pinacolato)diboron (1.990 g), potassium acetate (1.538 g l), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.427 g), and 1,4-dioxane (50 mL) were successively added. The mixture was heated to 100 °C and reacted overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to obtain intermediate 48g (1.65 g).

[1075] 1 1H NMR (500 MHz, DMSO) δ 8.10 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.8, 2.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 1.53 (s, 9H), 1.28 (s, 12H).

[1076] MS (ESI, [M+H] + ) m / z: 335.2

[1077] Step 7: Preparation of Intermediate 48h

[1078] Referring to the preparation of Intermediates 44c and 44d in Reference Example 44, replace 30k with Intermediate 48d and 44b with 48g, and Intermediate 48h (0.221 g) was obtained by purification by column chromatography.

[1079] 1 1H NMR (500 MHz, DMSO) δ 8.00 (dd, J = 8.7, 2.3 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.25 (dd, J = 18.8, 8.5 Hz, 3H), 7.16 (d, J = 7.9 Hz, 1H), 7.12 (s, 1H), 6.42 (s, 1H), 3.86 (s, 3H), 3.83–3.77 (m, 1H), 2.52 (s, 4H), 2.18 (d, J = 11.9 Hz, 1H), 1.93 (s, 2H), 1.67 (d, J = 10.6 Hz, 1H), 1.53 (s, 9H), 1.44 (s, 1H), 1.37 (s, 9H), 1.27 (d, J = 6.9 Hz, 3H), 1.07 (s, 1H), 0.42 (d, J = 6.8 Hz, 3H).

[1080] MS (ESI, [M+H] + ) m / z: 788.0

[1081] Step 8: Preparation of Intermediate 48i

[1082] To the reaction flask were successively added 48h (100 mg), dichloromethane (10 mL) and TFA (5 mL), and the reaction was carried out at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated to dryness to obtain Intermediate 48i (100 mg).

[1083] Step 9: Preparation of Compound 48

[1084] 48i (100 mg), 44e (71.0 mg), N,N-dimethylformamide (6 mL), DIPEA (131 mg), and HATU (56 mg) were successively added to a reaction flask, and the reaction was stirred at room temperature. After the reaction was completed, the reaction solution was directly purified by reverse column chromatography to obtain compound 48 (93 mg).

[1085] 1 1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.06 (dd, J = 8.6, 2.3 Hz, 1H), 7.83–7.71 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 8.4 Hz, 2H), 7.22 (ddd, J = 33.6, 19.6, 8.4 Hz, 6H), 6.41 (s, 1H), 4.55 (dd, J = 11.8, 5.0 Hz, 1H), 4.52–4.37 (m, 1H), 3.99 (t, J = 10.5 Hz, 1H), 3.84 (d, J = 26.1 Hz, 3H), 3.80–3.73 (m, 1H), 3.14–3.09 (m, 1H), 2.87 (s, 5H), 2.81–2.72 (m, 3H), 2.69 (d, J = 9.0 Hz, 2H), 2.60 (dt, J = 16.9, 3.9 Hz, 3H), 2.47 (d, J = 4.5 Hz, 1H), 2.31 (q, J = 12.6 Hz, 2H), 2.25–2.10 (m, 2H), 2.02–1.87 (m, 3H), 1.78 (s, 3H), 1.69 (s, 1H), 1.53 (s, 5H), 1.28–1.20 (m, 4H), 0.48 (dd, J = 51.1, 6.7 Hz, 3H).

[1086] MS (ESI, [M+H] + ) m / z: 1080.4

[1087] Example 49: Synthesis of Compound 49

[1088]

[1089] Step 1: Preparation of Intermediate 49a

[1090] Oxalyl chloride (2.137 g, 1.425 mL) was added to a mixed solution of 3-boro-4-methoxybenzoic acid (1.1 g), dichloromethane (100 mL), and N,N-dimethylformamide (0.1 mL) under an ice bath. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. Dichloromethane (100 mL) was added to dissolve the residue, and the solution was slowly added dropwise to ammonia water (6.56 g, 6.56 mL). The mixture was stirred at room temperature for 30 min. After the reaction ended, stirring was stopped, and the reaction mixture was neutralized with an aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain intermediate 49a (0.8 g).

[1091] 1 H NMR (500 MHz, DMSO) δ 8.06 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.7, 2.4 Hz, 1H), 7.79 (s, 2H), 7.10 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.84 (s, 3H), 3.17 (d, J = 5.2 Hz, 1H).

[1092] MS (ESI, [M+H] + ) m / z: 196.0

[1093] Step 2: Preparation of intermediate 49b

[1094] Referring to the method described in Step 7 of Example 48, using intermediate 49a instead of intermediate 48g, intermediate 49b (0.11 g) was synthesized.

[1095] MS (ESI, [M+H] + ) m / z: 731.2

[1096] Step 3: Preparation of intermediate 49c

[1097] Referring to the method described in Step 8 of Example 48, using intermediate 49b instead of intermediate 48h, intermediate 49c (0.10 g) was synthesized.

[1098] MS (ESI, [M+H] + ) m / z: 631.2

[1099] Step 4: Preparation of compound 49

[1100] Referring to the method described in Step 9 of Example 48, using intermediate 49c instead of intermediate 48i, compound 49 (0.087 g) was synthesized.

[1101] MS (ESI, [M+H] + ) m / z: 1079.4

[1102] 1 1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.03 (ddd, J = 9.2, 6.9, 2.3 Hz, 1H), 7.93 (d, J = 13.4 Hz, 1H), 7.85–7.70 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.21 (tt, J = 19.4, 9.5 Hz, 7H), 6.42 (s, 1H), 4.55 (dd, J = 11.8, 5.0 Hz, 1H), 4.52–4.37 (m, 1H), 4.01–3.88 (m, 1H), 3.82 (d, J = 23.9 Hz, 3H), 3.79–3.72 (m, 1H), 3.45 (s, 2H), 3.10 (s, 2H), 2.94–2.72 (m, 7H), 2.69 (s, 2H), 2.60 (dt, J = 17.4, 4.2 Hz, 3H), 2.45 (d, J = 7.6 Hz, 1H), 2.29 (s, 3H), 2.18 (dt, J = 13.7, 4.8 Hz, 2H), 1.92 (d, J = 11.7 Hz, 3H), 1.77 (d, J = 14.0 Hz, 2H), 1.53 (s, 6H), 1.31–1.15 (m, 5H), 0.47 (dd, J = 38.6, 6.8 Hz, 3H).

[1103] Example 50: Preparation of Compound 50

[1104]

[1105] Step 1: Preparation of Intermediate 50a

[1106] To the reaction flask were successively added 4-bromo-2-chloro-5-methoxypyridine (5.00 g), dimethyl sulfate (2.64 g). After reacting at 120 °C for 2 h, ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL) were added, and the reaction was carried out at 25 °C. After monitoring the reaction to completion, water and EA were added to dilute the reaction solution, and it was separated into layers. The organic phase was concentrated and purified by column chromatography to obtain Intermediate 50a (3.59 g).

[1107] MS (ESI, [M + H] + ) m / z: 217.97

[1108] 1 1H NMR (500 MHz, DMSO-d6) δ 7.53 (s, 1H), 6.80 (s, 1H), 3.70 (s, 3H), 3.40 (s, 3H).

[1109] Step 2: Preparation of Intermediate 50b

[1110] Referring to the preparation method of Intermediate 44b in Reference Example 44, replace 44a with Intermediate 50a to obtain Intermediate 50b (1.19 g).

[1111] MS(ESI,[M+H] + ) m / z: 184.07

[1112] 1 H NMR(500 MHz, DMSO-d6) δ 6.83 (s, 1H), 6.71 (s, 1H), 3.69 (s, 3H), 3.52 (s, 3H).

[1113] Step 3: Preparation of Intermediate 50c

[1114] Referring to the preparation of Intermediates 44c and 44d in Reference Example 44, replace 44b with Intermediate 50b and replace 30k with Intermediate 48d, and after purification by column chromatography, Intermediate 50c (201 mg) is obtained.

[1115] MS(ESI,[M+H] + ) m / z: 719.27

[1116] Step 4: Preparation of Compound 50

[1117] Referring to the preparation steps of Compound 32 in Reference Example 32, replace 32b with Intermediate 50c and replace 30m with Intermediate 44e. After the reaction is completed, purification by column chromatography gives Compound 50 (160 mg, without salt formation with maleic acid).

[1118] MS(ESI,[M+H] + ) m / z: 1067.43

[1119] 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.76 (d, J = 14.2 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 6.9 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.19 (s, 5H), 6.33 (s, 2H), 4.59–4.38 (m, 2H), 3.92 (dp, J = 20.9, 6.9 Hz, 2H), 3.65 (s, 2H), 3.57 (s, 1H), 3.48 (s, 5H), 3.17 (s, 1H), 3.11 (d, J = 11.0 Hz, 1H), 2.97 (t, J = 15.7 Hz, 1H), 2.90–2.63 (m, 8H), 2.63–2.51 (m, 4H), 2.49–2.40 (m, 3H), 2.20–2.16 (m, 1H), 2.08–1.71 (m, 7H), 1.54 (s, 5H), 1.31 (d, J = 7.0 Hz, 2H), 1.28–1.19 (m, 3H), 0.57 (d, J = 6.8 Hz, 3H).

[1120] Example 51: Synthesis of Compound 51

[1121]

[1122] Referring to the method described in Example 43, Compound 51 (95 mg) was synthesized by replacing 2,4-dimethoxypyrimidine-5-boronic acid with intermediate 51a.

[1123] MS (ESI, [M+H] + ) m / z: 1066.4

[1124] 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.76 (d, J = 17.5 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.46–7.36 (m, 3H), 7.27–7.07 (m, 7H), 6.40 (s, 1H), 5.18–5.10 (m, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 4.52–4.39 (m, 3H), 4.02–3.89 (m, 1H), 3.88–3.79 (m, 1H), 3.78–3.70 (m, 3H), 3.22–3.07 (m, 3H), 2.96–2.56 (m, 12H), 2.48–2.42 (m, 1H), 2.40–2.24 (m, 3H), 2.23–2.11 (m, 2H), 2.04–1.69 (m, 7H), 1.66–1.45 (m, 5H), 1.28–1.23 (m, 3H), 1.22–1.18 (m, 1H), 0.54–0.38 (m, 3H).

[1125] Example 52: Synthesis of Compound 52

[1126]

[1127] Step 1: Preparation of Intermediate 52a

[1128] Referring to the method described in Step 10 of Example 30, using Intermediate 46i instead of Intermediate 30k, Intermediate 52a (0.11 g) was synthesized.

[1129] MS (ESI, [M+H] + ) m / z: 737.2

[1130] Step 2: Preparation of Intermediate 52b

[1131] Referring to the method described in Step 11 of Example 30, using Intermediate 52a instead of Intermediate 30l, Intermediate 52b (0.11 g) was synthesized.

[1132] MS (ESI, [M+H] + ) m / z: 637.2

[1133] Step 3: Preparation of Compound 52

[1134] Referring to the method described in Step 13 of Example 30, using Intermediate 52b instead of Intermediate 30m, Compound 52 (0.05 g) was synthesized.

[1135] MS (ESI, [M+H] + ) m / z: 1085.4

[1136] 1 H NMR(500MHz,DMSO)δ11.07(s,1H),8.27(d,J=22.6Hz,1H),7.94–7.83(m,2H),7.59(d,J=8.0Hz,1H),7.45(dd,J=8.4,5.6Hz,2H),7.32–7.21(m,3H),6.28(d,J=17.5Hz,1H),4.55(dd,J=11.8,5.0Hz,1H),4.47(d,J=16.7Hz,1H),3.97(d,J=1.7Hz,3H),3.90(d,J=19.6Hz,3H),3.82(dq,J=13.8,6.9Hz,1H),3.44(s,3H),3.15(ddd,J=35.5,16.5,7.5Hz,2H),2.93(d,J=12.9Hz,2H),2.85–2.65(m,7H),2.60(dt,J=17.4,4.2Hz,3H),2.47–2.35(m,2H),2.32(s,1H),2.25–2.09(m,2H),1.99(s,2H),1.79(s,3H),1.57(s,6H),1.28(dt,J=35.9,7.1Hz,6H),0.46(dd,J=48.1,6.8Hz,3H).

[1137] Example 53: Synthesis of Compound 53

[1138]

[1139] Referring to the method described in Example 51, using intermediate 46i to replace intermediate 48d and 2-(dimethylamino)-4-methoxypyrimidine-5-ylboronic acid to replace intermediate 51a, compound 53 (98 mg) was obtained.

[1140] MS(ESI,[M+H] + )m / z:1098.4

[1141] 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.99 (d, J = 17.9 Hz, 1H), 7.95 - 7.84 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.35 - 7.26 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 6.36 - 6.25 (m, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 4.53 - 4.39 (m, 1H), 4.02 - 3.89 (m, 1H), 3.88 - 3.77 (m, 4H), 3.44 (s, 3H), 3.43 - 3.40 (m, 1H), 3.24 - 3.19 (m, 1H), 3.17 (s, 6H), 3.14 - 3.08 (m, 1H), 2.99 - 2.90 (m, 1H), 2.89 - 2.66 (m, 8H), 2.64 - 2.57 (m, 2H), 2.48 - 2.44 (m, 1H), 2.42 - 2.31 (m, 2H), 2.22 - 1.90 (m, 3H), 1.88 - 1.69 (m, 3H), 1.68 - 1.39 (m, 6H), 1.34 - 1.29 (m, 2H), 1.28 - 1.22 (m, 3H), 0.55 - 0.38 (m, 3H).

[1142] Example 54: Synthesis of Compound 54

[1143]

[1144] Step 1: Preparation of Intermediate 54b

[1145] To the reaction flask were successively added tert-butyl 4-piperidinecarboxylate (1.5 g), Intermediate 54a (1.896 g), DCE (5 ml), acetic acid (0.097 g), and sodium triacetoxyborohydride (5.15 g), and the reaction was carried out at room temperature. After the reaction was completed, water was added, and the mixture was extracted with dichloromethane. The extract was purified by column chromatography to obtain Intermediate 54b (1.58 g).

[1146] Step 2: Preparation of Intermediate 54c

[1147] To the reaction flask were successively added Intermediate 54b (1.5 g), MeOH (50 ml), and potassium carbonate (1.707 g), and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was directly concentrated and purified by column chromatography to obtain Intermediate 54c (1.20 g).

