Compounds comprising a spirocyclic structure

Abstract

The present application belongs to the field of medicine, and relates to a compound containing a spiro ring structure, a preparation method of the compound, a pharmaceutical composition containing the compound, and use of the compound in treating related diseases (for example, inflammatory diseases).

Description

Technical Field

[0001] This application relates to compounds comprising a spirocyclic structure, methods for their preparation, pharmaceutical compositions containing the compound, and their use in treating related diseases (such as inflammatory diseases). Background Technology

[0002] STAT6 is a transcription factor responsible for intracellular signal transduction of IL-4 and IL-13. When IL-4 and IL-13 bind to receptors on the cell membrane, the IL-4Rα subunit, shared by these two cytokine receptors, is phosphorylated. STAT6 then binds to phosphorylated IL-4Rα, and STAT6 is phosphorylated. Phosphorylated STAT6 forms a dimer and migrates to the nucleus, where it acts as a transcription factor to promote the expression of various genes. Therefore, STAT6 plays a crucial role in intracellular signal transduction of IL-4 and IL-13, and it is anticipated that activation of STAT6 and inhibition of its function will lead to the treatment of inflammatory and allergic diseases related to IL-4 and IL-13. STAT6 inhibitors, which inhibit STAT6 activation and function, are extremely useful as preventative or therapeutic agents for various IL-4 and IL-13-related conditions.

[0003] PROTAC (proteolysis targeting chimera) molecules are bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds induce the target protein to be recognized by the cell's proteasome, causing its degradation and effectively reducing its concentration in cells. By introducing ligands that bind to different target proteins into PROTAC molecules, the application of PROTAC technology to the treatment of various diseases has become possible, and this technology has received widespread attention in recent years. There is a need to develop novel PROTAC drugs for the treatment of STAT6-related diseases. Invention Details

[0005] On the one hand, this application relates to compounds of formula II, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0006] in, L a It does not exist or is selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 Imyethynyl, When L a No, ring E is selected from 7-15 membered heterospirocycloalkyl or 7-15 membered heterospirocycloalkenyl; When L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The acetylenic group, the R L Selected from hydrogen, deuterium, halogens, -CN, C 1-10 Alkyl or C 1-10 Heteroalkyl, with ring E selected from C 3-15 Cycloalkyl, 4-15 membered heterocyclic alkyl, C 3-15 Cycloalkenyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl or 5-15 heteroaryl groups; Each R 2 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, =O, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl; R 3 Selected from the following groups optionally substituted with one or more R': C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 Alkyl-N=, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-; R u Selected from H, -OH or C 1-12 alkyl; R v Selected independently from C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-, the C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 Alkyl groups are optionally substituted with one or more deuterium, halogen, -OH, -NH2, or -CN; Ring F is selected from C 6-12 Aryl or 5-12 heteroaryl groups; R 4 Selected from H, or optionally substituted with one or more R'' groups: R s C(O)-, R s C(O)O-、R s OC(O)-, R s S(O)-、R s S(O)2-、R s R t NC(O)-, R s C(O)NR t -、R sS(O)2NR t -or R s R t NS(O)2-; R t Each independently selected from H or C 1-12 alkyl; R s Selected independently from C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 The aryl or 5-12 heteroaryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-; Each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. dThe following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 4-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 4-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-; R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, -CHO, -COOH, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 3-12 The cycloalkyl or 3-12-membered heterocycloalkyl group is optionally substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2 or -CHO; j and k are independently selected from 0, 1, 2, 3, or 4; CLM is selected from the E3 ubiquitin ligase binding region; L is selected from the linking group.

[0007] In some embodiments, the E3 ubiquitin ligase-binding moiety is selected from the cereblon E3 ubiquitin ligase-binding moiety, the VHL E3 ubiquitin ligase-binding moiety, the IAP E3 ubiquitin ligase-binding moiety, or the MDM2 E3 ubiquitin ligase-binding moiety.

[0008] In some implementations, the CLM is selected from small molecule compounds.

[0009] In some implementations, the CLM is covalently linked to the L.

[0010] In some embodiments, the compound of formula II, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula II-A or II-B, their stereoisomers, or pharmaceutically acceptable salts thereof. or , Among them, CLM, L, ring E, L a R 2 R 3 Ring F, R 4 R 5 The definitions of j and k are as described in this application.

[0011] In some implementations, each R 2 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, =O, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl S-, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0012] In some implementations, each R 2 Each is independently selected from deuterium, halogens (e.g., -F, -Cl, -Br or -I), -OH, -NH2, -CN, -NO2, =O or C. 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl, or cyclopropyl).

[0013] In some implementations, each R 2 Each can be independently selected from -F, -OH, methyl, or =O.

[0014] In some implementation schemes, R 3 Selected from the following groups optionally substituted with one or more R': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl-N=, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 quinone heteroaryl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R uR v P(=O)-.

[0015] In some implementation schemes, R 3 Selected from the following groups optionally substituted with one or more R': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl-N=, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-. In some implementations, R u Selected from C 1-6 Alkyl group. In some embodiments, the R... u Selected from methyl.

[0016] In some implementation schemes, R 3 Selected from the following groups optionally substituted with one or more R': 4-6 membered heterocyclic alkyl (e.g., 4-6 membered heterocyclic alkyl containing 1-2 heteroatoms selected from N, O, or S), or R v C(O)-.

[0017] In some implementation schemes, R v Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl.

[0018] In some implementation schemes, R v Selected independently from C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl.

[0019] In some implementation schemes, R v Each is independently selected from methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R v Each is independently selected from ethyl or cyclopropyl. In some embodiments, R 3Selected from the following groups optionally substituted with one or more R': , , , , , , , , , , ,or In some implementations, R 3 Selected from the following groups optionally substituted with one or more R': , , ,or In some implementations, R 3 Selected from the following groups optionally substituted with one or more R': , ,or .

[0020] In some implementations, each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 quinone heteroaryl, C 3-6 cycloalkyl C 1-3 Alkyl-, 4-6 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-6 Cycloalkenyl C 1-3 alkyl-, 4-6 membered heterocyclic alkenyl C 1-3 Alkyl-, C 6-10 Aryl C 1-3 Alkyl-, 5-6-membered heteroaryl C 1-3 alkyl-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 membered heteroaryl C 3-6 cycloalkyl C 1-3 Alkyl-, 4-6 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-6 Cycloalkenyl C 1-3 alkyl-, 4-6 membered heterocyclic alkenyl C 1-3 Alkyl-, C 6-10 Aryl C 1-3 Alkyl-, 5-6-membered heteroaryl C 1-3The alkyl group is optionally substituted by one or more elements selected from deuterium, halogen, -OH, -NH2 or -CN.

[0021] In some implementations, each R' is independently selected from deuterium, halogens (e.g., -F, -Cl, -Br or -I), -OH, -NH2, -CN, C 1-6 Alkyl, phenyl, 5-6 heteroaryl or 5-6 heteroaryl C 1-3 alkyl-, the C 1-6 The alkyl group is optionally substituted with one or more substances selected from deuterium, halogen, -OH, -NH2, or -CN. In some embodiments, each R' is independently selected from a 5-membered heteroaryl group. In some embodiments, each R' is independently selected from a pyrazolyl or triazolyl group.

[0022] In some embodiments, each R' is independently selected from -F, -CN, 1,2,3-triazolyl, pyrazolyl, 1,2,3-triazolylethyl, or cyanomethyl. In some embodiments, each R' is independently selected from -CN, 1,2,3-triazolyl, pyrazolyl, or cyanomethyl. In some embodiments, each R' is independently selected from -CN, 1,2,3-triazolyl, or pyrazolyl.

[0023] In some implementation schemes, R 3 Selected from , , , , , , , , , , , , or In some implementations, R 3 Selected from , , ,or In some implementations, R 3 Selected from , or In some implementations, R 3 Selected from or .

[0024] In some implementation schemes, R 3 Selected from R that is optionally replaced by one or more R' v C(O)-. In some implementations, R vSelected independently from C 1-3 Alkyl groups (e.g., ethyl groups). In some embodiments, each R' is independently selected from 5-6-membered heteroaryl groups (e.g., 5-membered N-containing heteroaryl groups, for example, containing 1-3 N atoms). In some embodiments, R... 3 Selected from C atoms substituted with a 5-membered N-containing heteroaryl group (e.g., containing 1-3 N atoms). 1-3 Alkyl-C(O)-.

[0025] In some implementation schemes, R 4 Selected from H, or R optionally replaced by one or more R'' s C(O)- or R s R t NC(O)-. In some implementations, R 4 Selected from H, or R optionally replaced by one or more R'' s R t NC(O)-.