[1148] 11H NMR (500 MHz, DMSO-d6) δ 3.14–3.07 (m, 2H), 3.07–3.01 (m, 1H), 2.80–2.73 (m, 2H), 2.73–2.66 (m, 1H), 2.65–2.56 (m, 2H), 2.41–2.31 (m, 1H), 2.17–2.12 (m, 2H), 1.79–1.69 (m, 4H), 1.53–1.40 (m, 4H), 1.38 (s, 9H).

[1149] Steps 3 and 4: Preparation of Intermediate 54e

[1150] Referring to the methods described in Steps 1 and 2 of Example 54, using Intermediate 54c instead of tert-butyl 4-piperidinecarboxylate and 1-(2,2,2-trifluoroacetyl)azetidin-3-one instead of Intermediate 54a, Intermediate 54e (350 mg) was obtained.

[1151] Steps 5, 6, and 7: Preparation of Compound 54

[1152] Referring to the methods described in Steps 1, 2, and 3 of Example 34, using Intermediate 54e instead of tert-butyl 4-piperidinecarboxylate, Compound 54 (120 mg) was synthesized.

[1153] MS (ESI, [M+H] + ) m / z: 1168.4

[1154] 1 1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.32–8.26 (m, 1H), 7.92–7.87 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.45–7.35 (m, 3H), 7.26–7.19 (m, 3H), 6.66–6.53 (m, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.53–4.37 (m, 1H), 3.97 (s, 3H), 3.93–3.81 (m, 4H), 3.47–3.41 (m, 4H), 3.23–3.06 (m, 3H), 2.96–2.69 (m, 10H), 2.64–2.54 (m, 3H), 2.43–2.28 (m, 3H), 2.24–2.08 (m, 3H), 2.05–1.89 (m, 2H), 1.83–1.41 (m, 12H), 1.29–1.19 (m, 7H), 0.54–0.41 (m, 3H).

[1155] Example 55: Preparation of Compound 55

[1156]

[1157] Step 1: Preparation of Intermediate 55a

[1158] Add z9 (400 mg), 2,2,6,6 - tetramethylpiperidine 1 - oxide (312 mg), acetonitrile (10 mL), and water (1 mL) into a reaction flask in sequence, and react at 25 °C. After the reaction is completed, add water, extract with dichloromethane. The extract is concentrated and purified by column chromatography to obtain Intermediate 55a (160 mg).

[1159] MS (ESI, [M + H] + ) m / z: 315.09

[1160] Step 2: Preparation of Compound 55

[1161] Add Intermediate 55a (50 mg), Intermediate 30m (100 mg), HATU (89 mg), N,N - diisopropylethylamine (60 mg), and DMF (5 mL) into a reaction flask in sequence, and react at 25 °C. After the reaction ends, add water and EA to dilute the reaction solution, separate the layers. The organic phase is concentrated and purified by column chromatography to obtain Compound 55 (40 mg).

[1162] MS (ESI, [M + H] + ) m / z: 933.28

[1163] 1 1H NMR (500 MHz, DMSO - d6) δ 11.07 (s, 1H), 8.36–8.28 (m, 1H), 7.88 (td, J = 5.9, 2.7 Hz, 1H), 7.66–7.57 (m, 1H), 7.43 (ddd, J = 12.6, 7.3, 3.5 Hz, 3H), 7.23 (t, J = 10.4 Hz, 3H), 6.69–6.59 (m, 1H), 4.61–4.41 (m, 2H), 4.11 (dt, J = 32.6, 14.4 Hz, 1H), 3.98 (d, J = 1.3 Hz, 2H), 3.95–3.78 (m, 5H), 3.44 (dd, J = 5.3, 2.6 Hz, 4H), 3.33 (s, 1H), 3.29 (s, 1H), 3.06 (d, J = 13.6 Hz, 1H), 2.76 (tt, J = 11.5, 5.2 Hz, 1H), 2.54 (s, 2H), 2.42–2.34 (m, 1H), 2.28–1.42 (m, 6H), 1.29 (d, J = 6.9 Hz, 2H), 1.24 (s, 3H), 0.49 (ddd, J = 43.0, 6.8, 2.6 Hz, 3H).

[1164] Example 56: Preparation of Compound 56

[1165]

[1166] Step 1: Preparation of Intermediate 56a

[1167] At -10 °C, potassium tert-butoxide (1 M solution in tetrahydrofuran, 1.53 mL) was added dropwise to acrylamide (90 mg). To the reaction flask were successively added z7h (500 mg), acrylamide (150 mg) and tetrahydrofuran (100 mL). The temperature was lowered to -10 °C, and potassium tert-butoxide (1 M solution in tetrahydrofuran, 1.72 mL) was added dropwise. The reaction was carried out at 25 °C. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain intermediate 56a (194 mg).

[1168] MS (ESI, [M+H] + ) m / z: 287.10

[1169] 1 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.65–7.59 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.04 (dd, J = 4.1, 1.6 Hz, 1H), 4.67 (tq, J = 6.1, 3.2 Hz, 1H), 4.57 (dd, J = 11.9, 5.0 Hz, 1H), 3.32–3.19 (m, 3H), 2.94 (ddd, J = 32.1, 16.6, 2.9 Hz, 2H), 2.77 (ddd, J = 17.2, 11.9, 5.3 Hz, 1H), 2.65–2.56 (m, 1H), 2.23–2.14 (m, 1H).

[1170] Step 2: Preparation of Intermediate 56b

[1171] To the reaction flask were successively added intermediate 56a (160 mg), IBX (469 mg) and acetonitrile (5 mL). The reaction was carried out at 70 °C. After completion of the reaction, the mixture was filtered by suction, and the filtrate was concentrated. Intermediate 1h (247 mg), methanol (50 mL), sodium acetate (183 mg) and sodium cyanoborohydride (88 mg) were added, and the reaction was carried out at room temperature. After completion of the reaction, the mixture was directly concentrated and purified by column chromatography to obtain intermediate 56b (105 mg).

[1172] MS (ESI, [M+H] + ) m / z: 453.21

[1173] Step 3: Preparation of Compound 56

[1174] To the reaction flask, intermediate 56b (78 mg), intermediate 30m (110 mg), HATU (98 mg), N,N - diisopropylethylamine (66 mg) and DMF (5 mL) were added successively. The reaction was carried out at 25 °C. After the reaction was completed, water and EA were added to dilute the reaction solution. After liquid - liquid separation, the organic phase was concentrated and then purified by column chromatography to obtain compound 56 (90 mg).

[1175] MS(ESI,[M + H] + )m / z: 1071.40

[1176] 1 H NMR(500 MHz, DMSO - d6)δ11.07(s, 1H), 8.30(s, 1H), 7.89(dd, J = 5.8, 2.9 Hz, 1H), 7.60(d, J = 8.1 Hz, 1H), 7.44–7.36(m, 3H), 7.26–7.18(m, 3H), 6.58(dd, J = 15.5, 12.1 Hz, 1H), 4.56(dd, J = 11.8, 5.0 Hz, 1H), 4.46(dt, J = 32.4, 14.1 Hz, 1H), 3.97(d, J = 1.3 Hz, 3H), 3.90(d, J = 22.1 Hz, 5H), 3.44(d, J = 2.8 Hz, 3H), 3.30(s, 1H), 3.10(dd, J = 30.2, 15.9 Hz, 2H), 2.96–2.67(m, 9H), 2.65–2.54(m, 2H), 2.49–2.28(m, 3H), 2.21–1.88(m, 3H), 1.78(s, 3H), 1.55(d, J = 16.2 Hz, 5H), 1.27(d, J = 6.9 Hz, 4H), 0.43(d, J = 6.8 Hz, 3H).

[1177] Example 57: Preparation of Compound 57

[1178]

[1179] Step 1: Preparation of Intermediate 57a

[1180] To the reaction flask, intermediate z23 (150 mg), IBX (280 mg) and DMSO (2 mL) were added successively. The reaction was carried out at room temperature. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate. The extract was concentrated. The residue was added with intermediate 1h (221 mg), methanol (60 mL), sodium acetate (164 mg) and sodium cyanoborohydride (79 mg). The reaction was carried out at room temperature. After the reaction was completed, it was directly concentrated and purified by column chromatography to obtain intermediate 57a (147 mg).

[1181] MS(ESI,[M + H]+ ) m / z: 466.23

[1182] 1 H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 4.11–4.06 (m, 1H), 3.41 (s, 2H), 3.13 (dd, J = 16.0, 7.8 Hz, 1H), 3.05 (dd, J = 15.8, 7.7 Hz, 1H), 2.76 (s, 6H), 2.52 (d, J = 15.9 Hz, 5H), 2.46 (s, 2H), 2.28 (tt, J = 12.3, 6.3 Hz, 1H), 2.11 (dddt, J = 18.2, 13.8, 9.3, 4.2 Hz, 2H), 1.77 (s, 4H), 1.55–1.43 (m, 2H).

[1183] Step 2: Preparation of Compound 57

[1184] Add intermediate 57a (65 mg), intermediate 30m (90 mg), HATU (81 mg), N,N-diisopropylethylamine (54 mg) and DMF (10 mL) to the reaction flask in sequence, react at 25 °C. After the reaction is completed, add water and EA to dilute the reaction solution, separate the layers, concentrate the organic phase and purify it by column chromatography to obtain compound 57 (82 mg).

[1185] MS (ESI, [M+H] + ) m / z: 1084.42

[1186] 11H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.29 (d, J = 10.2 Hz, 1H), 7.89 (dd, J = 5.8, 2.8 Hz, 1H), 7.80 (s, 1H), 7.41 (dd, J = 8.5, 3.8 Hz, 3H), 7.32 (d, J = 7.9 Hz, 1H), 7.24–7.18 (m, 2H), 7.08 (d, J = 7.9 Hz, 1H), 6.58 (s, 1H), 4.46 (dt, J = 32.4, 14.1 Hz, 1H), 4.10 (dd, J = 11.8, 4.9 Hz, 1H), 3.97 (d, J = 1.2 Hz, 3H), 3.93 (s, 2H), 3.88 (s, 2H), 3.44 (d, J = 2.7 Hz, 4H), 3.16–3.04 (m, 2H), 2.93–2.67 (m, 8H), 2.55 (dq, J = 18.6, 4.4 Hz, 4H), 2.31 (dd, J = 12.4, 7.9 Hz, 3H), 2.16–1.89 (m, 3H), 1.80 (s, 3H), 1.66–1.47 (m, 5H), 1.28–1.20 (m, 4H), 0.47 (dd, J = 42.7, 6.8 Hz, 3H).

[1187] Example 58: Synthesis of Compound 58

[1188]

[1189] Step 1: Preparation of Intermediate 58a

[1190] Referring to the method described in Step 12 of Example 30, using Intermediate z16 instead of Intermediate z8, Intermediate 58a (0.124 g) was synthesized.

[1191] MS (ESI, [M+H] + ) m / z: 452.3

[1192] 11H NMR (500 MHz, DMSO) δ 10.83 (s, 1H), 7.79 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 4.10 (dd, J = 11.8, 4.9 Hz, 1H), 3.38 (d, J = 6.9 Hz, 2H), 3.26 (t, J = 3.6 Hz, 1H), 3.03 (ddd, J = 32.5, 16.0, 6.6 Hz, 3H), 2.79 (d, J = 5.7 Hz, 2H), 2.77–2.69 (m, 4H), 2.64–2.60 (m, 2H), 2.58–2.53 (m, 1H), 2.34–2.25 (m, 1H), 2.19–2.07 (m, 2H), 1.81–1.73 (m, 4H), 1.54–1.44 (m, 2H).

[1193] Step 2: Preparation of Compound 58

[1194] Referring to the method described in Step 13 of Example 30, using Intermediate 58a instead of Intermediate 30n, Compound 58 (0.068 g) was synthesized.

[1195] 1 1H NMR (500 MHz, DMSO) δ 10.87 (s, 1H), 8.29 (d, J = 10.0 Hz, 1H), 7.89 (dd, J = 5.8, 2.8 Hz, 1H), 7.80 (s, 1H), 7.44–7.35 (m, 3H), 7.33 (d, J = 7.9 Hz, 1H), 7.24–7.18 (m, 2H), 7.07 (dd, J = 9.3, 7.0 Hz, 1H), 6.58 (dd, J = 16.1, 11.5 Hz, 1H), 4.53–4.39 (m, 1H), 4.10 (dd, J = 11.8, 4.9 Hz, 1H), 3.97 (d, J = 1.2 Hz, 3H), 3.90 (d, J = 22.1 Hz, 3H), 3.87–3.79 (m, 1H), 3.44 (d, J = 2.7 Hz, 3H), 3.34 (s, 2H), 3.07 (s, 2H), 2.73 (ddd, J = 17.0, 12.1, 5.3 Hz, 7H), 2.61–2.52 (m, 3H), 2.30 (d, J = 12.8 Hz, 3H), 2.12–2.06 (m, 1H), 1.98 (t, J = 15.4 Hz, 1H), 1.78 (s, 3H), 1.57 (s, 6H), 1.29–1.19 (m, 5H), 0.47 (dd, J = 42.7, 6.8 Hz, 3H).

[1196] MS (ESI, [M+H] +)m / z: 1070.4108

[1197] Example 59: Synthesis of Compound 59

[1198]

[1199] Step 1: Preparation of Intermediate 59a

[1200] Referring to the method described in Step 12 of Example 30, using Intermediate z23 instead of Intermediate z8, Intermediate 59a (0.150 g) was synthesized.

[1201] MS (ESI, [M+H] + )m / z: 467.2

[1202] 1 H NMR (500 MHz, DMSO) δ 10.49 (s, 1H), 8.02 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 3.81 (t, J = 6.7 Hz, 2H), 3.42–3.41 (m, 2H), 3.14 (dd, J = 16.0, 7.8 Hz, 2H), 3.06 (dd, J = 15.9, 7.7 Hz, 2H), 2.81 (dd, J = 11.9, 6.0 Hz, 2H), 2.78–2.75 (m, 3H), 2.74–2.68 (m, 1H), 2.61 (d, J = 10.8 Hz, 2H), 2.54 (d, J = 7.7 Hz, 1H), 2.46 (d, J = 7.3 Hz, 2H), 2.16 (tt, J = 11.1, 3.8 Hz, 1H), 1.82–1.73 (m, 4H), 1.55–1.44 (m, 2H).

[1203] Step 2: Preparation of Compound 59

[1204] Referring to the method described in Step 13 of Example 30, using Intermediate 59a instead of Intermediate 30n, Compound 59 (0.066 g) was synthesized.

[1205] 11H NMR (500 MHz, DMSO) δ 10.50 (s, 1H), 8.29 (d, J = 10.2 Hz, 1H), 8.02 (s, 1H), 7.89 (dd, J = 5.8, 2.8 Hz, 1H), 7.46–7.40 (m, 2H), 7.40–7.33 (m, 2H), 7.21 (dd, J = 8.4, 3.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.58 (dd, J = 16.1, 11.4 Hz, 1H), 4.49 (t, J = 13.5 Hz, 1H), 3.97 (s, 3H), 3.90 (d, J = 22.1 Hz, 3H), 3.88–3.83 (m, 1H), 3.81 (t, J = 6.7 Hz, 2H), 3.44 (d, J = 2.8 Hz, 5H), 3.18–3.13 (m, 1H), 3.09–3.03 (m, 1H), 2.98–2.87 (m, 2H), 2.87–2.65 (m, 8H), 2.56 (s, 3H), 2.32 (s, 2H), 2.20–2.06 (m, 1H), 1.98 (s, 1H), 1.80 (s, 3H), 1.57 (s, 5H), 1.28–1.19 (m, 5H), 0.47 (dd, J = 42.7, 6.7 Hz, 3H).

[1206] MS (ESI, [M+H] + ) m / z: 1085.4201

[1207] Example 60: Synthesis of Compound 60

[1208]

[1209] Steps 1 and 2: Preparation of Intermediate 60b

[1210] To the reaction flask were successively added intermediate z21 (200 mg), DMSO (5 ml), and IBX (391 mg), and the reaction was carried out at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and then intermediate 1h (308 mg), sodium acetate (115 mg), DCE (10 ml), isopropanol (2 ml), and sodium cyanoborohydride (176 mg) were added, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography to obtain intermediate 60b (150 mg).

[1211] MS (ESI, [M+H] + ) m / z: 453.2

[1212] Step 3: Preparation of Compound 60

[1213] Referring to the method described in Step 7 of Example 54, using intermediate 60b instead of intermediate 54g, compound 60 (45 mg) was synthesized.

[1214] MS(ESI,[M+H] + )m / z:1071.4

[1215] 1 H NMR(500MHz,DMSO)δ10.50(s,1H),8.29(d,J=10.3Hz,1H),8.03(s,1H),7.92–7.87(m,1H),7.44–7.35(m,4H),7.24–7.18(m,2H),7.12(d,J=8.0Hz,1H),6.63–6.54(m,1H),4.53–4.38(m,1H),3.97(s,3H),3.94–3.87(m,4H),3.85–3.78(m,3H),3.44(s,3H),3.21–3.02(m,3H),2.94–2.70(m,9H),2.41–

[1216] 2.26(m,2H),2.15–1.92(m,2H),1.87–1.71(m,3H),1.67–1.43(m,6H),1.29–1.19(m,6H),0.54–0.41(m,3H).

[1217] Example 61: Synthesis of Compound 61

[1218]

[1219] Referring to the method described in Example 60, using intermediate z36-2 instead of intermediate z21, compound 61 (70 mg) was synthesized.

[1220] MS(ESI,[M+H] + )m / z:1085.4

[1221] 11H NMR (500 MHz, DMSO) δ 10.69 (s, 1H), 8.29 (d, J = 10.2 Hz, 1H), 7.91–7.86 (m, 1H), 7.44–7.35 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H), 7.24–7.18 (m, 2H), 7.08 (d, J = 7.8 Hz, 1H), 6.69 (s, 1H), 6.63–6.54 (m, 1H), 4.54–4.38 (m, 1H), 3.99–3.95 (m, 5H), 3.93–3.88 (m, 3H), 3.87–3.78 (m, 1H), 3.49–3.38 (m, 5H), 3.15–3.00 (m, 2H), 2.97–2.89 (m, 1H), 2.87–2.74 (m, 6H), 2.73–2.65 (m, 3H), 2.48–2.28 (m, 4H), 2.20–1.91 (m, 2H), 1.86–1.72 (m, 3H), 1.68–1.40 (m, 6H), 1.29–1.19 (m, 5H), 0.57–0.41 (m, 3H).

[1222] Example 62: Synthesis of Compound 62

[1223]

[1224] Step 1: Preparation of Intermediate 62a

[1225] Referring to the method described in Step 6 of Example 30, using Intermediate 2-hydroxy-3-amino-5-chloropyridine instead of Intermediate 3-amino-5-chloro-1-methyl-2(1H)-pyridone, Intermediate 62a (2.3 g) was synthesized.

[1226] MS (ESI, [M+H] + ) m / z: 709.1

[1227] Step 2: Preparation of Intermediate 62b

[1228] Referring to the method described in Step 7 of Example 30, using Intermediate 62a instead of Intermediate 30g, Intermediate 62b (2.1 g) was synthesized.

[1229] MS (ESI, [M+H] + ) m / z: 681.1

[1230] Step 3: Preparation of Intermediate 62c

[1231] Referring to the method described in Step 8 of Example 30, using Intermediate 62b instead of Intermediate 30h, Intermediate 62c (1.32 g) was synthesized.

[1232] MS (ESI, [M+H] + ) m / z: 663.1

[1233] 1 H NMR (500 MHz, DMSO) δ 12.21 (s, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.42–7.38 (m, 3H), 7.14 (d, J = 8.1 Hz, 2H), 6.66 (s, 1H), 4.43 (p, J = 6.9 Hz, 1H), 4.07 (s, 2H), 2.69 (s, 4H), 2.10 (s, 1H), 1.68 (d, J = 13.0 Hz, 1H), 1.57 (d, J = 12.8 Hz, 1H), 1.42 (s, 9H), 1.30 (d, J = 6.9 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H).

[1234] Step 4: Preparation of intermediates 62d and 62e

[1235] For preparative resolution: Column: CHIRALART Amylose-SA (Innovation 004, 30×250 mm, 5 μm) Mobile phase: A: Carbon dioxide B: Ethanol. Flow rate: 80 mL / min Column temperature: 25 °C Detection wavelength: 254 nm

[1236] The front peak was prepared to obtain intermediate 62d (0.521 g).

[1237] MS (ESI, [M+H] + ) m / z: 663.1

[1238] The rear peak was prepared to obtain intermediate 62e (0.500 g).

[1239] MS (ESI, [M+H] + ) m / z: 663.1

[1240] Step 5: Preparation of intermediate 62f

[1241] Referring to the method described in Step 10 of Example 30, using intermediate 62e instead of intermediate 30k and 2-(dimethylamino)-4-methoxypyrimidine-5-ylboronic acid instead of intermediate 2,4-dimethoxypyrimidine-5-boronic acid, intermediate 62f (0.2 g) was synthesized.

[1242] MS (ESI, [M+H] + ) m / z: 857.8

[1243] Step 6: Preparation of intermediate 62g

[1244] Referring to the method described in Step 11 of Example 30, using intermediate 62f instead of intermediate 30l, intermediate 62g (0.2 g) was synthesized.

[1245] MS(ESI,[M+H] + ) m / z: 636.2

[1246] Step 7: Preparation of Compound 62

[1247] Referring to the method described in Step 13 of Example 30, using intermediate 62g instead of intermediate 30m, compound 62 (0.048 g) was synthesized.

[1248] MS(ESI,[M+H] + ) m / z: 1084.4

[1249] 1 1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 11.07 (s, 1H), 8.00 (d, J = 11.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48–7.36 (m, 4H), 7.25 (d, J = 8.1 Hz, 1H), 7.20 (dd, J = 8.2, 5.5 Hz, 2H), 6.60 (t, J = 10.7 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.46 (dd, J = 30.1, 13.6 Hz, 1H), 3.95 (d, J = 22.6 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 2H), 3.17 (s, 8H), 2.99–2.91 (m, 2H), 2.88 (d, J = 8.5 Hz, 2H), 2.82–2.72 (m, 4H), 2.60 (dt, J = 17.4, 4.5 Hz, 2H), 2.34 (s, 2H), 2.21–2.10 (m, 2H), 1.99 (dd, J = 15.3, 9.6 Hz, 3H), 1.84 (s, 3H), 1.59 (s, 6H), 1.27–1.20 (m, 6H), 0.48 (dd, J = 44.4, 6.7 Hz, 3H).

[1250] Example 63: Preparation of Compound 63

[1251]

[1252] Step 1: Preparation of Intermediate 63a

[1253] 63ab (20 g), DMF (200 mL), 4-methoxybenzyl chloride (27 g) and potassium carbonate (39 g) were successively added to a reaction flask, and the reaction was carried out at 80 °C. After monitoring the completion of the reaction, water and EA were added to the reaction solution for dilution, and the layers were separated. The organic phase was concentrated and purified by column chromatography to obtain intermediate 63a (37 g). MS (ESI, [M+H] + ) m / z: 295.04

[1254] 1 H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 2.9 Hz, 1H), 7.41–7.33 (m, 2H), 6.97–6.89 (m, 2H), 5.12 (s, 2H), 3.74 (s, 3H).

[1255] Step 2: Preparation of intermediate 63b

[1256] Intermediate 63a (20 g), methanol (300 mL), THF (100 mL) and Raney nickel (20 g) were successively added to a reaction flask, and the reaction was carried out at room temperature under hydrogen protection. After monitoring the completion of the reaction, the reaction solution was concentrated and purified by column chromatography to obtain intermediate 63b (6.5 g).

[1257] MS (ESI, [M+H] + ) m / z: 265.06

[1258] 1 H NMR (500 MHz, DMSO-d6) δ 7.33–7.25 (m, 2H), 7.18 (d, J = 2.6 Hz, 1H), 6.92–6.86 (m, 2H), 6.37 (d, J = 2.5 Hz, 1H), 5.54 (s, 2H), 4.99 (s, 2H), 3.72 (s, 3H).

[1259] Step 3: Preparation of intermediate 63c

[1260] Intermediate 30e (6 g) and THF (300 mL) were successively added to a reaction flask, and the temperature was cooled to -30 °C. A THF solution (20 mL) of 2 M lithium diisopropylamide was added dropwise. After the addition was completed, the reaction was carried out at room temperature. After monitoring the completion of the reaction, the reaction solution was quenched with a saturated ammonium chloride aqueous solution, and extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain intermediate 63c (5.08 g).

[1261] MS (ESI, [M+H] + ) m / z: 601.14

[1262] 11H NMR (500 MHz, DMSO-d6) δ 7.57 (t, J = 8.0 Hz, 1H), 7.27 (dt, J = 10.4, 1.6 Hz, 1H), 7.02 (dt, J = 8.6, 1.4 Hz, 1H), 6.63 (d, J = 4.3 Hz, 1H), 6.49 (d, J = 4.3 Hz, 1H), 4.70 (hept, J = 7.1 Hz, 1H), 4.22 (tt, J = 17.6, 8.1 Hz, 2H), 4.07 (s, 2H), 3.06 (tt, J = 12.3, 3.7 Hz, 1H), 2.68 (d, J = 44.3 Hz, 2H), 2.18–2.07 (m, 1H), 1.95 (qd, J = 12.6, 4.3 Hz, 1H), 1.47 (d, J = 7.0 Hz, 5H), 1.41 (s, 9H), 1.25 (s, 3H), 0.91 (d, J = 7.1 Hz, 3H).

[1263] Step 4: Preparation of Intermediate 63d

[1264] To a reaction flask were successively added Intermediate 63c (4.50 g), dichloromethane (300 mL) and triethylamine (3.78 g). The temperature was lowered to -30 °C, and a solution of methanesulfonic anhydride (2.60 g) in dichloromethane (10 mL) was added dropwise. After the addition was complete, the reaction was carried out at -30 °C for 15 min. Then, a solution of Intermediate 63b (2.57 g) in dichloromethane (10 mL) was added dropwise. After the addition was complete, the temperature was raised to -10 °C for reaction. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the extract was concentrated and purified by column chromatography to obtain Intermediate 63d (3.25 g).

[1265] MS (ESI, [M+H] + ) m / z: 847.20

[1266] 1 1H NMR (500 MHz, DMSO-d6) δ 7.58 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.7 Hz, 3H), 7.17 (s, 1H), 6.90 (d, J = 8.7 Hz, 3H), 6.55–6.08 (m, 3H), 5.02 (s, 2H), 4.68 (d, J = 24.2 Hz, 1H), 4.03 (d, J = 7.1 Hz, 3H), 3.73 (s, 3H), 2.98 (s, 1H), 2.81–2.58 (m, 2H), 1.98–1.81 (m, 2H), 1.40 (s, 15H), 1.33–1.20 (m, 3H), 1.14 (d, J = 17.6 Hz, 3H).

[1267] Step 5: Preparation of Intermediate 63e

[1268] To the reaction flask, add intermediate 63d (3.25 g), ethanol (75 mL), tetrahydrofuran (75 mL), and 4 M aqueous sodium hydroxide solution (48 mL) in sequence. React at 85 °C. After the reaction is completed, add ethyl acetate to the reaction solution for extraction. Concentrate the extract to obtain intermediate 63e (4.44 g).

[1269] MS(ESI,[M+H] + ) m / z: 819.16

[1270] Step 6: Preparation of intermediate 63f

[1271] To the reaction flask, add intermediate 63e (4.44 g), DMF (40 mL), N,N - diisopropylethylamine (2.10 g), and 2-(1H - benzotriazol - 1 - yl)-1,1,3,3 - tetramethyluronium tetrafluoroborate (2.61 g) in sequence. React at 80 °C. After the reaction is completed, add ethyl acetate to the reaction solution for extraction. Concentrate the extract and purify it by column chromatography. Perform resolution (instrument: YMC high - pressure preparative chromatograph; chromatographic column: CHIRALART Cellulose - SB, 30x250 mm, 5 μm; mobile phase: ethanol / dichloromethane / n - hexane) to obtain intermediate 63f" (1.57 g) and intermediate 63f (1.55 g) successively.