[0026] In some implementation schemes, R t Selected independently from C 1-6 Alkyl group. In some embodiments, R t Selected independently from C 1-3 Alkyl group. In some embodiments, R t Each is independently selected from methyl groups.

[0027] In some implementation schemes, R s Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, the 4-7 member may be selected from 4, 5, 6, or 7 members.

[0028] In some implementation schemes, R s Selected independently from C 1-3 Alkyl group. In some embodiments, R s Each is independently selected from methyl groups.

[0029] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 The aryl or 5-6 heteroaryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-.

[0030] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 Aryl (e.g., phenyl) or 5-6 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 The aryl group (e.g., phenyl) or 5-6 heteroaryl group is optionally substituted with one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-3 Alkyl, C2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkyl S-, C 1-3 Alkyl NH- or (C 1-3 Alkyl)2N-.

[0031] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl compounds.

[0032] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0033] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, or -CN.

[0034] In some implementation schemes, R 4 Selected from hydrogen or -CON(CH3)2.

[0035] In some implementations, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl C 1-3 Alkyl-, 4-7 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-7 Cycloalkenyl C 1-3 alkyl-, 4-7 membered heterocyclic alkenyl C 1-3 Alkyl-, phenyl-C 1-3 Alkyl- or 5-6-membered heteroaryl C 1-3 alkyl-.

[0036] In some implementations, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-6 Alkyl, phenyl, 5-6 quinone heteroaryl or C 3-6 cycloalkyl C 1-3 alkyl-.

[0037] In some implementations, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, or optionally by one or more R d Replacement C 1-4 Alkyl or C 3-6 cycloalkyl C 1-3 alkyl-.

[0038] In some implementations, each R 5 Each is independently selected from halogens (e.g., -F, -Cl, -Br, or -I) or optionally by one or more R... d Substituted methyl or cyclopropylmethyl-.

[0039] In some implementation schemes, R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, -CHO, -COOH, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-11 Cycloalkyl or 4-11 membered heterocycloalkyl, wherein the C 3-11 The cycloalkyl or 4-11 membered heterocycloalkyl group is optionally substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2, or -CHO. In some embodiments, the C 3-11 Selected from C3, C4, C5, C6, C7, C8, C9, C 10 Or C11 In some implementations, the 4-11 yuan is selected from 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan or 11 yuan.

[0040] In some implementation schemes, R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, -CHO, -COOH, C 1-4 Alkoxy, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 5-6 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 5-6 The cycloalkyl or 4-6 membered heterocycloalkyl group may optionally be substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2 or -CHO.

[0041] In some implementation schemes, R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, C 1-12 Alkoxy, C 1-12 Alkyl NH- or (C 1-12 Alkyl)2N-.

[0042] In some implementation schemes, R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkoxy, C 1-6 Alkyl NH-, or (C 1-6 Alkyl)2N-.

[0043] In some implementation schemes, R d Selected from deuterium, halogens, -OH, -NH2, -CN, or -NO2. In some embodiments, R 5 Selected from halogens (e.g., -F).

[0044] In some implementation schemes, R d Selected from C 1-12 Alkyl, the C 1-12 The alkyl group is optionally substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2, or -CHO. In some embodiments, R d Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2, or -CHO. In some embodiments, R d Selected from C 1-4 Alkyl, the C 1-6The alkyl group may optionally be substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2 or -CHO.

[0045] In some implementation schemes, R 5 Selected from -F, methyl or .

[0046] In some implementations, the L in -L-CLM is connected to the ring F.

[0047] In some implementations, ring F is selected from C. 6-10 The ring F is an aryl or 9-10 membered heteroaryl group. In some embodiments, ring F is selected from 9-membered heteroaryl groups. In some embodiments, the heteroaryl group in ring F is a dicyclic heteroaryl group. In some embodiments, the heteroaryl group in ring F is selected from benzo5-membered heteroaryl or pyrido5-membered heteroaryl. In some embodiments, the heteroatom in ring F is selected from N, O, S, or Se. In some embodiments, the heteroatom in ring F is selected from N. In some embodiments, the number of heteroatoms in ring F is 1 or 2.

[0048] In some implementations, ring F is selected from ,in, Indicates a single or double bond; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 Z 8 and Z 9 Each element is independently selected from O, S, N, NH, Se, C, or CH. In some embodiments, the ring F is selected from... in, Indicates a single or double bond; Z 1 Z 2 Z 7 Z 8 and Z 9 Each is independently selected from O, S, N, NH, Se, C, or CH.

[0049] In some implementation schemes, ring F, or or Selected from , , , , , , or In some implementations, ring F is selected from... .

[0050] In some implementations, j is selected from 0, 1, or 2. In some implementations, j is selected from 0 or 1. In some implementations, k is selected from 0, 1, or 2. In some implementations, k is selected from 0 or 1.

[0051] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , ,or In some implementations, the structural portion Selected from In some implementations, the structural portion by j R 5 replace.

[0052] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , or In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from The "*" end is connected to L.

[0053] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , or In some implementations, the structural portion Selected from or In some implementations, the structural portion Selected from or The "*" end is connected to L.

[0054] In some implementations, when L a No, the ring E is selected from 9-11 quinone (e.g., 9, 10 or 11) heterospirocycloalkyl or 9-11 quinone (e.g., 9, 10 or 11) heterospirocycloalkenyl.

[0055] In some implementations, when L a No, the heteroatom in ring E is selected from nitrogen, oxygen, sulfur, selenium, silicon, boron, or phosphorus atoms. In some embodiments, when L a No, the heteroatom in ring E is selected from nitrogen, oxygen, or sulfur atoms. In some embodiments, when L... a No, the heteroatom in ring E is selected from nitrogen or oxygen atoms. In some embodiments, when L a No, the number of heteroatoms in ring E is 1, 2, or 3. In some embodiments, when L... a No, the number of heteroatoms in ring E is 1 or 2.

[0056] In some implementations, when L a It does not exist; ring E is selected from... , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, when L a It does not exist; ring E is selected from... or .

[0057] In some implementations, L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)-or ethynyl group.

[0058] In some implementation schemes, R L Selected from hydrogen, deuterium, halogens, CN, C 1-6 Alkyl or C 1-6 Heteroalkyl groups.

[0059] In some implementation schemes, R L Selected from hydrogen, -F, or methyl.

[0060] In some implementations, L a Selected from -O-, -S-, -N(CH3)-, -CH2-, -CF2-, -C(CH3)2-, =CH-, =CF-, -C(=CH2)-, -C(=CF2)- or -C≡C-.

[0061] In some implementations, ring E is selected from C. 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl compounds.

[0062] In some implementations, C in ring E 3-12 Selected from C 3-10 C 4-10 Or C 4-6 Or selected from C3, C4, C5, C6, C7, C8, C9 or C 10 .

[0063] In some implementation schemes, the 4-12 yuan in ring E is selected from 4-7 yuan or 5-6 yuan; or selected from 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan.

[0064] In some implementations, C in ring E 6-12 Selected from C 6-10 Or selected from C6, C7, C8, C9 or C 10 .

[0065] In some implementation schemes, the 5-12 yuan in ring E is selected from 5-10 yuan or 5-6 yuan; or selected from 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan.

[0066] In some implementations, ring E is selected from C. 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl.

[0067] In some implementations, when L a No, the heteroatom in ring E is selected from nitrogen, oxygen, sulfur, selenium, silicon, boron, or phosphorus atoms. In some embodiments, the number of heteroatoms in ring E is 1, 2, or 3.

[0068] In some implementations, ring E is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, ring E is selected from... , , ,or In some implementations, ring E is selected from... or .

[0069] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, the structural portion Selected from , , ,or In some implementations, the structural portion Selected from ,or .

[0070] In some implementations, when L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The alkynyl group, with ring E selected from 4-6 membered heterocyclic alkyl groups. In some embodiments, when L... a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The alkynyl group, with the cyclic E selected from... , or In some implementations, when L a Selected from -O-, ring E selected from .

[0071] In some specific implementation schemes, the structural part Selected from , , , , , , , , , , , , , , , , , , , or .

[0072] In some specific implementation schemes, the structural part Selected from , , , , , , , , , , , , or In some specific implementation schemes, the structural components... Selected from .

[0073] In some specific implementation schemes, R 3 It substitutes for the nitrogen atom in ring E.

[0074] In some implementation schemes, or Selected from the structural segments described in Table 1.

[0075] Table 1

[0076] In some implementations, the or Selected from , , , , , , , , , Or, selected from , , or In some implementations, the... or Selected from , , , , , , ,or Or, selected from In some implementations, the... or Selected from , , , ,or Or, selected from In some implementations, the... or Selected from In some implementations, the... or Selected from .