[1272] Intermediate 63f": MS(ESI,[M + H]+) m / z: 801.15

[1273] Intermediate 63f: MS(ESI,[M + H] + ) m / z: 801.15

[1274] Intermediate 63f: 11H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 2.9 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.24–7.18 (m, 2H), 7.16 (d, J = 9.4 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.90–6.86 (m, 2H), 6.70 (s, 1H), 5.10 (d, J = 13.9 Hz, 1H), 4.95 (d, J = 13.9 Hz, 1H), 4.44 (h, J = 6.9 Hz, 1H), 4.16–4.03 (m, 2H), 3.74 (s, 3H), 2.71 (tt, J = 12.2, 3.7 Hz, 2H), 2.11 (d, J = 9.6 Hz, 1H), 1.86 (s, 1H), 1.67 (d, J = 12.9 Hz, 1H), 1.56 (d, J = 12.6 Hz, 1H), 1.42 (s, 9H), 1.30 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 7.0 Hz, 1H), 0.85 (d, J = 6.7 Hz, 3H).

[1275] Step 7: Preparation of Intermediate 63g

[1276] To the reaction flask were successively added Intermediate 63f (500 mg), 2-(dimethylamino)-4-methoxypyrimidin-5-ylboronic acid (491 mg), bis(triphenylphosphine)palladium(II) dichloride (175 mg), potassium phosphate (793 mg) and DMF (40 mL), and the reaction was carried out at 100 °C. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain Intermediate 63g (717 mg).

[1277] MS (ESI, [M+H] + ) m / z: 874.32

[1278] Step 8: Preparation of Compound 63

[1279] Referring to the preparation steps of Compound 32 in Reference Example 32, Intermediate 63g was used to replace 32b, and Intermediate 44e was used to replace 30m. After completion of the reaction, the product was purified by column chromatography to obtain Compound 63 (58 mg, without salt formation with maleic acid).

[1280] MS (ESI, [M+H] + ) m / z: 1102.42

[1281] 11H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 11.07 (s, 1H), 8.01 (d, J = 16.7 Hz, 1H), 7.62–7.55 (m, 2H), 7.48 (d, J = 6.8 Hz, 2H), 7.25 (dd, J = 13.9, 8.9 Hz, 2H), 7.08 (s, 1H), 6.60 (t, J = 12.8 Hz, 1H), 4.59–4.37 (m, 2H), 3.87 (s, 4H), 3.44 (s, 2H), 3.17 (s, 9H), 2.93–2.66 (m, 9H), 2.62–2.57 (m, 2H), 2.46–2.29 (m, 3H), 2.20–2.15 (m, 1H), 1.98 (s, 1H), 1.76 (d, J = 33.1 Hz, 3H), 1.56 (d, J = 20.6 Hz, 5H), 1.28–1.19 (m, 6H), 0.53 (dd, J = 43.2, 6.7 Hz, 3H).

[1282] Example 64: Preparation of Compound 64

[1283]

[1284] Step 1: Preparation of Intermediate 64b

[1285] Referring to the preparation of Intermediates 44c and 44d in Reference Example 44, Intermediate 50b was replaced with Intermediate 44b, and after purification by column chromatography, Intermediate 64b (92 mg) was obtained.

[1286] MS (ESI, [M+H] + ) m / z: 736.26

[1287] Step 4: Preparation of Compound 64

[1288] Referring to the preparation steps of Compound 32 in Reference Example 32, Intermediate 64b was replaced with 32b, and Intermediate 44e was replaced with 30m. After the reaction was completed, purification by column chromatography gave Compound 64 (45 mg, without salt formation with maleic acid).

[1289] MS (ESI, [M+H] + ) m / z: 1084.42

[1290] 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.89 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.39 (t, J = 15.4 Hz, 3H), 7.21 (dd, J = 25.5, 8.1 Hz, 3H), 6.57 (s, 1H), 6.33 (d, J = 9.3 Hz, 1H), 4.60–4.40 (m, 2H), 3.92 (d, J = 33.1 Hz, 2H), 3.64 (s, 2H), 3.56 (s, 1H), 3.45 (d, J = 15.2 Hz, 7H), 3.24–3.09 (m, 3H), 3.03–2.68 (m, 10H), 2.60 (d, J = 16.9 Hz, 3H), 2.18 (s, 2H), 2.00 (s, 2H), 1.81 (s, 3H), 1.58 (s, 6H), 1.32 (d, J = 7.5 Hz, 2H), 1.24 (d, J = 6.1 Hz, 2H), 0.48 (dd, J = 65.9, 6.7 Hz, 3H).

[1291] Example 65: Synthesis of Compound 65

[1292]

[1293] Referring to the method described in Example 64, Intermediate 65 (85 mg) was synthesized by using Intermediate 46i instead of Intermediate 30k.

[1294] MS (ESI, [M+H] + ) m / z: 1084.4

[1295] 11H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.93–7.81 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.53–7.49 (m, 1H), 7.48–7.42 (m, 2H), 7.31–7.21 (m, 3H), 6.35–6.24 (m, 2H), 4.59–4.41 (m, 2H), 3.97–3.84 (m, 2H), 3.63 (s, 2H), 3.56 (s, 1H), 3.47 (s, 3H), 3.44 (s, 3H), 3.42–3.39 (m, 2H), 3.22–3.07 (m, 3H), 3.02–2.92 (m, 1H), 2.86–2.67 (m, 9H), 2.63–2.55 (m, 3H), 2.48–2.42 (m, 3H), 2.21–2.14 (m, 1H), 2.07–1.97 (m, 1H), 1.87–1.74 (m, 3H), 1.66–1.50 (m, 5H), 1.36–1.23 (m, 4H), 0.58–0.39 (m, 3H).

[1296] Example 66: Synthesis of Compound 66

[1297]

[1298] Step 1: Preparation of Intermediate 66a

[1299] Referring to the method described in Step 1 of Example 42, using Intermediate z5 instead of Intermediate z1, Intermediate 66a (0.150 g) was synthesized.

[1300] MS (ESI, [M+H] + ) m / z: 414.3

[1301] Step 2: Preparation of Intermediate 66b

[1302] Referring to the method described in Step 2 of Example 42, using Intermediate 66a instead of Intermediate 42a, Intermediate 66b (0.070 g) was synthesized.

[1303] Step 3: Preparation of Compound 66

[1304] Referring to the method described in Step 3 of Example 42, using Intermediate 66b instead of Intermediate 42b, Compound 66 (0.080 g) was synthesized.

[1305] MS (ESI, [M+H] + ) m / z: 976.3

[1306] 11H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.30 (d, J = 12.5 Hz, 1H), 7.88 (dd, J = 6.8, 2.5 Hz, 1H), 7.54 (dd, J = 14.8, 7.9 Hz, 1H), 7.46–7.35 (m, 3H), 7.23–7.17 (m, 2H), 7.14–7.03 (m, 1H), 6.66 (t, J = 13.2 Hz, 1H), 4.54 (dd, J = 12.3, 4.7 Hz, 1H), 4.50–4.37 (m, 1H), 4.26–4.13 (m, 1H), 3.96 (d, J = 3.1 Hz, 3H), 3.94–3.88 (m, 3H), 3.83 (td, J = 14.9, 7.9 Hz, 1H), 3.44 (d, J = 3.2 Hz, 2H), 3.39 (t, J = 4.6 Hz, 2H), 3.08 (s, 2H), 2.94 (dd, J = 28.1, 15.6 Hz, 2H), 2.75 (dd, J = 13.0, 4.3 Hz, 2H), 2.60 (d, J = 18.0 Hz, 3H), 2.37 (s, 1H), 2.19 (s, 2H), 2.01–1.89 (m, 1H), 1.80 (dd, J = 25.0, 12.3 Hz, 1H), 1.67 (d, J = 16.3 Hz, 1H), 1.48 (t, J = 16.6 Hz, 1H), 1.29–1.20 (m, 5H), 0.55–0.40 (m, 3H).

[1307] Example 67: Synthesis of Compound 67

[1308]

[1309] Step 1: Preparation of Intermediate 67a

[1310] To the reaction flask were successively added intermediate 30m (200 mg), N,N'-carbonyldiimidazole (102 mg), DIPEA (162 mg)), and THF (8 ml). The reaction was carried out at room temperature. After completion of the reaction, the reaction solution was concentrated and the residue was purified by column chromatography to obtain intermediate 67a (198 mg).

[1311] MS (ESI, [M+H] + ) m / z: 731.2

[1312] Step 2: Preparation of Intermediate 67b

[1313] To the reaction flask were successively added intermediate 67a (198 mg), acetonitrile (5 ml), and methyl iodide (1.685 ml). The reaction was carried out at 40 °C. After completion of the reaction, the reaction solution was concentrated and the residue was purified by column chromatography to obtain intermediate 67b (105 mg).

[1314] MS(ESI,[M+H] + )m / z:745.2

[1315] Step 3: Preparation of Compound 67

[1316] To the reaction flask were successively added intermediate 67b (104 mg), intermediate z1 (55.0 mg), DMSO (4 ml) and DIPEA (61.5 mg). The reaction was carried out at room temperature. After the reaction was completed, water was added, and the mixture was extracted with dichloromethane. The extract was purified by column chromatography to obtain intermediate 67 (105 mg).

[1317] MS(ESI,[M+H] + )m / z:934.2

[1318] 1 H NMR(500MHz,DMSO)δ11.09(s,1H),8.34–8.29(m,1H),7.91–7.86(m,1H),7.78(d,J=8.1Hz,

[1319] 1H),7.46–7.40(m,3H),7.37(d,J=8.1Hz,1H),7.26–7.20(m,2H),6.68–6.62(m,1H),4.97(s,2H),4.88(s,2H),4.62(dd,J=11.9,5.0Hz,1H),4.00–3.97(m,3H),3.95–3.90(m,3H),3.88–3.79(m,2H),3.47–3.43(m,3H),2.83–2.69(m,3H),2.66–2.58(m,1H),2.33–2.18(m,3H),2.14–1.76(m,2H),1.73–1.61(m,1H),1.54–1.43(m,1H),1.31–1.27(m,2H),1.25–1.22(m,2H),0.57–0.43(m,3H).

[1320] Example 68: Preparation of Compound 68

[1321]

[1322] Step 1: Preparation of Intermediate 68a

[1323] To the reaction flask were successively added tert-butyl 4-piperidinecarboxylate (5.00 g), 1-tert-butoxycarbonyl-3-pyrrolidone (5.00 g), sodium triacetoxyborohydride (11.44 g) and dichloroethane (100 mL), and the reaction was carried out at room temperature. After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the extract was concentrated and purified by column chromatography to obtain intermediate 68a (8.9 g).

[1324] 1 H NMR (500 MHz, DMSO-d6) δ 3.48 (dd, J = 10.3, 7.2 Hz, 1H), 3.39–3.34 (m, 1H), 3.14 (dtd, J = 21.0, 10.4, 7.0 Hz, 1H), 2.91 (dt, J = 15.0, 9.7 Hz, 1H), 2.81 (dt, J = 11.3, 4.1 Hz, 1H), 2.70 (dq, J = 26.3, 9.8 Hz, 2H), 2.16 (tt, J = 11.1, 4.0 Hz, 1H), 2.07–1.99 (m, 2H), 1.97 (dd, J = 11.3, 2.7 Hz, 1H), 1.74 (qd, J = 6.4, 3.4 Hz, 2H), 1.61 (dt, J = 20.7, 10.6 Hz, 1H), 1.54–1.51 (m, 1H), 1.49–1.44 (m, 1H), 1.39 (d, J = 1.5 Hz, 18H).

[1325] Step 2: Preparation of intermediate 68b

[1326] To the reaction flask were successively added intermediate 68a (300 mg), trifluoroacetic acid (1 mL) and DCM (10 mL), and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was directly concentrated to obtain a concentrate.

[1327] To another reaction flask were successively added intermediate z9 (200 mg), IBX (373 mg) and DMSO (2 mL), and the reaction was carried out at room temperature. After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the extract was concentrated. Dichloroethane (20 mL) was added and transferred to the above concentrate. Sodium acetate (219 mg) and sodium cyanoborohydride (105 mg) were added, and the reaction was carried out at room temperature. After the reaction was completed, it was quenched with water, extracted with dichloromethane, and the extract was concentrated and purified by column chromatography to obtain intermediate 68b (251 mg).

[1328] MS (ESI, [M+H] + ) m / z: 481.24

[1329] Step 3: Preparation of compound 68

[1330] To the reaction flask were successively added intermediate 33k (90 mg), intermediate 68b (67 mg), HATU (64 mg), N,N - diisopropylethylamine (54 mg) and DMF (2 mL). The reaction was carried out at 25 °C. After monitoring the completion of the reaction, water and EA were added to dilute the reaction solution. After liquid - liquid separation, the organic phase was concentrated and then purified by column chromatography to obtain compound 68 (88 mg).

[1331] MS(ESI,[M + H] + )m / z: 1099.43

[1332] 1 H NMR(500 MHz, DMSO - d6)δ11.07(s, 1H), 8.29(d, J = 10.0 Hz, 1H), 7.88(dd, J = 5.9, 2.8 Hz, 1H), 7.60(d, J = 8.1 Hz, 1H), 7.40(d, J = 3.7 Hz, 3H), 7.25(d, J = 8.2 Hz, 1H), 7.23–7.18(m, 2H), 6.63–6.54(m, 1H), 4.59–4.37(m, 2H), 3.97(s, 3H), 3.93(s, 2H), 3.88(s, 2H), 3.43(d, J = 2.8 Hz, 3H), 3.26–3.10(m, 3H), 2.99–2.69(m, 9H), 2.65–2.54(m, 3H), 2.49–2.28(m, 6H), 2.18(d, J = 12.3 Hz, 1H), 2.02–1.72(m, 5H), 1.58(s, 6H), 1.27(d, J = 6.9 Hz, 4H), 0.48(dd, J = 42.8, 6.7 Hz, 3H).

[1333] Example 69: Preparation of Compound 69

[1334]

[1335] Step 2: Preparation of Intermediate 69a

[1336] To the reaction flask were successively added intermediate z9 (200 mg), IBX (373 mg) and DMSO (2 mL). The reaction was carried out at room temperature. After completion of the reaction, it was quenched with saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The extract was concentrated, and intermediate 54c (214 mg), dichloroethane (40 mL), isopropanol (10 mL) and sodium triacetoxyborohydride (353 mg) were added. The reaction was carried out at room temperature. After completion of the reaction, it was quenched with water and extracted with dichloromethane. The extract was concentrated and then purified by column chromatography to obtain intermediate 69a (179 mg).

[1337] MS(ESI,[M + H] +)m / z: 551.32

[1338] 1 H NMR(500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.59–4.52 (m, 1H), 3.52 (d, J = 78.0 Hz, 1H), 3.16 (dq, J = 23.1, 7.7 Hz, 3H), 2.96–2.71 (m, 7H), 2.51 (s, 3H), 2.49–2.43 (m, 1H), 2.40–1.57 (m, 12H), 1.39 (s, 10H), 1.31–1.13 (m, 1H).

[1339] Step 2: Preparation of Compound 69

[1340] With reference to the preparation of Compound 32 in Reference Example 32, Intermediate 69a was replaced with 32b, and Intermediate 33k was replaced with 30m. After the reaction was completed, the reaction solution was purified by column chromatography to obtain Compound 69 (99 mg, without salt formation with maleic acid).

[1341] MS(ESI, [M+H] + )m / z: 1113.44

[1342] 1 H NMR(500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.29 (d, J = 9.7 Hz, 1H), 7.89 (dd, J = 5.8, 2.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.45–7.36 (m, 3H), 7.25 (d, J = 8.2 Hz, 1H), 7.24–7.19 (m, 2H), 6.59 (dd, J = 16.4, 12.6 Hz, 1H), 4.59–4.40 (m, 2H), 3.98–3.80 (m, 8H), 3.44 (d, J = 2.8 Hz, 3H), 3.17 (td, J = 16.9, 16.4, 9.6 Hz, 3H), 2.99–2.73 (m, 9H), 2.60 (dt, J = 17.3, 4.8 Hz, 2H), 2.32 (s, 4H), 2.21–2.15 (m, 2H), 2.00–1.38 (m, 15H), 1.28–1.20 (m, 4H), 0.48 (dd, J = 43.1, 6.7 Hz, 3H).

[1343] Example 70: Synthesis of Compound 70

[1344]

[1345] Step 1: Preparation of Intermediate 70a

[1346] Referring to the method described in Step 13 of Example 30, using Intermediate 2-[(tert-butoxy)carbonyl]-2-azaspiro[3.5]nonane-7-carboxylic acid to replace Intermediate 30n, Intermediate 70a (0.300 g) was synthesized.

[1347] MS(ESI,[M+H] + ) m / z: 888.3

[1348] Step 2: Preparation of Intermediate 71b

[1349] Referring to the method described in Step 11 of Example 30, using Intermediate 70a to replace Intermediate 30l, Intermediate 70b (0.28 g) was synthesized.

[1350] MS(ESI,[M+H] + ) m / z: 788.3

[1351] Step 3: Preparation of Compound 70

[1352] Referring to the method described in Step 12 of Example 30, using Intermediate 70b to replace Intermediate 1h and Intermediate z9 to replace Intermediate z8, Compound 70 (0.16 g) was synthesized.

[1353] MS(ESI,[M+H] + ) m / z: 1070.4

[1354] 11H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.32–8.26 (m, 1H), 7.89 (dd, J = 5.9, 2.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 8.6, 3.8 Hz, 3H), 7.23 (dd, J = 15.3, 7.9 Hz, 3H), 6.58 (t, J = 14.9 Hz, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 4.45 (dt, J = 32.8, 14.0 Hz, 1H), 3.97 (d, J = 1.4 Hz, 3H), 3.90 (d, J = 22.0 Hz, 3H), 3.84 (dd, J = 14.2, 7.0 Hz, 1H), 3.44 (d, J = 2.7 Hz, 3H), 3.12 (d, J = 12.5 Hz, 3H), 3.02–2.89 (m, 3H), 2.76 (ddd, J = 17.1, 12.0, 5.4 Hz, 4H), 2.60 (dt, J = 17.4, 4.3 Hz, 2H), 2.48–2.26 (m, 4H), 2.23–2.10 (m, 2H), 2.02–1.85 (m, 3H), 1.83–1.62 (m, 2H), 1.61–1.34 (m, 7H), 1.31–1.19 (m, 5H), 0.48 (dd, J = 42.2, 6.8 Hz, 3H).

[1355] Example 71: Synthesis of Compound 71

[1356]

[1357] Step 1: Preparation of Intermediate 71a

[1358] Referring to the method described in Step 13 of Example 30, using Intermediate 2-Boc-2-azaspiro[3.3]heptane-6-carboxylic acid instead of Intermediate 30n, Intermediate 71a (0.312 g) was synthesized.

[1359] MS (ESI, [M+H] + ) m / z: 860.3

[1360] Step 2: Preparation of Intermediate 71b

[1361] Referring to the method described in Step 11 of Example 30, using Intermediate 71a instead of Intermediate 30l, Intermediate 71b (0.3 g) was synthesized.

[1362] MS (ESI, [M+H] + ) m / z: 760.3

[1363] Step 3: Preparation of Compound 71

[1364] Referring to the method described in step 12 of Example 30, using intermediate 71b instead of intermediate 1h and intermediate z9 instead of intermediate z8, compound 71 (0.106 g) was synthesized.

[1365] MS(ESI,[M+H]+) m / z: 1042.3807

[1366] 1 H NMR(500 MHz, DMSO) δ 11.07(s, 1H), 8.29(dd, J = 10.0, 3.4 Hz, 1H), 7.87(dt, J = 7.1, 3.0 Hz, 1H), 7.60(d, J = 8.1 Hz, 1H), 7.45–7.38(m, 3H), 7.26–7.17(m, 3H), 6.62(dd, J = 15.0, 10.7 Hz, 1H), 4.56(dd, J = 11.8, 5.0 Hz, 1H), 4.44(t, J = 13.5 Hz, 1H), 3.97(s, 3H), 3.90(d, J = 22.2 Hz, 3H), 3.87–3.79(m, 1H), 3.43(d, J = 2.8 Hz, 3H), 3.19(s, 4H), 3.09(s, 2H), 2.96–2.71(m, 5H), 2.60(dt, J = 17.4, 4.2 Hz, 2H), 2.49–2.35(m, 4H), 2.30(s, 4H), 2.19(s, 2H), 1.94(q, J = 10.5 Hz, 2H), 1.76(d, J = 13.3 Hz, 1H), 1.60(d, J = 14.1 Hz, 1H), 1.42(t, J = 15.1 Hz, 1H), 1.30–1.19(m, 3H), 0.55–0.41(m, 3H).

[1367] Examples 72 and 73: Referring to the method described in Example 71, the following intermediates were used to replace 2-Boc-2-azaspiro[3.3]heptane-6-carboxylic acid respectively to prepare compounds 72 and 73. As shown in Table 1-1.

[1368] Table 1-1

[1369]

[1370]

[1371] Example 74: Preparation of Compound 74

[1372]

[1373] Step 1: Preparation of Intermediate 74a

[1374] 5-Bromo-2,4-dichloropyrimidine (20 g), cesium carbonate (57 g) and isopropanol (150 mL) were successively added to a reaction flask and reacted at room temperature. After the reaction was completed, water and ethyl acetate were added, and the layers were separated. The extract was concentrated and purified by column chromatography to obtain intermediate 74a (22.83 g).

[1375] MS (ESI, [M+H] + ) m / z: 250.95

[1376] Step 2: Preparation of intermediate 74b

[1377] Intermediate 74a (8.75 g), sodium methoxide (3.76 g) and methanol (50 mL) were successively added to a reaction flask and reacted at 60 °C. After the reaction was completed, water and dichloromethane were added, and the layers were separated. The extract was concentrated and purified by column chromatography to obtain intermediate 74b (2.97 g).

[1378] MS (ESI, [M+H] + ) m / z: 247.00

[1379] 1 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 5.33 (hept, J = 6.2 Hz, 1H), 3.88 (s, 3H), 1.35 (d, J = 6.2 Hz, 6H).

[1380] Step 3: Preparation of intermediate 74c

[1381] Referring to the preparation method of intermediate 44b in Example 44, intermediate 74b was used to replace 44a to obtain intermediate 74c (0.85 g).

[1382] MS (ESI, [M+H] + ) m / z: 213.10

[1383] Step 4: Preparation of intermediates 74d and 74e

[1384] Intermediate 74c (372 mg), intermediate 46i (300 mg), bis(triphenylphosphine)palladium dichloride (62 mg), potassium phosphate (563 mg) and DMF (25 mL) were successively added to a reaction flask and reacted at 100 °C. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain intermediate 74d (49 mg) and intermediate 74e (69 mg) successively.

[1385] Intermediate 74d: MS (ESI, [M+H] + ) m / z: 765.29

[1386] Intermediate 74e: MS(ESI, [M+H] + ) m / z: 765.29

[1387] Step 5: Preparation of Compound 74

[1388] Refer to the preparation of Compound 32 in Reference Example 32. Replace 32b with Intermediate 74d and replace 30m (30 mg) with Intermediate 44e. After the reaction is completed, the reaction solution is purified by column chromatography to obtain Compound 74 (23 mg, not salted with maleic acid).

[1389] MS(ESI, [M+H] + ) m / z: 1113.44

[1390] 1 H NMR(500 MHz, DMSO-d6) δ 11.07(s, 1H), 8.26(d, J = 5.5 Hz, 1H), 7.91(d, J = 20.7 Hz, 1H), 7.84(d, J = 9.3 Hz, 1H), 7.61(d, J = 8.0 Hz, 1H), 7.45(dd, J = 8.7, 3.5 Hz, 2H), 7.25(q, J = 10.2 Hz, 3H), 6.29(t, J = 15.2 Hz, 1H), 5.32(p, J = 6.2 Hz, 1H), 4.56(dd, J = 11.9, 5.0 Hz, 1H), 4.47(s, 1H), 3.95(s, 4H), 3.91–3.77(m, 2H), 3.44(s, 3H), 3.24–3.08(m, 3H), 2.94(s, 2H), 2.89–2.64(m, 7H), 2.64–2.57(m, 2H), 2.41(dd, J = 28.4, 15.1 Hz, 2H), 2.30(s, 1H), 2.21–2.15(m, 1H), 2.10–1.93(m, 2H), 1.83(s, 2H), 1.53(d, J = 53.8 Hz, 7H), 1.35–1.29(m, 2H), 1.29–1.25(m, 3H), 1.18(d, J = 6.0 Hz, 3H), 0.47(dd, J = 46.8, 6.8 Hz, 3H).

[1391] Example 75: Preparation of Compound 75

[1392]

[1393] Step 1: Preparation of Compound 75

[1394] Refer to the preparation method of Compound 74 in Step 5 of Reference Example 74. Replace 74d with Intermediate 74e to obtain Compound 75 (23 mg).

[1395] MS(ESI,[M+H] + ) m / z: 1113.44

[1396] 1 H NMR(500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.26 (d, J = 5.4 Hz, 1H), 7.92 (d, J = 13.8 Hz, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.26 (dd, J = 14.2, 8.1 Hz, 3H), 6.30 (d, J = 18.4 Hz, 1H), 5.42 (p, J = 6.2 Hz, 1H), 4.59–4.39 (m, 2H), 3.95 (s, 3H), 3.82 (p, J = 6.9 Hz, 1H), 3.44 (s, 3H), 3.23–3.10 (m, 3H), 3.00–2.70 (m, 9H), 2.64–2.56 (m, 3H), 2.49–2.38 (m, 2H), 2.32 (d, J = 11.3 Hz, 1H), 2.20–2.15 (m, 1H), 1.98 (d, J = 12.8 Hz, 1H), 1.78 (d, J = 31.2 Hz, 3H), 1.58 (s, 4H), 1.32 (d, J = 6.8 Hz, 3H), 1.29–1.20 (m, 10H), 0.43 (d, J = 6.8 Hz, 3H).

[1397] Example 76: Preparation of Compound 76

[1398]

[1399] Step 1: Preparation of Intermediate 76a

[1400] To a reaction flask were successively added 5-bromo-2-chloro-4-isopropoxypyrimidine (17 g), sodium methoxide (7.3 g) and methanol (50 mL), and the reaction was carried out at 60 °C. After the reaction was completed, water and dichloromethane were added, and the layers were separated. The extract was concentrated and purified by column chromatography to obtain Intermediate 76a (1.34 g).

[1401] MS(ESI,[M+H] + ) m / z: 247.00

[1402] 1 H NMR(500 MHz, DMSO-d6) δ 8.47 (s, 1H), 5.15 (hept, J = 6.2 Hz, 1H), 3.97 (s, 3H), 1.32 (d, J = 6.2 Hz, 6H).

[1403] Step 2: Preparation of Intermediate 76b

[1404] Referring to the preparation method of Intermediate 44b in Reference Example 44, replacing 44a with Intermediate 76a, Intermediate 76b (0.85 g) was obtained.

[1405] MS (ESI, [M+H] + ) m / z: 213.10

[1406] 1 H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.81 (s, 2H), 5.22 (p, J = 6.2 Hz, 1H), 3.88 (s, 3H), 1.31 (d, J = 6.1 Hz, 6H).

[1407] Step 3: Preparation of Intermediate 76c

[1408] Referring to the preparation of Intermediates 44c and 44d in Reference Example 44, replacing 44b with Intermediate 74b and 30k with Intermediate 46i, and purifying by column chromatography, Intermediate 76c (184 mg) was obtained.

[1409] MS (ESI, [M+H] + ) m / z: 765.29

[1410] 1 H NMR (500 MHz, DMSO-d6) δ 8.22 (d, J = 20.2 Hz, 1H), 7.90 (ddd, J = 12.5, 4.9, 2.7 Hz, 2H), 7.49–7.43 (m, 2H), 7.29 (q, J = 7.7 Hz, 2H), 6.29 (d, J = 1.5 Hz, 1H), 5.31–5.20 (m, 1H), 4.34 (t, J = 5.0 Hz, 1H), 3.90 (s, 2H), 3.86 (s, 1H), 3.45 (s, 3H), 1.40 (s, 9H), 1.35 (s, 10H), 1.26 (s, 5H), 1.06 (d, J = 7.1 Hz, 3H), 0.46 (dd, J = 46.8, 6.7 Hz, 3H).

[1411] Step 4: Preparation of Compound 76

[1412] Referring to Step 5 of Reference Example 74 for the preparation of Compound 74, replacing 74d with Intermediate 76c, Compound 76 (23 mg) was obtained.