[0077] In some implementations, the CLM is selected from the following structures: , , , , , , , , Where u is selected from 0, 1 or 2; Ring D is independently selected from 5-25 element rings; R 7 Each independently selected from H or C 1-6 alkyl; X 11 Each of the following is independently selected from O, S, C(O), CH2, or NH; X 4 Selected independently from C(R) f ) or N; R f C atoms independently selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted with one or more substituents.1-6 alkyl; L 1 Each is independently selected from the bond, -NH-, -O-, -S-, -CONH-, or -CON(C). 1-6 alkyl)-; Each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, =O, and optionally substituted by one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 alkyl)NH-, (C 1-10 Alkyl)2N-, Halogenated C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; n is selected from 0, 1, 2, 3, 4 or 5.

[0078] In some implementations, u is selected from 0 or 1.

[0079] In some implementations, the CLM is selected from .

[0080] In some embodiments, ring D is selected from 5-20 membered rings; in some embodiments, the 5-20 membered ring is selected from 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, 15-membered, 16-membered, 17-membered, 18-membered, 19-membered, or 20-membered rings. In some embodiments, the ring is selected from cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. In some embodiments, the heteroatom in the heterocycloalkyl, heterocycloalkenyl, or heteroaryl group is selected from nitrogen, oxygen, or sulfur, and the number of heteroatoms is selected from 1, 2, 3, 4, 5, or 6.

[0081] In some implementations, ring D is selected from... , , , , ,or ,in, Ring A does not exist, or is selected from C. 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl or 5-6-membered heteroaryl groups; Cyclic C is selected from 5-6 member heteroaryl groups; X 5 Selected from C(O), CH2, or NH; X 6 Selected from O, CH2, NH or Optionally, ring D is divided by n R. 1 replace.

[0082] In some implementations, ring D is selected from... , , , , , , , , ,or Optionally, ring D is divided by n R. 1 replace.

[0083] In some implementations, structural components Selected from , , , , , , , , , , , , ,or In some implementations, the structural portion Selected from , , , , , , , , , ,or In some implementations, ring A is absent or selected from C. 5-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0084] In some implementation schemes, C 5-20 The cycloalkenyl group is selected from C 5-8 Cycloalkenyl. In some embodiments, the 5-20 quinone heterocyclic alkenyl is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 quinone heterocyclic alkenyl.

[0085] In some implementations, ring A is absent, or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0086] In some embodiments, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, azircycloheptenyl, oxacycloheptenyl, azirspirooctenyl, azirspirononenyl, azirspirodecenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl. In some embodiments, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dihydropyrrolyl, tetrahydropyridyl, azircycloheptenyl, cycloheptenyl, or phenyl.

[0087] In some embodiments, ring B is selected from phenyl or a 6-membered heteroaryl group. In some embodiments, ring B is selected from phenyl or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S. In some embodiments, ring B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring B is phenyl. In some embodiments, ring B is pyridyl.

[0088] In some specific implementations, cyclic C is selected from 5-membered heteroaryl groups.

[0089] In some specific embodiments, the ring C is selected from a 5-membered heteroaryl group containing 1-3 (e.g., 1-2) heteroatoms selected from N, O or S.

[0090] In some specific embodiments, the ring C is selected from isoxazolyl, imidazolyl, furanyl, pyrazolyl, isothiazolyl, or thiophene.

[0091] In some embodiments, ring C is selected from isoxazolyl or imidazole. In some embodiments, ring C is isoxazolyl.

[0092] In some implementation schemes, R 1 The replacement position is selected from ring A or ring B. In some embodiments, R 1 The replacement position is selected from ring A. In some embodiments, R 1 The replacement position is selected from ring B. In some embodiments, R 1 The replacement position is selected from ring C. In some embodiments, R 1 It does not exist (i.e., n is 0).

[0093] In some implementations, ring A is connected to L. In some implementations, ring B is connected to L. In some implementations, ring C is connected to L. In some implementations, ring A is connected to L. 1 Connection. In some implementations, ring B is connected to L. 1 Connection. In some implementations, ring C is connected to L. 1 connect.

[0094] In some implementations, ring D is selected from... or In some implementations, ring D is selected from... , ,or In some implementations, ring D is selected from... .

[0095] In some implementations, structural fragments Selected from or .

[0096] In some implementations, structural fragments Selected from , , , , or .

[0097] In some implementations, structural fragments Selected from , , , , or .

[0098] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0099] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0100] In some implementations, structural fragments Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0101] In some implementations, structural fragments Selected from .

[0102] In some implementations, structural fragments Selected from or .

[0103] In some implementation schemes, R 7 Each is independently selected from H or methyl. In some embodiments, R 7 Each is selected independently from H.

[0104] In some implementation schemes, X 11 They are selected independently from C(O) or CH2.

[0105] In some implementation schemes, X 4 Selected independently from C(R) f ) or N.

[0106] In some implementation schemes, X 4 Each is independently selected from CH or N. In some implementations, X 4 Each is independently selected from CH. In some implementations, X 4 Each is independently selected from N.

[0107] In some implementation schemes, R f Each of the following is independently selected from H, halogen, -OH, -NH2, -CN, deuterium, or methyl.

[0108] In some implementation schemes, R f Each is independently selected from H, -F, or deuterium.

[0109] In some implementations, L 1 Each is independently selected from the bond, -NH-, -O-, -S-, -CONH-, or -CON(CH3)-.

[0110] In some implementations, L 1 Each is independently selected from the bond, -NH-, -O-, or -CONH-. In some embodiments, L 1 Each is selected independently from the key. In some implementations, L 1 Each is independently selected from -NH-.

[0111] In some implementations, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, =O, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0112] In some implementations, each R1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0113] In some implementations, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, =O, C 1-3 Alkyl or C 1-3 Alkyl group.

[0114] In some implementations, each R 1 It is independently selected from -F, -Cl, =O, methyl or methoxy.

[0115] In some implementations, n is selected from 0, 1, 2, or 3.

[0116] In some implementations, the CLM is selected from the following structural parts: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , Among them, R a Each is independently selected from -OH, halogen, -NH2, -CN, and C. 1-8 Alkyl or C 1-8 Alkoxy; q is selected from 0, 1, 2, 3, or 4; X 4 Selected from N or optionally substituted (e.g., halogenated, C) 1-3 (alkyl, -OH, deuterated) CH; L1 is selected from -CH2-, -O-, -NH- or -C(O)NH-.

[0117] In some implementation schemes, R a Each is independently selected from -OH, halogen, -NH2, -CN, and C. 1-3 Alkyl or C 1-3 Alkyl group.

[0118] In some implementation schemes, R a Each of the following is independently selected from -OH, -F, -Cl, -NH2, -CN, methyl, or methoxy.

[0119] In some implementations, the CLM is selected from the following structural parts: , , , , , , , , or , , , , Among them, R a , q, X 4 The definitions of L1 are as described in this application.

[0120] In some implementations, the CLM is selected from the structures in Table 2.

[0121] Table 2

[0122] In some implementations, the CLM is selected from , , , , , , , , , , , , , , , , or In some implementations, the CLM is selected from... , , , , , , , , , , , , , , or In some implementations, the CLM is selected from... , , , , , , , , , , , ,or .

[0123] In some implementations, the CLM is selected from , , , , , or In some implementations, the CLM is selected from... , , , , , , , ,or In some implementations, the CLM is selected from... or .

[0124] In some embodiments, L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 imide or C 2-15 Alkyne group, optionally, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the alkynyl group are independently and optionally surrounded by -O-, -NH-, or -N(C) 1-3 Alkyl)-, -S-, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 4-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl or 5-15 aryl substitution.

[0125] In some embodiments, L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 imide or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the alkynyl group are independently and optionally surrounded by -O-, -NH-, or -N(C) 1-3 Alkyl)-, -S-, C 3-11 cycloalkyl, C 3-11 Cycloalkenyl, 4-11 membered heterocyclic alkyl, 4-11 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 aryl substitution.

[0126] In some embodiments, L is selected from C that is optionally substituted with one or more substituents.1-6 Alkylene or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, -NH-, -N(C 1-3 Alkyl)-, -S-, C 4-9 cycloalkyl, C 4-6 Cycloalkenyl, 4-11 membered heterocyclic alkyl, C 6-10 Aryl or 6-10 heteroaryl substitution.

[0127] In some specific embodiments, L is selected from C that is optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally selected from C. 4-9 cycloalkyl, C 4-6 Cycloalkenyl, 4-11 membered heterocyclic alkyl, C 6-10 Aryl or 6-10 heteroaryl substitution.

[0128] In some embodiments, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, or optionally substituted with deuterium, halogen, -OH, -NH2, or -CN, and the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0129] In some embodiments, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, and optionally substituted with halogen: C 1-3 Alkyl, C 1-3 Alkoxy or C 3-4 Cycloalkyl.

[0130] In some embodiments, the substituent in the definition of L is selected from -F, -Cl, methyl, CH3O-, CHF2O-, or CF3O-.

[0131] In some implementations, L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -LNK 3 -Cy4 -LNK 4 -,in, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkyl, 4-12 membered heterocyclic alkenyl, C 6-10 Aryl, or 5-10 heteroaryl; LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -N(C) 1-3 Alkyl group, -O-, -S-, or optionally with one or more R groups c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 1-10 Heteroalkylene, C 2-10 Heteroeneyl, or C 2-10 Hetero-ynyl group; Each R b and R c Each of the following groups, independently selected from deuterium, halogen, =O, -OH, -NH2, -CN, or optionally substituted by deuterium, halogen, -OH, -NH2, or -CN, is selected: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0132] In some implementations, Cy 1 Cy 2 and Cy 3 They are not both keys. In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 They are not both keys. In some implementations, Cy 2 and Cy 3 As a key. In some implementations, LNK 1 and LNK 2 Selected from key. In some implementations, LNK 3 and LNK4 Selected bond.

[0133] In some embodiments, L is selected from -Cy 1 -, -Cy 2 -, -LNK 1 -, -Cy 1 -LNK-, -Cy 1 -Cy 2 -, -LNK 1 -Cy 1 -LNK-, -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -Cy 2 -, -Cy 1 -LNK-Cy 2 -, -LNK 1 -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -Cy 3 -, -Cy 1 -LNK-Cy 2 -Cy 3 -, -Cy 1 -Cy 2 -LNK 2 -Cy 3 -, -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -, -Cy 1 -LNK-Cy 2 -Cy 3 -LNK 3 -, -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -, or -Cy 1 -LNK-Cy 2 -Cy3 -Cy 4 -LNK 4 -

[0134] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -N(C) 1-3 Alkyl group, -O-, -S-, or optionally with one or more R groups c The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 1-4 Heteroalkylene, C 2-4 Heteroeneyl, or C 2-4 Hetero-ynyl group.

[0135] In some embodiments, the heteroalkylene group is selected from monooxanealkylene, monothiazanealkylene, or monoazazanealkylene. In some embodiments, the heteroenyl group is selected from monooxaneyl, monothiazaneyl, or monoazaenyl. In some embodiments, the heteroynyl group is selected from monooxaneyl, monothiazaneyl, or monoazaynyl.

[0136] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the key, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-4 alkyne or C 1-4 Heteroalkylene.

[0137] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Selected independently from key, C 1-3 Alkylene or C 2-4 Alynyl group.

[0138] In some implementations, -LNK 1 -、LNK 2 LNK 3 and LNK 4 Each is independently selected from the following: -CH2-, -CH2CH2-, -CF2CH2-, -CH2CH2CH2-, -O-, -N(CH3)CH2- or -OCH2-.

[0139] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-9 cycloalkyl, C 4-6 Cycloalkenyl, 4-11 membered heterocyclic alkyl, C 6-10 Aryl or 6-10 heteroaryl compounds.

[0140] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 C in 4-9 Selected from C4, C5, C6, C7, C8, or C9. In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 The range of 4-11 yuan is selected from 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, or 11 yuan. In some implementation schemes, Cy 1 Cy 2 Cy 3 or Cy 4 C in 6-10 Selected from C6, C7, C8, C9 or C 10 In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 The 6-10 yuan range can be selected from 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan.

[0141] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. bThe following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, piperazine, tetrahydropyridyl, azirspiroheptyl, azirspirohoctyl, azirspirononyl, azirspirodealkyl, azirspiroundecyl, diazirspirononyl, azirspirodealkyl, diazirspirodealkyl, diazirspiroundecyl, azirbicyclohexyl, azirbicyclooctyl, azirbicyclononyl, diazirbicycloheptyl, diazirbicyclooctyl, octahydrocyclopentylpyrroleyl, phenyl, tetrahydrophenyl, phenyl, naphthyl, pyridyl, or indole.

[0142] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0143] In some implementations, each R b and R cEach of the following groups, independently selected from deuterium, halogen, =O, -OH, -NH2, -CN, or optionally substituted by deuterium, halogen, -OH, -NH2, or -CN, is selected: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl) NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic alkyl.

[0144] In some implementations, each R b and R c Each of the following groups, independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, or optionally substituted with a halogen: C 1-3 Alkyl, C 1-3 alkoxy, or C 3-4 Cycloalkyl.

[0145] In some implementations, each R b and R c Each is independently selected from -F, -Cl, methyl, CH3O-, CHF2O-, or CF3O-.

[0146] In some implementations, L is selected from the structural segments in Table 3.

[0147] Table 3

[0148] In some implementations, L is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, L is selected from... , , , , , , , , , , , , , , , , ,or In some implementations, the... or The structural segments are selected from those described in Table 1; the CLM is selected from those described in Table 2, and L is selected from those described in Table 3.

[0149] This application relates to compounds of formula VI or VIA, their stereoisomers, or pharmaceutically acceptable salts thereof. ,or , Among them, CLM, L, R 2 R 3 R 4 R 5 j, k, L a The definition of ring E is as described in this application.

[0150] In some embodiments, the heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, heterocyclic group, heteroalkyl group, heteroalkenyl, heteroynyl, heteroalkylene group, heteroalkenyl, heteroynylene group comprises one or more heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -N-, -S-, silicon, phosphorus, boron, -C(=O)-, -C(=O)NH-, -C(=O)O-, -S(=O)-, or -S(=O)2-; in some embodiments, the heterocyclic alkenyl, heteroaryl, heteroalkyl group, heteroalkylene ... Heterocyclic alkyl, heterocyclic, heteroalkyl, heteroalkenyl, heteroynyl, heteroalkylene, heteroalkenyl, and heteroynylene comprise one or more heteroatoms or heterogroups independently selected from -O-, -NH-, -N-, or -S-. In some embodiments, the heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, heterocyclic, heteroalkyl, heteroalkenyl, heteroynyl, heteroalkylene, heteroalkenyl, and heteroynylene comprise one or more heteroatoms or heterogroups independently selected from -O-, -NH-, or -N-. In some embodiments, the number of heteroatoms or heterogroups is independently selected from 1, 2, 3, 4, 5, or 6; or from 1, 2, 3, or 4; or from 1, 2, or 3; or from 1 or 2.

[0151] In some embodiments, the halogenation is selected from fluorination, chlorination, or bromination. In some embodiments, the halogenation is selected from fluorination or chlorination. In some embodiments, the halogenation is selected from fluorination.

[0152] In some implementations, the C 1-12 Or C 1-10 Selected from C 1-9 C 1-8 C 1-7 C 1-6 C 1-4 C 1-3 or C 1-2 In some implementations, C 1-6 Selected from C 1-4 C 1-3 or C 1-2 In some implementations, the C 1-4 Selected from C4, C3, C2, or C1. In some embodiments, C... 1-3 Choose from C3, C2, or C1.

[0153] In some implementations, the C 2-12 Or C 2-10 Selected from C 2-8 C 2-6 C 2-5 C 2-4 C 2-3 In some implementations, the C 2-6 Selected from C 2-4 or C2-3 In some implementations, the C 2-4 Choose from C4, C3, or C2.

[0154] In some implementations, the C 3-6 Selected from C 3-5 C 3-4 C 4-6 C 4-5 or C 5-6 In some implementations, the C 6-10 Selected from C 6-9 C 6-8 C 6-7 C 7-10 C 7-9 C 7-8 C 8-10 C 8-9 or C 9-10 In some implementations, the C 3-10 Selected from C 3-9 C 3-8 C 3-7 C 3-6 C 3-5 C 3-4 C 4-10 C 4-9 C 4-8 C 4-7 C 4-6 C 4-5 C 5-10 C 5-9 C 5-8 C 5-7 C 5-6 C 6-10 C 6-9 C 6-8 C 6-7 C 7-12 C 7-10 C 7-9 C 7-8 C 8-12 C 8-10 C 8-9 C 9-12 or C 9-10 In some implementations, the C 3-15 Selected from C 3-12 Or C 3-10 In some implementations, the C 3-12 Selected from C 3-10 In some implementations, the C 6-12 Selected from C 6-10 .