[1413] MS (ESI, [M+H] + ) m / z: 1113.44

[1414] 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.24 (d, J = 20.7 Hz, 1H), 7.94–7.85 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.48–7.42 (m, 2H), 7.29 (t, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 1H), 6.28 (d, J = 18.0 Hz, 1H), 5.26 (h, J = 6.2 Hz, 1H), 4.58–4.41 (m, 2H), 4.03–3.76 (m, 6H), 3.44 (s, 3H), 3.23–3.08 (m, 3H), 2.95–2.71 (m, 8H), 2.60 (dt, J = 17.3, 4.2 Hz, 3H), 2.48–2.32 (m, 3H), 2.20–2.15 (m, 1H), 1.99 (dd, J = 15.0, 11.2 Hz, 1H), 1.81 (s, 3H), 1.64–1.48 (m, 5H), 1.35 (s, 9H), 1.29–1.20 (m, 3H), 0.46 (dd, J = 47.6, 6.7 Hz, 3H).

[1415] Examples 77 - 86: Referring to the reaction in Step 5 or Step 6 of Example 37, compounds 77 - 86 were prepared by replacing 30m with the following intermediates. As shown in Table 1 - 2.

[1416] Table 1 - 2

[1417]

[1418]

[1419]

[1420]

[1421]

[1422] Examples 87, 88: Synthesis of Compounds 87 and 88

[1423]

[1424] Step 1: Preparation of Intermediate 87a

[1425] Referring to the method described in Step 3 of Example 37, Intermediate z1 was replaced with Intermediate z5 to synthesize Intermediate 87a (0.7 g).

[1426] MS (ESI, [M + H] + ) m / z: 482.2

[1427] Step 2: Preparation of intermediates 87b and 88a

[1428] The intermediate 87a was prepared and separated by high pressure (apparatus: YMC high pressure preparative chromatograph; chromatographic column: COSMOSIL Cholester, 20 * 250 mm, 5 μm; mobile phase: water (10 mmol ammonium acetate + 0.1% ammonia water) / acetonitrile), and intermediates 87b (260 mg) and 88a (255 mg) were obtained successively.

[1429] Intermediate 87b: MS (ESI, [M + H] + ) m / z: 482.2

[1430] Intermediate 88a: MS (ESI, [M + H] + ) m / z: 482.2

[1431] Step 3: Preparation of compounds 87 and 88

[1432] Referring to the method described in Step 5 of Example 37, using intermediate 87b instead of intermediate 37e, compound 87 (0.078 g) was synthesized.

[1433] MS (ESI, [M + H] + ) m / z: 1044.3

[1434] 11H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.29 (d, J = 10.4 Hz, 1H), 7.86 (dd, J = 5.8, 2.9 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 8.4, 4.0 Hz, 3H), 7.21 (dd, J = 8.4, 3.5 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.59 (t, J = 12.8 Hz, 1H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.49 (d, J = 14.4 Hz, 1H), 3.96 (d, J = 1.1 Hz, 3H), 3.90 (d, J = 22.1 Hz, 3H), 3.78 (s, 3H), 3.42 (d, J = 2.6 Hz, 3H), 2.95 (s, 3H), 2.76 (dq, J = 17.1, 5.3 Hz, 3H), 2.62 (tt, J = 17.3, 4.2 Hz, 2H), 2.47 (dd, J = 10.6, 6.4 Hz, 2H), 2.26–2.08 (m, 2H), 1.95 (s, 2H), 1.75 (s, 1H), 1.59 (s, 7H), 1.43 (s, 2H), 1.27 (d, J = 7.0 Hz, 2H), 1.24–1.17 (m, 2H), 0.47 (dd, J = 42.4, 6.8 Hz, 3H).

[1435] Referring to the method described in Step 5 of Example 37, using intermediate 88a instead of intermediate 37e, compound 88 (0.106 g) was synthesized.

[1436] MS (ESI, [M+H] + ) m / z: 1044.3 1 1H NMR (500 MHz, DMSO) δ...

Claims

1. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, represents a single bond or a double bond; CLM is selected from a small molecule E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; L is selected from a linking group; R is selected from hydrogen, halogen, CN, or the following groups which are optionally substituted: OH, NH2, -CHO, -COOH, -CONH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 AlkylCOO-, C 1-12 Alkyl OCO-, C 1-12 AlkylCONH-, C 1-12 Alkyl NHCO-, (C 1-12 Alkyl)2NCO-, C 1-12 Alkyl S(O)2NH-, C 1-12 Alkyl NHS(O)2-, (C 1-12 Alkyl)2NS(O)2-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; m is selected from 0, 1, 2, 3, 4 or 5; R 1 and R 2 are each independently selected from an optionally substituted 3-12 membered ring; R 3 is selected from H, halogen, CN, or an optionally substituted group: OH, NH2, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl; Ring K is selected from 5-12 membered heteroaryl or C 6-12 Aryl.

2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the small molecule E3 ubiquitin ligase binding portion of the E3 ubiquitin ligase is selected from a cereblon E3 ubiquitin ligase binding portion, a VHL E3 ubiquitin ligase binding portion, an IAP E3 ubiquitin ligase binding portion, or an MDM2 E3 ubiquitin ligase binding portion.

3. The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein CLM is selected from structural fragments Ic, Ia or Ib: represents a single bond or a double bond; Ring E is selected from the group consisting of: 5-15 5- to 15-membered cycloalkenyl, 5- to 15-membered heterocycloalkenyl, phenyl or 5- to 6-membered heteroaryl; Ring F is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl; Ring G is absent or is selected from imidazolidinyl, pyrrolidinyl, pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or furanyl; Every R 5 or R 6 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl; q' and r are independently selected from 0, 1, 2, 3 or 4; L a and L b are independently selected from a bond, O, S, -CO-, -COO-, or the following groups which are optionally substituted: NH, -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; X is independently selected from C(R d ) or N; X 1 , X 2 , X a1 and X a2 are independently selected from O, S, C(R d )、C(R d )2、N or N(R e ); or, X and X 2 , or X and X a2 Connected to each other to form a 7-12 membered bridged heterocycloalkyl group; R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy; X a , X f , X g , X h and X k are independently selected from C, CH or N; X b , X c , X d and X e Each independently selected from O, S, CH2 or NH; Ring C is selected from 5-20 membered rings; or Ring C is selected from 5-15 membered rings, and the rings include monocyclic, bicyclic or tricyclic structures.

4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring E is selected from the group consisting of: 5-15 5- to 15-membered cycloalkenyl, 5- to 15-membered heterocycloalkenyl, phenyl or 5- to 6-membered heteroaryl; Alternatively, ring E is selected from the group consisting of: 5-12 5- to 12-membered cycloalkenyl, 5- to 12-membered heterocycloalkenyl, phenyl or 5- to 6-membered heteroaryl; Alternatively, ring E is selected from the group consisting of: 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring E is selected from the group consisting of: 5-8 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring E is selected from absent, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring E is selected from absent, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, Ring E is selected from absent, C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl or oxazolyl; Alternatively, Ring E is selected from absent, cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, azaspirocyclooctenyl, azaspirocyclononenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl or dihydrooxazinyl; Optionally, ring F is selected from phenyl or pyridyl; Alternatively, ring F is selected from phenyl; Optionally, ring G is absent or selected from imidazolidinyl, pyrroledione, isoxazolyl or furanyl; Alternatively, ring G is selected from absent, isoxazolyl or furanyl; Optionally, the structural fragment Selected from benzene ring, pyridine, Alternatively, the structure fragment Selected from benzene ring, pyridine, Alternatively, the structure fragment Selected from benzene ring, pyridine, Alternatively, the structure fragment Selected from benzene ring, pyridine, Optionally, each R 5 or R 6 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 5 or R 6 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 5 or R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 3-12 membered heterocycloalkyl; Or, each R 5 or R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylCOC(O)-substituted 3-10 membered heterocycloalkyl; Or, each R 5 or R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 5 or R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 5 or R 6 are independently selected from halogen, -CN, -OH, -NH2 or C 1-4 alkyl; Or, each R 5 or R 6 independently selected from F, Cl, Br, I or C 1-3 alkyl; Or, R 5 is selected from F or methyl; Optionally, L a and L b are independently selected from a bond, O, S, -CO-, -COO-, or the following groups which are optionally substituted: NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a and L b are independently selected from a bond, O, S, -COO-, or the following groups which are optionally substituted: NH, C 1-3 Alkyl, C 1-3 heteroalkyl or -CONH-; Or, L a and L b are independently selected from a bond, NH, O, S, or the following optionally substituted groups: C 1-3 Alkyl or -CONH-; Or, L a and L b are independently selected from a bond, NH, O, or the following groups which are optionally substituted: -CH2- or -CONH-; Or, L a and L b are independently selected from a bond, O, S, -CO-, -COO-, NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a and L b are independently selected from a bond, O, S, -COO-, NH, C 1-3 Alkyl, C 1-3 heteroalkyl or -CONH-; Or, L a and L b are independently selected from a bond, NH, O, S, C 1-3 Alkyl or -CONH-; Or, L a and L b are each independently selected from a bond, NH, O, -CH2- or -CONH-; Optionally, X is independently selected from CH or N; Optionally, X 1 and X 2 are independently selected from O, S, C(R d )、C(R d )2 or N; Or, X 1 and X 2 are independently selected from O, C(R d ) or C(R d )2; Or, X 1 and X 2 Each is independently selected from O, CH or CH2; Optionally, X a1 and X a2 are independently selected from O, S, C(R d )、C(R d )2 or N; Or, X a1 and X a2 Each independently selected from CH or CH2; Or, X 1 , X 2 , X a1 and X a2 are independently selected from O, S, C(R d )、C(R d )2 or N; Or, X 1 , X 2 , X a1 and X a2 Each is independently selected from O, CH or CH2; Or, X and X 2 , or X and X a2 Connected to each other to form a 7-10 membered bridged heterocycloalkyl group; Or, X and X 2 , or X and X a2 Connected to each other to form a 7-9 membered bridged heterocycloalkyl group; Or, X and X 2 , or X and X a2 Connected to each other to form a 7-8 membered bridged heterocycloalkyl group; Optionally, R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H, halogen, CN, hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H or C 1-3 alkyl; Or, R d and R e Selected from H; Optionally, X h and X k are independently selected from C, CH or N; Optionally, X a Selected from N; Optionally, X f Selected from C; Optionally, X g Selected from CH; Optionally, X h and X k are independently selected from CH or N; Or, X a , X f , X h and X k are independently selected from C, CH or N, X g Selected from CH; Or, X a , X h and X k are independently selected from C, CH or N, X f Selected from C, X g Selected from CH; Or, X h and X k are independently selected from CH or N, X a Select from N;X f Selected from C, X g Selected from CH; Optionally, X b and X c Selected from CH2; Optionally, X e Selected from CH2; Optionally, X d is selected from O, S, CH2 or NH; Or, X b and X c Selected from CH2; X e Selected from CH2; X d Selected from NH; Optionally, the structural fragment Selected from and / or, Structure fragment Selected from 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of b Substitute the following groups: C 1-50 Alkyl, C 2-50 Alkenyl or C 1-50 Alkynyl, the C 1-50 Alkyl, C 2-50 Alkenyl or C 1-50 Optionally, one or more methylene groups in the alkynyl group are replaced by a group selected from: -NH-, -N(C 1-12 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-15 Cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, R b Selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -NH(C 1-6 alkyl), or -NH(C 1-6 Alkyl)2; Alternatively, the L is selected from optionally one or more R b Substitute the following groups: C 1-20 Alkyl, C 2-20 Alkenyl or C 2-20 Alkynyl, the C 1-20 Alkyl, C 2-20 Alkenyl or C 2-20 Optionally, one or more methylene groups in the alkynyl group are replaced by a group selected from: -NH-, -N(C 1-12 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-15 Cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; Alternatively, the L is selected from optionally one or more R b Substitute the following groups: C 1-15 Alkyl, C 2-15 Alkenyl or C 2-15 Alkynyl, the C 1-15 Alkyl, C 2-15 Alkenyl or C 2-15 Optionally, one or more methylene groups in the alkynyl group are replaced by a group selected from: -NH-, -N(C 1-12 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-15 Cycloalkyl, C 3-15 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, the L is selected from optionally one or more R b Substitute the following groups: C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, the C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Optionally, one or more methylene groups in the alkynyl group are replaced by a group selected from: -NH-, -N(C 1-10 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, the L is selected from optionally one or more R b Substitute the following groups: C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Optionally, one or more methylene groups in the alkynyl group are replaced by a group selected from: -NH-, -N(C 1-6 alkyl)-, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkenyl; Alternatively, the L is selected from optionally one or more R b Substituted C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by one or more methylene groups selected from the group consisting of: -NH-, -O-, -S-, -C(O)-, C 3-10 Cycloalkyl or 3-12 membered heterocycloalkyl; Alternatively, the L is selected from optionally one or more R b Substituted C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by one or more methylene groups selected from the group consisting of: -NH-, -C(O)-, C 4-9 Cycloalkyl or 4-11 membered heterocycloalkyl; Optionally, the L is selected from -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -L 8 -; in, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; R 11 Select from H or C 1-12 alkyl; Each R a2 Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 alkyl)NH-, or (C 1-6 Alkyl)2NH-; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, C6 aryl or 5-8 membered heteroaryl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl or 3-12 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl or 3-12 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-11 Cycloalkyl, C 3-11 Cycloalkenyl, 3-11 membered heterocycloalkenyl or 3-11 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, -C(O)N(R 11 )-, -C(O)O-, or optionally one or more R a2 Substituted with the following groups: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Cycloalkyl, C 3-11 Cycloalkenyl, 3-10 membered heterocycloalkenyl or 3-12 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-, -C(O)-, -O-, -S-, or optionally one or more R a2 Substituted with the following groups: C 1-6 Alkyl, C 3-12 Cycloalkyl, 5-10 membered heterocycloalkenyl or 4-12 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from the group consisting of absence, -N(R 11 )-、-C(O)-、-O-、-S-、C 1-6 Alkyl, C 3-12 Cycloalkyl, 5-10 membered heterocycloalkenyl or 4-12 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, -O-, -S-, C 1-4 Alkyl, C 3-9 Cycloalkyl, 5-6 membered heterocycloalkenyl or 4-12 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2-, C 4-6 Cycloalkyl, C9 cycloalkyl, 6-membered heterocycloalkenyl, 4-9-membered or 11-membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 is independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2-, or 4-12 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 independently selected from independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2-, or 4-10 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 is independently selected from absent, -NH-, -C(O)-, -O-, -CH2-, -CH2CH2-, or 4-6 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are independently selected from absent, -NH-, -C(O)-, O, -CH2-, -CH2CH2-, C 4-6 Cycloalkyl, or 4-6 membered heterocycloalkyl; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are independently selected from absent, -CH2-, C 4-6 Cycloalkyl, or 4-6 membered heterocycloalkyl containing 1 or 2 nitrogen atoms; Alternatively, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 is independently selected from absent, -NH-, -N(CH3)-, -C(O)-, -S-, -O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, monoazabicyclohexane, diazaspironanyl, monoazabicyclononanyl, spironanyl, monoazaspironanyl, diazaspirononanyl, monoazaspironundecyl, monoazaspironundecyl, monoazaspiroheptyl, diazabicyclooctanyl, octahydrocyclopentapyrrolyl, tetrahydropyridinyl or monoazaspirooctane; Optionally, R 11 Select from H or C 1-10 alkyl; Or, R 11 Select from H or C 1-6 alkyl; Or, R 11 Select from H or C 1-4 alkyl; Or, R 11 Select from H or C 1-3 alkyl; Or, R 11 is selected from H, methyl or ethyl; and / or, Each R b Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -NH(C 1-3 alkyl), or -NH(C 1-3 Alkyl)2; Or, each R b Each independently selected from halogen, =O, -OH, -NH2 or -CN; and / or, Each R a2 Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -NH(C 1-3 alkyl), or -NH(C 1-3 Alkyl)2; Or, each R a2 Each is independently selected from halogen, =O, -OH, -NH2 or -CN; Optionally, L is selected from a bond, -Cy 1 -, -LNK 1 -, -Cy 1 -LNK 1 -, -Cy 1 -Cy 2 -, -Cy 1 -LNK 1 -Cy 2 -, -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -Cy 3 -, -Cy 1 -LNK 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -Cy 3 -LNK 1 -, -Cy 1 -Cy 2 -LNK 1 -Cy 3 -, -Cy 1 -Cy 2 -Cy 3 -Cy 4 -, -LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -, -LNK 1 -Cy 1 -LNK 2 -Cy 2 -Cy 3 -, -LNK 1 -Cy 1 -Cy 2 -LNK 2 -Cy 3 -, -LNK 1 -Cy 1 -Cy 2 -Cy 3 -LNK 2 -, -Cy 1 -LNK 1 -Cy 2 -LNK 2 -Cy 3 -or-LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -,in, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-15 Cycloalkyl, C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkenyl, 3-15 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl; LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 1-12 heteroalkyl; Each R ba and R bb Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 alkyl)NH-, or (C 1-6 Alkyl)2NH-; Optionally, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, C6 aryl or 5-8 membered heteroaryl; Alternatively, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; Alternatively, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl or 3-12 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-11 Cycloalkyl, C 3-11 Cycloalkenyl, 3-11 membered heterocycloalkenyl or 3-11 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from optionally one or more R ba Substituted with the following groups: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkenyl or 3-12 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 Independently selected from C 3-12 Cycloalkyl, 5-10 membered heterocycloalkenyl or 4-12 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 Independently selected from C 4-12 Cycloalkyl, 5-10 membered heterocycloalkenyl or 4-12 membered heterocycloalkyl; Alternatively, the Cy 1 , Cy 2 , Cy 3 or Cy 4 Independently selected from C 4-9 Cycloalkyl, 5-6 membered heterocycloalkenyl or 4-12 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 Independently selected from C 4-6 Cycloalkyl, C9 cycloalkyl, 6-membered heterocycloalkenyl, 4-9-membered or 11-membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 Independently selected from 3-12 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 Independently selected from 4-10 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 Independently selected from 4-6 membered heterocycloalkyl; Or, Cy 1 , Cy 2 , Cy 3 or Cy 4 independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, diazaspironanyl, monoazabicyclononanyl, spironanyl, monoazaspironanyl, diazaspiroundecyl, monoazaspiroundecyl, monoazaspiroheptane, diazabicyclooctanyl, octahydrocyclopentapyrrolyl, tetrahydropyridinyl or monoazaspirooctane; Optionally, the LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 heteroalkyl; Alternatively, the LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-8 heteroalkyl; Alternatively, the LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 heteroalkyl; Alternatively, the LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-6 Alkyl or C 1-6 heteroalkyl; Alternatively, the LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-6 Alkyl or C 1-6 Heteroalkyl, C 1-6 The heteroatom of the heteroalkyl group is selected from N, O or S; Alternatively, the LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-4 Alkyl or C 1-4 Heteroalkyl, C 1-4 The heteroatom of the heteroalkyl group is selected from N, O or S; Alternatively, the LNK 1 、LNK 2 and LNK 3 are independently selected from optionally one or more R bb Substituted with the following groups: -NH-, -S-, -O-, C 1-2 Alkyl or C 1-2 Heteroalkyl, C 1-4 The heteroatom of the heteroalkyl group is selected from N or O; Alternatively, the LNK 1 、LNK 2 and LNK 3 Each is independently selected from -NH-, -S-, -O-, C(O), -NHCH2-, -CH2NHCH2-, -(CH2)2O-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- or -C(O)CH2-; Alternatively, the LNK 1 、LNK 2 and LNK 3 Each independently selected from -NH-, -S-, -O-, C(O), -CH2-, -CH2CH2-, -NHCH2-, -CH2NHCH2-, -(CH2)2O- or -C(O)CH2-; Optionally, each R ba and R bb Each is independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, (C 1-4 alkyl)NH-, or (C 1-4 Alkyl)2NH-; Or, each R ba and R bb Each is independently selected from halogen, =O, -OH, -NH2 or -CN; Or, each R ba and R bb Each is independently selected from =O.