[0155] In some implementations, the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan. In some implementations, the 4-7 yuan is selected from 4-5 yuan, 4-6 yuan, 5-6 yuan, 5-7 yuan, or 5-6 yuan. In some implementations, the 5-10 yuan, 4-12 yuan, or 4-11 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, or 9-10 yuan. In some implementations, the 3-10 yuan or 3-9 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, and 9-10 yuan. In some implementations, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some implementations, the 3-12 yuan is selected from 3-10 yuan. In some implementations, the 5-12 yuan is selected from 5-10 yuan.

[0156] In some implementation schemes, the structural portion Selected from , ,or ; L is selected from , , , , , , , , , , , , , , , , ,or ; Structural parts Selected from or ; CLM is selected from , , , , , , , , , , , ,or .

[0157] This application also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0158] This application relates to compounds of formula X, their structural moieties, their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0159] Among them, R 2 R 3 R 4 R 5 , ring F, j, k, L a The definition of ring E is as described in this application.

[0160] In some implementation schemes, the structural portion , , The definition is as stated in this application.

[0161] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , or .

[0162] In some implementation schemes, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from , , or .

[0163] In some implementation schemes, the structural portion Selected from , , or , where R 5a Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, or (C 1-6 Alkyl)2N-. In some embodiments, R 5a Selected from halogens. In some embodiments, R 5a Selected from -F.

[0164] In some implementations, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The substituted phenyl or 5-6 heteroaryl group. In some embodiments, the 5-6 heteroaryl group is selected from pyridine.

[0165] In some implementation schemes, R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, -CHO, C 1-4 Alkoxy, C 1-4 Alkyl NH-, (C 1-4 The alkyl group is a 2N-, 4-6 membered heterocyclic alkyl group, wherein the 4-6 membered heterocyclic alkyl group is optionally substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2 or -CHO. In some embodiments, the 4-6 membered heterocyclic alkyl group is selected from aziridine, pyrrolidinyl, piperidinyl or piperazine.

[0166] This application relates to the following compounds, structural moieties, derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof: , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , or .

[0167] On the one hand, this application relates to compounds of formula XI, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0168] in, L a It does not exist or is selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 Ethyne group; When L a No, ring E is selected from 7-15 membered heterospirocycloalkyl or 7-15 membered heterospirocycloalkenyl; When L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The acetylenic group, the R L Selected from hydrogen, deuterium, halogens, -CN, C 1-10 Alkyl or C 1-10 Heteroalkyl, with ring E selected from C 3-15 Cycloalkyl, 4-15 membered heterocyclic alkyl, C 3-15 Cycloalkenyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl or 5-15 heteroaryl groups; Each R 2 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, =O, and C. 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl; R 3 Selected from the following groups optionally substituted with one or more R': C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 Alkyl-N=, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-; R u Selected from H, -OH or C 1-12 alkyl; R v Selected independently from C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-, the C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 Alkyl groups are optionally substituted with one or more deuterium, halogen, -OH, -NH2, or -CN; Ring F is selected from C 6-12 Aryl or 5-12 heteroaryl groups; R 4 Selected from H, or optionally substituted with one or more R'' groups: R s C(O)-, R s C(O)O-、R s OC(O)-, R s S(O)-、R s S(O)2-、R s R t NC(O)-, R s C(O)NR t -、R s S(O)2NR t -or R s R t NS(O)2-; R t Each independently selected from H or C 1-12 alkyl; R s Selected independently from C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 2-12 alkenyl, C2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 The aryl or 5-12 heteroaryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-; Each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 4-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 4-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-; R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, or (C 1-6 Alkyl)2N-; R 55 It does not exist, or is selected from one or more Rs. d1 The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 4-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 4-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-; Each R d1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, -CHO, -COOH, or optionally by one or more R dd The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-15 Cycloalkyl, 4-15 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-15 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl; Each R dd Each of the following is independently selected from deuterium, -CN, =O, halogen, -OH, -NH2, -NO2, -CHO, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C6-12 Aryl, 5-12 heteroaryl, R s C(O)-, R s C(O)O-、R s OC(O)-, R s S(O)-、R s S(O)2-、R s R t NC(O)-, R s C(O)NR t -、R s S(O)2NR t -or R s R t NS(O)2-; j and k are independently selected from 0, 1, 2, 3, or 4.

[0169] In some implementations, each R 2 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, =O, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl S-, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0170] In some implementations, each R 2 Each is independently selected from deuterium, halogens (e.g., -F, -Cl, -Br or -I), -OH, -NH2, -CN, -NO2, =O or C. 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl, or cyclopropyl).

[0171] In some implementations, each R 2 Each can be independently selected from -F, -OH, methyl, or =O.

[0172] In some implementation schemes, R 3 Selected from the following groups optionally substituted with one or more R': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl-N=, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 quinone heteroaryl, R v C(O)-, Rv C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-.

[0173] In some implementation schemes, R 3 Selected from the following groups optionally substituted with one or more R': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl-N=, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-. In some implementations, R 3 Selected from: 4-6 membered heterocyclic alkyl groups (e.g., 4-6 membered heterocyclic alkyl groups containing 1-2 heteroatoms selected from N, O, or S), or R v C(O)-.

[0174] In some implementation schemes, R u Selected from C 1-6 Alkyl group. In some embodiments, the R... u Selected from methyl.

[0175] In some implementation schemes, R v Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl.

[0176] In some implementation schemes, R v Selected independently from C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl.

[0177] In some implementation schemes, R v Each is independently selected from methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, Rv Each is independently selected from ethyl or cyclopropyl.

[0178] In some implementation schemes, R 3 Selected from the following groups optionally substituted with one or more R': , , , , , , , , , , ,or In some implementations, R 3 Selected from the following groups optionally substituted with one or more R': , , ,or In some implementations, R 3 Selected from the following groups optionally substituted with one or more R': , ,or In some implementations, each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 quinone heteroaryl, C 3-6 cycloalkyl C 1-3 Alkyl-, 4-6 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-6 Cycloalkenyl C 1-3 alkyl-, 4-6 membered heterocyclic alkenyl C 1-3 Alkyl-, C 6-10 Aryl C 1-3 Alkyl-, 5-6-membered heteroaryl C 1-3 alkyl-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 membered heteroaryl C 3-6 cycloalkyl C 1-3 Alkyl-, 4-6 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-6 Cycloalkenyl C 1-3 alkyl-, 4-6 membered heterocyclic alkenyl C 1-3 Alkyl-, C 6-10Aryl C 1-3 Alkyl-, 5-6-membered heteroaryl C 1-3 The alkyl group is optionally substituted by one or more elements selected from deuterium, halogen, -OH, -NH2 or -CN.

[0179] In some implementations, each R' is independently selected from deuterium, halogens (e.g., -F, -Cl, -Br or -I), -OH, -NH2, -CN, C 1-6 Alkyl, phenyl, 5-6 heteroaryl or 5-6 heteroaryl C 1-3 alkyl-, the C 1-6 The alkyl group is optionally substituted with one or more substances selected from deuterium, halogen, -OH, -NH2, or -CN. In some embodiments, each R' is independently selected from a 5-membered heteroaryl group. In some embodiments, each R' is independently selected from a pyrazolyl or triazolyl group.

[0180] In some embodiments, each R' is independently selected from -F, -CN, 1,2,3-triazolyl, pyrazolyl, 1,2,3-triazolylethyl, or cyanomethyl. In some embodiments, each R' is independently selected from -CN, 1,2,3-triazolyl, pyrazolyl, or cyanomethyl. In some embodiments, each R' is independently selected from -CN, 1,2,3-triazolyl, or pyrazolyl.

[0181] In some implementation schemes, R 3 Selected from , , , , , , , , , , , , or In some implementations, R 3 Selected from .

[0182] In some implementation schemes, R 3 Selected from R that is optionally replaced by one or more R' v C(O)-. In some implementations, R v Selected independently from C 1-3 Alkyl groups (e.g., ethyl groups). In some embodiments, each R' is independently selected from 5-6-membered heteroaryl groups (e.g., 5-membered N-containing heteroaryl groups, for example, containing 1-3 N atoms). In some embodiments, R... 3Selected from C atoms substituted with a 5-membered N-containing heteroaryl group (e.g., containing 1-3 N atoms). 1-3 Alkyl-C(O)-.

[0183] In some implementation schemes, R 4 Selected from H, or R optionally replaced by one or more R'' s C(O)- or R s R t NC(O)-. In some implementations, R 4 Selected from H, or R optionally replaced by one or more R'' s R t NC(O)-.

[0184] In some implementation schemes, R t Selected independently from C 1-6 Alkyl group. In some embodiments, R t Selected independently from C 1-3 Alkyl group. In some embodiments, R t Each is independently selected from methyl groups.

[0185] In some implementation schemes, R s Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, the 4-7 member may be selected from 4, 5, 6, or 7 members.

[0186] In some implementation schemes, R s Selected independently from C 1-3 Alkyl group. In some embodiments, R s Each R'' is independently selected from methyl groups. In some embodiments, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 The aryl or 5-6 heteroaryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-.

[0187] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 Aryl (e.g., phenyl) or 5-6 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 The aryl group (e.g., phenyl) or 5-6 heteroaryl group is optionally substituted with one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkyl S-, C 1-3 Alkyl NH- or (C 1-3 Alkyl)2N-.

[0188] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl compounds.

[0189] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0190] In some implementations, each R'' is independently selected from deuterium, halogen, -OH, -NH2, or -CN.

[0191] In some implementation schemes, R 4 Selected from hydrogen or -CON(CH3)2.

[0192] In some implementations, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl C 1-3 Alkyl-, 4-7 membered heterocyclic alkyl C 1-3 Alkyl-, C3-7 Cycloalkenyl C 1-3 alkyl-, 4-7 membered heterocyclic alkenyl C 1-3 Alkyl-, phenyl-C 1-3 Alkyl- or 5-6-membered heteroaryl C 1-3 alkyl-.

[0193] In some implementations, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-6 Alkyl, phenyl, 5-6 quinone heteroaryl or C 3-6 cycloalkyl C 1-3 alkyl-.

[0194] In some implementations, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-4 Alkyl, or C 3-6 cycloalkyl C 1-3 alkyl-.

[0195] In some implementations, each R d Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or -NO2.

[0196] In some implementations, each R 5 Selected independently from halogens and C 1-4 Alkyl, or C 3-6 Cycloalkylmethyl-.

[0197] In some implementations, each R 5 Each is independently selected from -F, -Cl, methyl, ethyl, or .

[0198] In some implementation schemes, R 55 It does not exist.

[0199] In some implementation schemes, R 55 Selected from one or more R d1 The following groups are substituted: C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl C 1-3 Alkyl-, 4-7 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-7 Cycloalkenyl C 1-3alkyl-, 4-7 membered heterocyclic alkenyl C 1-3 Alkyl-, phenyl-C 1-3 Alkyl- or 5-6-membered heteroaryl C 1-3 alkyl-.

[0200] In some implementation schemes, R 55 Selected from one or more R d1 The following groups are substituted: phenyl or 5-6 membered heteroaryl.

[0201] In some implementation schemes, R 55 Selected from one or more R d1 The following groups are substituted: phenyl or pyridyl.

[0202] In some implementations, each R d1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, -CHO, -COOH, or optionally by one or more R dd The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-11 Cycloalkyl, 4-11 member heterocycloalkyl, C 3-11 Cycloalkenyl, 4-11 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0203] In some implementations, each R d1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, -CHO, -COOH, or optionally by one or more R dd The following groups are substituted: C 1-6 Alkyl, 4-11 membered heterocyclic alkyl, phenyl or 5-6 membered heteroaryl.

[0204] In some implementations, each R d1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, -CHO, -COOH, or optionally by one or more R dd The following groups may be substituted: piperidinyl, piperazine, morpholinyl, oxazabicyclohexyl, oxazabicyclooctyl, octahydropyrrolopyrrole, oxazaspirononane, oxazaspironundecyl or pyrazolyl.

[0205] In some implementations, each R d1Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, -CHO, -COOH, or optionally by one or more R dd The following groups are substituted: , , , , , , , ,or .

[0206] In some implementation schemes, R d1 Selected from , , , , , , , , , ,or .

[0207] In some implementations, the C 3-11 Selected from C3, C4, C5, C6, C7, C8, C9, C 10 Or C 11 In some implementations, the 4-11 yuan is selected from 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan or 11 yuan.

[0208] In some implementations, each R dd Each of the following is independently selected from deuterium, -CN, =O, halogen, -OH, -NH2, -NO2, -CHO, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl, R s C(O)-, R s S(O)- or R s S(O)2-.

[0209] In some implementations, each R dd Selected independently from halogens and C 1-4 Alkyl, C 3-4 cycloalkyl or C 1-4 Alkyl C(O)-.

[0210] In some implementations, each Rdd Each is independently selected from halogen, methyl, ethyl, CH3C(O)- or cyclopropyl.

[0211] In some implementation schemes, R 55 Selected from ,in, Ring Z is selected arbitrarily by one or more R a1 The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl; Ring Y is selected from one or more Rs arbitrarily. a2 The following groups are substituted: C 3-15 Cycloalkyl, 4-15 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-15 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl; Each R a1 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, -CHO, -COOH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, or (C 1-6 Alkyl)2N-; Each R a2 Each of the following is independently selected from deuterium, -CN, =O, halogen, -OH, -NH2, -NO2, -CHO, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, R s C(O)-, R s S(O)-、R s S(O)2-、R s R t NC(O)-, R s C(O)NR t -、R s S(O)2NR t -or R s R t NS(O)2-.

[0212] In some implementations, ring Z is selected from one or more R a1The following groups are substituted: phenyl or 5-6 membered heteroaryl.

[0213] In some implementations, ring Z is selected from one or more R a1 The following groups are substituted: phenyl or pyridyl.

[0214] In some implementations, ring Y is selected from one or more R a2 The following groups may be substituted: 4-11-membered heterocyclic alkyl, 4-11-membered heterocyclic alkenyl, or 5-6-membered heteroaryl.

[0215] In some implementations, ring Y is selected from one or more R a2 The following groups may be substituted: piperidinyl, piperazine, morpholinyl, oxazabicyclohexyl, oxazabicyclooctyl, octahydropyrrolopyrrole, oxazaspirononane, oxazaspironundecyl or pyrazolyl.

[0216] In some implementations, ring Y is selected from one or more R a2 The following groups are substituted: , , , , , , , ,or .

[0217] In some implementations, each R a1 Each of the following is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, methylamino, or dimethylamino.

[0218] In some implementations, each R a2 Selected independently from halogens and C 1-4 Alkyl, C 3-4 cycloalkyl or C 1-4 Alkyl C(O)-.

[0219] In some implementations, each R a2 Each is independently selected from halogen, methyl, ethyl, CH3C(O)- or cyclopropyl.

[0220] In some implementation schemes, ring Y is selected from , , , , , , , , , ,or .

[0221] In some implementation schemes, R 55 Selected from , , , , , , , , , , or .

[0222] In some implementations, ring F is selected from C. 6-10 The ring F is an aryl or 9-10 membered heteroaryl group. In some embodiments, ring F is selected from 9-membered heteroaryl groups. In some embodiments, the heteroaryl group in ring F is a dicyclic heteroaryl group. In some embodiments, the heteroaryl group in ring F is selected from benzo5-membered heteroaryl or pyrido5-membered heteroaryl. In some embodiments, the heteroatom in ring F is selected from N, O, S, or Se. In some embodiments, the heteroatom in ring F is selected from N. In some embodiments, the number of heteroatoms in ring F is 1 or 2.

[0223] In some implementations, ring F is selected from ,in, Indicates a single or double bond; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 Z 8 and Z 9 Each element is independently selected from O, S, N, NH, Se, C, or CH. In some embodiments, the ring F is selected from... in, Indicates a single or double bond; Z 1 Z 2 Z 7 Z 8 and Z 9 Each is independently selected from O, S, N, NH, Se, C, or CH.

[0224] In some implementation schemes, ring F, or or Selected from , , , , , , or In some implementations, ring F is selected from... .

[0225] In some implementations, j is selected from 0, 1, or 2. In some implementations, k is selected from 0, 1, or 2.

[0226] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , ,or In some implementations, the structural portion Selected from In some implementations, the structural portion by j R 5 Replaced, and by 1 R 55 replace.

[0227] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , or In some implementations, the structural portion Selected from .

[0228] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , or In some implementations, the structural portion Selected from or .

[0229] In some implementations, when L a No, the ring E is selected from 9-11 quinone (e.g., 9, 10 or 11) heterospirocycloalkyl or 9-11 quinone (e.g., 9, 10 or 11) heterospirocycloalkenyl.

[0230] In some implementations, when L a No, the heteroatom in ring E is selected from nitrogen, oxygen, sulfur, selenium, silicon, boron, or phosphorus atoms. In some embodiments, when L a No, the heteroatom in ring E is selected from nitrogen, oxygen, or sulfur atoms. In some embodiments, when L... a No, the heteroatom in ring E is selected from nitrogen or oxygen atoms. In some embodiments, when L a No, the number of heteroatoms in ring E is 1, 2, or 3. In some embodiments, when L... a No, the number of heteroatoms in ring E is 1 or 2. In some embodiments, when L a It does not exist; ring E is selected from... , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, when La It does not exist; ring E is selected from... or .