6. The compound according to any one of claims 1 to 19, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen, or, optionally substituted by: halogen, OH, NH2, CN, -CHO, -COOH, -CONH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 AlkylCOO-, C 1-12 Alkyl OCO-, C 1-12 AlkylCONH-, C 1-12 Alkyl NHCO-, (C 1-12 Alkyl)2NCO-, C 1-12 Alkyl S(O)2NH-, C 1-12 Alkyl NHS(O)2-, (C 1-12 Alkyl)2NS(O)2-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted, the following groups: C 1-12 Alkyl, C 2-12 alkenyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted by one or more R'', halogen, OH, NH2, CN, -CHO, -COOH, -CONH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 AlkylCOO-, C 1-12 Alkyl OCO-, C 1-12 AlkylCONH-, C 1-12 Alkyl NHCO-, (C 1-12 Alkyl)2NCO-, C 1-12 Alkyl S(O)2NH-, C 1-12 Alkyl NHS(O)2-, (C 1-12 Alkyl)2NS(O)2-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 Aryl or 5-12 membered heteroaryl, wherein Optionally, R'' is selected from halogen, OH, NH2, CN, =O, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, -C(O)H, -C(O)OH, -C(O)NH2, -C(O)OC 1-10 Alkyl, -OC(O)C 1-10 Alkyl, -C(O)NHC 1-10 Alkyl, -C(O)N(C 1-10 Alkyl)2, -NHC(O)C 1-10 Alkyl, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, -C(O)NHC 1-10 Alkyl, -C(O)N(C 1-10 Alkyl)2, -NHC(O)C 1-10 Alkyl, C 3-10 The 3- to 10-membered cycloalkyl or heterocycloalkyl is optionally substituted by one or more of the following groups: halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, -C(O)OR c 、-OC(O)R c 、-C(O)NHR c 、-NHC(O)R c 、-S(O)NHR c 、-NHS(O)R c 、-S(O)2NHR c or -NHS(O)2R c , R c Selected from hydrogen or C 1-10 alkyl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R"', the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R"', the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-8 Aryl or 5-8 membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R"', the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R"', the following groups: C 1-6 Alkyl, C 2-6 alkenyl, 5-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R"', the following groups: C 1-4 Alkyl, C 2-4 alkenyl, 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, C6 aryl or 6-membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R"', the following groups: C 2-3 Alkyl, C 2-3 alkenyl, 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, C6 aryl or 6-membered heteroaryl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R'', ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl, pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl; Alternatively, R is selected from hydrogen, or, optionally substituted with one or more R'', ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl or pyrimidinyl; Alternatively, R is selected from hydrogen, Optionally, R'' is selected from halogen, OH, NH2, CN, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, -C(O)OH, -C(O)NH2, -C(O)NHC 1-10 Alkyl, -C(O)N(C 1-10 alkyl) 2 or 3-10 membered heterocycloalkyl, the C 1-10 The alkyl or 3-10 membered heterocycloalkyl group is optionally substituted by one or more of the following groups: OH, C 1-6 Alkyl, -NHC(O)R c or -C(O)NHR c ; Alternatively, R'' is selected from halogen, OH, NH2, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, -C(O)OH, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 alkyl) 2 or 3-6 membered heterocycloalkyl, the C 1-6 The alkyl or 3-6 membered heterocycloalkyl group is optionally substituted by one or more of the following groups: OH, C 1-4 Alkyl, -NHC(O)R c or -C(O)NHR c ; Alternatively, R'' is selected from halogen, OH, NH2, CN, =O, C 1-3 Alkyl, C 1-3 Alkoxy, (C 1-3 Alkyl)2N-, -C(O)OH, -C(O)NH2, -C(O)NHC 1-3 Alkyl, -C(O)N(C 1-3 alkyl) 2 or 5-6 membered heterocycloalkyl, the C 1-3 The alkyl or 5-6 membered heterocycloalkyl group is optionally substituted by one or more of the following groups: OH, C 1-3 Alkyl, -NHC(O)R c or -C(O)NHR c ; Alternatively, R"' is selected from OH, CN, =O, methyl, methoxy, isopropyl O-, (CH3)2N-, -C(O)OH, -C(O)NH2, piperazinyl, -C(O)N(CH3)2 or -C(O)NHCH3, wherein the methyl or piperidinyl is optionally substituted with one or more of the following groups: OH, methyl, -NHC(O)H, -NHC(O)CH3 or -C(O)NHCH3 Alternatively, R'' is selected from OH, CN, methyl, methoxy, (CH3)2N-, -C(O)N(CH3)2, -C(O)NHCH3, -CH2NHC(O)H, -CH2NHC(O)CH3, -CH2C(O)NHCH3, -C(O)OH, -C(O)NH2, =O, -CH2OH or -OCH(CH3)2; Among them, R c Selected from hydrogen or C 1-6 alkyl; Or, R c Selected from hydrogen or C 1-3 alkyl; Or, R c is selected from hydrogen or methyl; Optionally, R 1 is selected from the following optionally substituted groups: C 6-12 Aryl, 5-12 membered heterocyclyl or 5-12 membered heteroaryl; Or, R 1 is selected from the following groups optionally substituted by one or more R': C 6-12 aryl, 5-12 membered heterocyclic group or 5-12 membered heteroaryl, wherein R' is selected from halogen, OH, NH2, CN, =O, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl NH- or (C 1-12 Alkyl)2N-; Or, R 1 is selected from the following groups optionally substituted by one or more R': C 6-10 Aryl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl; Or, R 1 is selected from the following groups optionally substituted by one or more R': C6 aryl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Or, R 1 is selected from the following groups optionally substituted by one or more R': C6 aryl, 6-membered heterocyclyl or 6-membered heteroaryl; Or, R 1 is selected from the following groups optionally substituted by one or more R': phenyl or a 6-membered N-containing heterocyclic group; Or, R 1 is selected from the following groups optionally substituted by one or more R': phenyl or 6-membered N-containing heterocyclic alkenyl; Or, R 1 is selected from the following groups optionally substituted with one or more R': phenyl or dihydropyridinyl; R 1 Selected from Wherein, said R' is selected from halogen, OH, NH2, CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-; Alternatively, R' is selected from halogen, OH, NH2, CN, =O, C 1-6 Alkyl or C 2-6 Alkenyl, C 2-6 Alkynyl; Alternatively, R' is selected from halogen (eg, fluorine, chlorine, bromine or iodine), OH, NH2, CN, =O or C 1-6 alkyl; Alternatively, R' is selected from fluorine, chlorine, bromine, iodine, =O or C 1-3 alkyl; Alternatively, R' is selected from chlorine, =O or methyl; Optionally, R 2 Selected from the following groups which are optionally substituted: 5-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl; Or, R 2 Selected from the following groups optionally substituted by one or more R": 5-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, wherein R" is selected from halogen, OH, NH2, CN, =O, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl NH- or (C 1-12 Alkyl)2N-; Or, R 2 Selected from the following groups optionally substituted by one or more R": 5-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl; Or, R 2 is selected from the following groups optionally substituted by one or more R": 5-6 membered heterocyclyl, C6 aryl or 5-6 membered heteroaryl; Or, R 2 is selected from the following groups optionally substituted by one or more R": C6 aryl or 6-membered heteroaryl; Or, R 2 is selected from phenyl optionally substituted with one or more R"; Wherein, R" is selected from halogen, OH, NH2, CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-; Alternatively, R" is selected from halogen, OH, NH2, CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Alternatively, R" is selected from halogen, OH, NH2, CN, =O or C 1-6 alkyl; Alternatively, R" is selected from fluorine, chlorine, bromine, iodine, CN or C 1-3 alkyl; Alternatively, R" is selected from fluorine, chlorine, CN or methyl; Optionally, R 3 Selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Or, R 3 Selected from H, halogen, OH, NH2, CN or C 1-3 alkyl; Or, R 3 Select from H or C 1-3 alkyl; Optionally, ring K is selected from 5-10 membered heteroaryl or C 6-10 Aryl; Alternatively, ring K is selected from 5-6 membered heteroaryl or C6 aryl; Alternatively, ring K is selected from 5-6 membered heteroaryl; Alternatively, ring K is selected from 5-membered heteroaryl; Alternatively, ring K is selected from a 5-membered N-containing heteroaryl group; Alternatively, ring K is selected from pyrrolyl, imidazolyl or pyrazolyl; Optionally, the structural fragment Selected from Alternatively, the structure fragment Selected from Where T 1 、T 2 and T 3 are independently selected from CH, N, O, S or NH; Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Alternatively, the structure fragment Selected from Among them, R f is selected from hydrogen, or, optionally substituted by one or more R"'s: C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Or, R f is selected from the following groups optionally substituted by one or more R'': C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl; Or, R f is selected from C optionally substituted by one or more selected from halogen, OH, NH2 or CN 1-4 alkyl; Or, R f is selected from C optionally substituted by one or more OH 2-3 alkyl; Among them, R g is selected from hydrogen, or, optionally substituted by one or more R"'s: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; Or, R g is selected from hydrogen, or, optionally substituted by one or more R"'s: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-8 Aryl or 5-8 membered heteroaryl; Or, R g is selected from hydrogen, or, optionally substituted by one or more R"'s: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl; Or, R g is selected from hydrogen, or, optionally substituted by one or more R"'s: C 1-6 Alkyl, C 2-6 alkenyl, 5-6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl; Or, R g is selected from hydrogen, or, optionally substituted by one or more R"'s: C 1-4 Alkyl, C 2-4 alkenyl, 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, C6 aryl or 6-membered heteroaryl; Or, R g is selected from hydrogen, or, optionally substituted by one or more R"'s: C 2-3 Alkyl, C 2-3 alkenyl, 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, C6 aryl or 6-membered heteroaryl; Or, R g is selected from hydrogen or, optionally substituted by one or more R'', ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl, pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl; Or, R g is selected from hydrogen or, optionally substituted with one or more R''', ethyl, isopropyl, propenyl, piperidinyl, dihydropyridinyl, phenyl or pyrimidinyl.

7. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from Formula IIA, Formula IIB, Formula IIIA, Formula IIIB, Formula IVA, Formula IVB, Formula VA, Formula VB, Formula VI, Formula VII, Formula VIII, Formula VIII-1, Formula VIII-2, Formula VIII-3, its stereoisomer or a pharmaceutically acceptable salt thereof in, X 5 is selected from N or CH; Ring A and Ring B are each independently selected from an optionally substituted 3-12 membered ring; j and t are independently selected from 0, 1, 2, 3, 4 or 5; Optionally, Ring A is selected from C 6-12 Aryl, 5-12 membered heterocyclyl or 5-12 membered heteroaryl; Alternatively, ring A is selected from C 6-10 Aryl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl; Alternatively, Ring A is selected from C6 aryl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Alternatively, Ring A is selected from C6 aryl, 6-membered heterocyclyl or 6-membered heteroaryl; Alternatively, ring A is selected from phenyl or a 6-membered N-containing heterocyclic group; Alternatively, ring A is selected from phenyl or dihydropyridinyl; Alternatively, ring A is selected from phenyl or 6-membered N-containing heterocyclic alkenyl; and / or, Ring B is selected from 5-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Alternatively, ring B is selected from a 5-10 membered heterocyclic group, a C 6-10 Aryl or 5-10 membered heteroaryl; Alternatively, Ring B is selected from a 5-6 membered heterocyclyl, a C6 aryl or a 5-6 membered heteroaryl; Alternatively, Ring B is selected from C6 aryl or 6-membered heteroaryl; Alternatively, Ring B is selected from phenyl.

8. The following compound, its stereoisomer or its pharmaceutically acceptable salt:

9. A compound of formula II'-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Ring E, Ring F, Ring G, R 5 ,q',X,L a , X 1 , X 2 The definitions are as described in any one of claims 1 to 8; L is selected from a linking group; The PTM is selected from a target protein molecule; or, A compound of formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9 or II-10, a portion thereof, a stereoisomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof: in, represents a single bond or a double bond; Ring E is selected from C 5-15 5- to 15-membered cycloalkenyl, 5- to 15-membered heterocycloalkenyl or 5- to 6-membered heteroaryl; Ring F is selected from a benzene ring group, a pyridine ring group, a pyridazine ring group or a pyrazine ring group; Every R 5 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl; q' is selected from 0, 1, 2, 3 or 4; X is independently selected from C(R d ) or N; L a is selected from O, S, -CO-, -COO-, or the following groups which are optionally substituted: NH, -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; X 1 and X 2 are independently selected from O, S, C(R d )、C(R d )2、N or N(R e ); Or, X and X 2 Connected to each other to form a 7-12 membered bridged heterocycloalkyl group; L aa is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group: NH, -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; X b1 and X b2 One of the following is selected from C(R d ) or C(R d )2, the other one is selected from O, S, N or N(R e ); X 11 and X 22 Each independently selected from C(R d ) or N; R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy; Optionally, ring E is selected from C 5-12 5- to 12-membered cycloalkenyl, 5- to 12-membered heterocycloalkenyl or 5- to 6-membered heteroaryl; Alternatively, ring E is selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl or 5-6 membered heteroaryl; Alternatively, ring E is selected from C 5-8 Cycloalkenyl, 5-10 membered heterocycloalkenyl or 5-6 membered heteroaryl; Alternatively, ring E is selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl or 5-6 membered heteroaryl; Alternatively, ring E is selected from the group consisting of: 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, Ring E is selected from absent, C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocycloalkenyl, pyrrolyl, pyrazolyl, furanyl or oxazolyl; Alternatively, Ring E is selected from absent, cyclopentenyl, monocyclohexenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, azaspirocyclooctenyl, azaspirocyclononenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl or dihydrooxazinyl; Alternatively, ring E is selected from C 5-12 5- to 12-membered cycloalkenyl or 5- to 12-membered heterocycloalkenyl; Optionally, ring F is selected from a benzene ring group; Optionally, each R 5 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 3-12 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylCOC(O)-substituted 3-10 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 5 independently selected from halogen, -CN, -OH or -NH2; Optionally, q' is selected from 0, 1 or 2; Optionally, X is independently selected from C(R d ); Alternatively, X is independently selected from N; Alternatively, X is independently selected from CH or N; Optionally, where L a is selected from O, S, -CO-, -COO-, or the following groups which are optionally substituted: NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a Selected from O, S, -CO-, -COO-, NH, -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a Selected from O, S, -CO-, -COO-, NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a Selected from NH, O, S, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH- or -COO-; Or, L a Selected from NH, O, S, C 1-3 Alkyl or -CONH-; Or, L a is selected from NH, O, -CH2- or -CONH-; Optionally, where X 1 and X 2 are independently selected from O, S, C(R d )、C(R d )2 or N; Or, X 1 and X 2 are independently selected from O, C(R d ) or C(R d )2; Or, X 1 and X 2 Each is independently selected from O, CH or CH2; Or, X and X 2 Connected to each other to form a 7-10 membered bridged heterocycloalkyl group; Or, X and X 2 Connected to each other to form a 7-9 membered bridged heterocycloalkyl group; Or, X and X 2 Connected to each other to form a 7-8 membered bridged heterocycloalkyl group; Optionally, where L aa is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group: NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L aa Selected from bond, O, S, -CO-, -COO-, NH, -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L aa Selected from bond, O, S, -CO-, -COO-, NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L aa Selected from bond, NH, O, S, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, or -COO-; Or, L aa Selected from bond, NH, O, S, C 1-3 Alkyl or -CONH-; Or, L aa self-bond, NH, O, -CH2- or -CONH-; Optionally, where X b1 and X b2 One of the following is selected from C(R d )2, the other one is selected from O, S, N or N(R e ); Or, X b1 and X b2 One of them is selected from CH2, and the other is selected from O, S or NH; Or, X b1 and X b2 One of them is selected from CH2, and the other is selected from O; Optionally, X 11 and X 22 Selected from C(R d ); or, X 11 and X 22 Each independently selected from CH; Optionally, wherein R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H, halogen, CN, hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy; Or, R d and R e are independently selected from H, halogen, CN, hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H or C 1-3 Alkyl; or, R d and R e Selected from H; or A compound of formula II-1B, II-2B, II-3B, II-4B, II-5B, II-6B, II-7B, II-8B, II-9B or II-10B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: L is selected from a linking group; The PTM is selected from a target protein molecule; or, A compound of formula III-1, a moiety, a stereoisomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof: in, represents a single bond or a double bond; Ring E is selected from C 5-15 5- to 15-membered cycloalkenyl or 5- to 15-membered heterocycloalkenyl; Ring F is selected from a benzene ring group, a pyridine ring group, a pyridazine ring group or a pyrazine ring group; X 3 is selected from CH or N; Every R 5 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl; q' is selected from 0, 1, 2, 3 or 4; X is independently selected from C(R d ) or N; L a is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group: NH, -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; X 1 and X 2 are independently selected from O, S, C(R d )、C(R d )2、N or N(R e ); Or, X and X 2 Connected to each other to form a 7-12 membered bridged heterocycloalkyl group; R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy; Optionally, ring E is selected from C 5-12 5- to 12-membered cycloalkenyl or 5- to 12-membered heterocycloalkenyl; Alternatively, ring E is selected from C 5-6 Cycloalkenyl or 5-9 membered heterocycloalkenyl; Alternatively, Ring E is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocycloalkenyl; Alternatively, ring E is selected from C 5-9 Cycloalkenyl; or, Ring A is selected from C 5-6 Cycloalkenyl; or, Ring E is selected from 5-9 membered heterocycloalkenyl; Alternatively, ring E is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, azaspirocyclononenyl or azaspirocyclooctenyl; Optionally, ring F is selected from a benzene ring group; Optionally, X 3 is selected from CH; optionally, X 3 Selected from N; Optionally, each R 5 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 3-12 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylCOC(O)-substituted 3-10 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 5 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 5 independently selected from halogen, -CN, -OH or -NH2; Optionally, q is selected from 0, 1 or 2; or, q is selected from 0 or 1; Optionally, X is independently selected from C(R d ); or, X is independently selected from N; Alternatively, X is independently selected from CH or N; Optionally, X 1 and X 2 are independently selected from O, S, C(R d )、C(R d )2 or N; Or, X 1 and X 2 are independently selected from O, C(R d ) or C(R d )2; Or, X 1 and X 2 Each is independently selected from O, CH or CH2; Or, X and X 2 Connected to each other to form a 7-10 membered bridged heterocycloalkyl group; Or, X and X 2 Connected to each other to form a 7-9 membered bridged heterocycloalkyl group; Or, X and X 2 Connected to each other to form a 7-8 membered bridged heterocycloalkyl group; Optionally, L a is selected from a bond, O, S, -CO-, -COO-, or an optionally substituted group: NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a Selected from bond, O, S, -CO-, -COO-, NH, -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a Selected from bond, O, S, -CO-, -COO-, NH, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L a Selected from bond, NH, O, S, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH- or -COO-; Or, L a Selected from bond, NH, O, S, C 1-3 Alkyl or -CONH-; Or, L a is selected from a bond, NH, O, -CH2- or -CONH-; Optionally, R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H, halogen, CN, hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy; Or, R d and R e are independently selected from H, halogen, CN, hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H or C 1-3 Alkyl; or, R d and R e Selected from H; or The compound of formula III-1B, its stereoisomer, or its pharmaceutically acceptable salt: L is selected from a linking group; The PTM is selected from a target protein molecule; or, A compound of formula IV-1, a moiety, a stereoisomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof: represents a single bond or a double bond; Every R 6 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl; r is selected from 0, 1, 2, 3 or 4; L b is selected from a bond, S, -CO-, -COO-, or an optionally substituted group: -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; X is independently selected from C(R d ) or N; X a1 and X a2 are independently selected from O, S, C(R d )、C(R d )2、N or N(R e ); Or, X and X a2 Connected to each other to form a 7-12 membered bridged heterocycloalkyl group; R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy; X h and X k are independently selected from CH or N; X b , X c and X e Each independently selected from O, S, CH2 or NH; Optionally, each R 6 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 6 independently selected from halogen, -CN, or optionally substituted: -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl OC(O)-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-6 Alkyl-OH, C 1-6 Alkyl OC(O)-, or optionally C 1-6 AlkylCOC(O)-substituted 3-12 membered heterocycloalkyl; Or, each R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, =O, -OH, -NH2, -CN, CHO, COOH, -C 1-4 Alkyl-OH, C 1-4 Alkyl OC(O)-, or optionally C 1-4 AlkylCOC(O)-substituted 3-10 membered heterocycloalkyl; Or, each R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl OC(O)-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; Or, each R 6 independently selected from halogen, -CN, -OH, -NH2, -CHO, C 1-4 Alkyl or C 1-4 Alkoxy; Or, each R 5 or R 6 independently selected from halogen, -CN, -OH or -NH2; Optionally, r is selected from 0, 1 or 2; Optionally, L b is selected from a bond, S, -CO-, -COO-, or an optionally substituted group: -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L b is selected from a bond, S, -CO-, -COO-, or an optionally substituted group: -N(C 1-6 Alkyl)-, C 1-6 Alkyl, C 1-6 heteroalkyl, -CONH-, -SONH-, or -S(O)2NH-; Or, L b Selected from bond, S, -CO-, -COO-, -N(C 1-3 Alkyl)-, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, -SONH- or -S(O)2NH-; or, L b Select from bond, S, C 1-3 Alkyl, C 1-3 heteroalkyl, -CONH-, or -COO-; Or, L b Select from bond, S, C 1-3 Alkyl or -CONH-; Optionally, X is independently selected from C(R d ); Alternatively, X is independently selected from N; Alternatively, X is independently selected from CH or N; Optionally, X a1 and X a2 are independently selected from O, S, C(R d )、C(R d )2 or N; Or, X a1 and X a2 are independently selected from O, C(R d )、C(R d )2 or N; Or, X a1 and X a2 are independently selected from O, C(R d ) or C(R d )2; Or, X a1 and X a2 Each is independently selected from O, CH or CH2; Or, X and X a2 Connected to each other to form a 7-10 membered bridged heterocycloalkyl group; Or, X and X a2 Connected to each other to form a 7-9 membered bridged heterocycloalkyl group; Or, X and X a2 Connected to each other to form a 7-8 membered bridged heterocycloalkyl group; Optionally, R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H, halogen, CN, or the following groups which are optionally substituted: hydroxyl, NH2, C 1-6 Alkyl or C 1-6 Alkoxy; Or, R d and R e are independently selected from H, halogen, CN, hydroxyl, NH2, C 1-3 Alkyl or C 1-3 Alkoxy; Or, R d and R e are independently selected from H or C 1-3 alkyl; Optionally, X b and X c Selected from CH2; Or, X e Selected from CH2; or, A compound of formula IV-1B, a stereoisomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof: in, L is selected from a linking group; The PTM is selected from a target protein molecule.

10. The compound, part, isomer, derivative or pharmaceutically acceptable salt of claim 9 can be used to bind and / or inhibit cerebellin; or, use in Protac molecules.

11. A pharmaceutical composition comprising the compound, moiety, isomer, derivative, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.

12. Use of the compound, portion, isomer, derivative, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

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