[0231] In some implementations, L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)-or ethynyl group.

[0232] In some implementation schemes, R L Selected from hydrogen, deuterium, halogens, CN, C 1-6 Alkyl or C 1-6 Heteroalkyl groups.

[0233] In some implementation schemes, R L Selected from hydrogen, -F, or methyl.

[0234] In some implementations, L a Selected from -O-, -S-, -N(CH3)-, -CH2-, -CF2-, -C(CH3)2-, =CH-, =CF-, -C(=CH2)-, -C(=CF2)- or -C≡C-.

[0235] In some implementations, ring E is selected from C. 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl compounds.

[0236] In some implementations, C in ring E 3-12 Selected from C 3-10 C 4-10 Or C 4-6 Or selected from C3, C4, C5, C6, C7, C8, C9 or C 10 .

[0237] In some implementation schemes, the 4-12 yuan in ring E is selected from 4-7 yuan or 5-6 yuan; or selected from 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan.

[0238] In some implementations, C in ring E 6-12 Selected from C 6-10 Or selected from C6, C7, C8, C9 or C 10 .

[0239] In some implementation schemes, the 5-12 yuan in ring E is selected from 5-10 yuan or 5-6 yuan; or selected from 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan.

[0240] In some implementations, ring E is selected from C. 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl.

[0241] In some implementations, when L a No, the heteroatom in ring E is selected from nitrogen, oxygen, sulfur, selenium, silicon, boron, or phosphorus atoms. In some embodiments, the number of heteroatoms in ring E is 1, 2, or 3.

[0242] In some implementations, ring E is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, ring E is selected from... , , ,or In some implementations, ring E is selected from... or .

[0243] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, the structural portion Selected from , , ,or In some implementations, the structural portion Selected from ,or .

[0244] In some implementations, when L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The alkynyl group, with ring E selected from 4-6 membered heterocyclic alkyl groups. In some embodiments, when L... a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The alkynyl group, with the cyclic E selected from... , or .

[0245] In some specific implementation schemes, the structural part Selected from , , , , , , , , , , , , , , , , , , , or .

[0246] In some specific implementation schemes, the structural part Selected from , , , , , , , , , , , , or .

[0247] In some specific implementation schemes, R 3 It substitutes for the nitrogen atom in ring E.

[0248] This application relates to compounds of formula XII, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0249] Among them, R 2 R 3 R 4 R 5 R 55 The definitions of k, j and ring E are as described in this application.

[0250] This application relates to the following compounds, their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof: , , , , , , , , , , ,or .

[0251] The compounds comprising spirocyclic structures described in this application are selected from compounds of formula II, II-A, II-B, VI, VIA, X, XI, or XII, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0252] This application relates to degradative molecules such as Protac molecules, which include compounds of formula X, XI, or XII, their moiety, their derivatives, or related specific compounds, their stereoisomers, or their pharmaceutically acceptable salts.

[0253] This application relates to the use of compounds of formula X, XI, or XII, their structural moieties, derivatives, or related specific compounds, their stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of Protac (or protein degrading agents). This application relates to the use of compounds of formula X, XI, or XII, their structural moieties, derivatives, or related specific compounds, their stereoisomers, or pharmaceutically acceptable salts thereof in Protac molecules, such as their use as structural moieties of Protac molecules, existing in the form of Protac molecules; and their use for degrading proteins, i.e., degrading related proteins in the form of Protac molecules.

[0254] This application also covers solutions obtained by arbitrarily combining, deleting, or changing the above-described embodiments.

[0255] On the other hand, this application relates to pharmaceutical compositions comprising the compounds of this application, their structural moieties, their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.

[0256] On the other hand, this application relates to a method of treating mammalian diseases, comprising administering to a mammal requiring treatment, preferably a human, a therapeutically effective amount of the compound of this application, its structural moiety, its derivatives, its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. Furthermore, this application also includes administering a therapeutically effective amount of other drugs (e.g., one or more other therapeutic drugs).

[0257] On the other hand, this application relates to the use of the compounds of this application, their structural moieties, their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of this application, in the preparation of medicaments for treating diseases. Furthermore, this application also includes therapeutically effective amounts of other medicaments (e.g., one or more other therapeutic agents).

[0258] On the other hand, this application relates to the use of the compounds, structural portions thereof, derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of diseases. Furthermore, this application also includes therapeutically effective amounts of other drugs (e.g., one or more other therapeutic drugs).

[0259] On the other hand, this application relates to compounds of this application, their structural portions, derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of diseases. Furthermore, this application also includes therapeutically effective amounts of other drugs (e.g., one or more other therapeutic drugs).

[0260] In some embodiments, the disease is selected from diseases treated by binding to cerebellar proteins in vivo and / or by degrading / inhibiting target proteins that bind to target ligands.

[0261] In some implementations, the disease is selected from STAT6-related or mediated diseases.

[0262] In some implementations, the disease (e.g., STAT6-related or mediated disease) is selected from inflammatory diseases.

[0263] Technical effect The compounds of this application exhibit binding, inhibitory, or degradation activities against the STAT6 protein, and demonstrate anti-inflammatory activity in vitro and in vivo (e.g., in mouse inflammation models). Furthermore, the compounds of this application also possess good in vitro liver microsomal stability and in vivo pharmacokinetic properties in mammals (e.g., mice, rats, and humans) (specifically, parameters such as AUC).

[0264] definition Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0265] In this document, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, "one or more" is selected from one, two, three, four, five, or six. In some embodiments, "one or more" is selected from one, two, or three. In some embodiments, "one or more" is selected from one or two.

[0266] Unless otherwise specified, Used to represent Hydrogen atoms at any position of a group can be replaced by a group connected by a "-", such as by an "L".

[0267] The term "non-existent" in a group refers to the absence of that group, where the connected groups are directly linked by covalent bonds. For example, in formula II, L a No, ring E and ring F are connected by covalent bonds.

[0268] The term "substitution" refers to the replacement of one or more hydrogen atoms or lone pairs of electrons on a specific atom 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; oxo substitution does not occur on aromatic groups. For example... Its ring A, ring B, or ring C can be n, for example, one or more R 1 Substituent substitution, wherein the R 1 It can be used to replace any position in ring A, ring B, or ring C (provided that the valence bond allows it).

[0269] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. “Optionally substituted” includes both unsubstituted and substituted forms; for example, an ethyl group “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., 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 and / or cannot be synthesized is introduced.

[0270] C in this articlem-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0271] 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 two Rs, then each R has an independent option.

[0272] Unless otherwise stated, when a bond cross-bonds two atoms in a ring (including monocyclic, fused, or spirocyclic rings), this bond can bond with any atom in the ring (including monocyclic, fused, or spirocyclic rings). For example, structural units. This indicates that the bonds on both sides can be connected to any two different atoms in ring A, ring B, or ring C.

[0273] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0274] The term "hydroxyl group" refers to the -OH group.

[0275] The term "amino" refers to the -NH2 group.

[0276] The term "cyano" refers to the -CN group.

[0277] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group is a hydrocarbon group. This alkyl group can be straight-chain or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., 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 portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0278] The term "alkylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkyl group. For example, the term "C1-6 alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C1-4 alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0279] The term "alkenyl" refers to a divalent group formed by removing a hydrogen atom from any position of an alkenyl group. For example, the term "C2-6 alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms; the term "C2-4 alkenyl" refers to an alkenyl group containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH-, or -CH2CH=CHCH2-.

[0280] The term "acetylenol" refers to a divalent group formed by removing a hydrogen atom from any position of an acetylenic group. For example, the term "C2-6 acetylenol" refers to an acetylenol containing 2 to 6 carbon atoms; the term "C2-4 acetylenol" refers to an acetylenol containing 2 to 4 carbon atoms, including but not limited to... , , or .

[0281] The term "heteroalkyl" refers to a straight-chain or branched alkyl group composed of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbon atoms in the chain, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms, and preferably having 1, 2, or 3 heteroatoms selected from S, O, and N. For example, C m A heteroalkyl group is defined as an alkyl group with heteroatoms inserted into the chain, consisting of m carbon atoms and at least one heteroatom (e.g., 1-3 heteroatoms selected from S, O, and N) located between any two carbon atoms. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroatoms or heteroatomic groups can be located at any internal position of the heteroalkyl group, including positions where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, etc., including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5, and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0282] The term "heteroalkylene" refers to a divalent group formed by removing a hydrogen atom from any position of a heteroalkyl group.

[0283] The term "alkoxy" refers to -O-alkyl.

[0284] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0285] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 4- to 16-membered, 4- to 12-membered, 4- to 10-membered, or 4- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, benzocyclohexenyl, etc. or .

[0286] The term "cycloalkyl" refers to a fully saturated carbon ring that may exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically 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.

[0287] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 16-membered, 3- to 11-membered, 3- to 10-membered, 3- to 7-membered, 3- to 6-membered, or 3- to 5-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0288] The term "spirocyclic ring" refers to a fully saturated or partially unsaturated polycyclic system in which the individual rings share a single carbon atom (called a spiro atom), including carbon rings and heterocyclic rings. Unless otherwise indicated, the spirocyclic ring is 5 to 20 rings, preferably 6 to 14 rings, and more preferably 8 to 12 rings. When the spirocyclic ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0289] The term "spirocycloalkyl" refers to a fully saturated polycyclic aromatic hydrocarbon sharing a single carbon atom (called a spiro atom) between its rings. Unless otherwise indicated, the spirocycloalkyl group is 5 to 20 quinary members, preferably 6 to 14 quinary members, and more preferably 8 to 12 quinary members. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups according to the number of spiro atoms shared between the rings, preferably monospirocycloalkyl and bispirocycloalkyl, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include... , , and .

[0290] The term "spiroheteroalkyl" refers to a fully saturated polycyclic ring in which one or more ring atoms are selected from N, O, and S(O). n P(O) n (where n is 0, 1, or 2) heteroatoms (preferably 1 or 2 heteroatoms), with the remaining ring atoms being carbon atoms. Unless otherwise indicated, the spiroheteroalkyl group is 5 to 20 quinary, preferably 6 to 14 quinary, and more preferably 6 to 10 quinary. Spiroheterocycles are classified into monospiroheterocycles, bispiroheterocycles, or multispiroheterocycles according to the number of shared spiro atoms between rings, preferably monospiroheterocycles or bispiroheterocycles, more preferably 4-quinary / 4-quinary, 4-quinary / 5-quinary, 4-quinary / 6-quinary, 5-quinary / 5-quinary, or 5-quinary / 6-quinary monospiroheterocycles. Non-limiting examples of spiroheteroalkyl groups include , , , , or wait.

[0291] The term "heterocyclic alkenyl" refers to a partially unsaturated (but not completely unsaturated) heteroaromatic group that may exist as a monocyclic, fused, bridged, and / or spirocyclic ring. Unless otherwise indicated, the heterocyclic alkenyl is typically a 3-12-membered, 3-10-membered, 3-8-membered, 3-6-membered, 4-12-membered, 4-10-membered, 4-8-membered, 4-6-membered, 5-10-membered, 5-8-membered, 5-7-membered, or 5-6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C=O, NO, and S(O)p, where p is 1 or 2). Examples of heterocyclic alkenyl groups include, but are not limited to, dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyl, dihydrofuranyl, dihydrooxazolyl, dihydroisooxazolyl, dihydrothiophenyl, dihydrothiazolyl, dihydroisothiazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, dihydropyranyl, aza-heptenyl, diaza-heptenyl, oxa-heptenyl, azaoxa-heptenyl, aza-heptendiyl, diaza-heptendiyl, oxa-heptendiyl, azaoxa-heptendiyl, pyridocyclohexenyl, and benzodihydropyrrole.

[0292] The term "heterospirocyclic alkenyl" refers to a partially unsaturated (but not completely unsaturated) heteroaromatic group that exists at least as a spirocyclic ring. Non-limiting examples of heterospirocyclic alkenyl groups include... , , , , , , , , , , , , , , , , , , , or .

[0293] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with 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 groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0294] The term "carbocyclic ring" refers to a cyclic structure composed of carbon atoms, including cycloalkyl, cycloalkenyl, or aryl groups, which can exist as monocyclic, fused, bridged, and / or spirocyclic rings.

[0295] The term "ring" can be selected from cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heterocyclol or heteroaryl.

[0296] The term "heterocyclic group" or "heterocycle" refers to a cyclic group that is fully saturated or partially unsaturated (but not fully unsaturated) of a heteroaromatic group, which may be a monocyclic, fused, bridged, and / or spirocyclic group, containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atoms selected from N, O, and S, with the remaining ring atoms being C. It may be a cyclic group that does not contain double bonds or has at least one or more double bonds. Preferred heterocyclic groups have a single 4- to 8-membered ring, especially a 5- to 8-membered ring (e.g., 5-, 6-, 7-, 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.

[0297] The term "heteroaryl" refers to an aromatic cyclic group having a conjugated electron system, which can be a monocyclic or fused polycyclic system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atoms selected from N, O, and S, with the remaining ring atoms being C. Preferred heteroaryls have a single 4- to 8-membered ring, especially a 5- to 8-membered ring (e.g., 5-, 6-, 7-, 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 heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0298] The terms “substituent,” “optionally substituted with one or more substituents,” or “optionally substituted,” where the substitution or substituent substitution is used, include all substituents mentioned in the context of this document, such as the terms “halogen,” “deuterium,” etc., mentioned below. "-NH2", "-NH(C" 1-4 Alkyl group), -N(C) 1-4 Alkyl)2”, “-OH”, “-OC” 1-4 Alkyl group, -CN, C 1-4"alkyl", "3-6 membered heterocyclic alkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include mercapto, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl Heteroalkyl, halogenated-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclic, heterocyclicoxy, heterocyclicthio, heterocyclic alkylene, heterocyclic alkoxy, heterocyclic alkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group The substituents, such as oxo and oxy, are optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, 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, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0299] The compound may optionally be substituted with one or more substituents selected from deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated - C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 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 group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 The ester group and oxo group, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl group, -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 group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0300] Unless otherwise specified, the term "heteroatom" means heteroatom or heterogroup (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, such as heteroatoms including but not limited to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B), and specific heteroatoms or heterogroups 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 "heterogeneous" means that the heteroatom or heteroatomic group (i.e., a group containing a heteroatom) is selected from oxygen, nitrogen, or sulfur.

[0301] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( The relative configuration of the center of a solid is represented by a wavy line ( ). ) indicates a wedge-shaped solid line key ( ) or wedge-shaped dashed key ( ), or use wavy lines ( ) indicates a straight solid line key ( ) and / or straight dashed key ( ).

[0302] For example, in this application, a wavy line is used ( ) represents one of the absolute configurations of a solid center (e.g. or one, specific express or ) or one of the relative configurations (e.g. express or When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, unless otherwise specified, they include... E、Z Geometric isomers. Similarly, all tautomer forms are included within the scope of this application.

[0303] Groups or structural portions in this application, 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 its specific options, optionally read in a left-to-right order, are respectively connected to the left and right groups of the group or fragment in the general formula, for example, in L selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from left to right, Cy 1 The left side and the corresponding segment on the left side of the general formula or (i.e., PTM, target protein small molecule) link, right side to right side fragment Connect, and the resulting fragment is Optionally, groups or structural moiety such as -LNK in this application 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 its specific options, can be read from right to left, corresponding to the left and right groups of the group or fragment in the general formula, for example, L is selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from right to left, Cy 1 The right side corresponds to the left side of the general formula. or (i.e., PTM) connection, the left side corresponds to the right segment in the general formula. The segments formed by the connection are Other groups are the same as described above.

[0304] The term “treatment” means administering the compound or formulation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) suppressing the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, even if the disease or disease state subsides.

[0305] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0306] The term "therapeutic effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0307] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0308] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0309] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0310] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the 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.

[0311] The word “comprise” or “comprise” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0312] Unless the context clearly indicates otherwise, singular terms in this document encompass the plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" in this document is intended to include "and".

[0313] Unless otherwise stated, all figures used herein to indicate the amount of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0314] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons. Specifically, any compound of this disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist in the form of two tautomers or any mixture of two tautomers, i.e. This disclosure includes all possible tautomers of the compounds disclosed herein, as a single tautomer, or any mixture of said tautomers in any proportion.

[0315] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C14 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.

[0316] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (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. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0317] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0318] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients.

[0319] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0320] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0321] In some implementations, the pharmaceutical composition is in oral form.

[0322] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation.

[0323] The pharmaceutical composition is also suitable for parenteral administration.

[0324] In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.001 to 2000 mg / kg body weight, in the form of single or separate doses.

[0325] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0326] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0327] An important consideration in synthetic route planning in this field is selecting appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. In some embodiments, the compounds of this application can be prepared by those skilled in the art of organic synthesis using the following intermediates or salts thereof through one or more steps in the following routes:

[0328]

[0329]

[0330]

[0331]

[0332]

[0333] Among them, CLM, L, R 2 R 3 R 4 R 5 R 55 , ring F, j, k, L a The definition of ring E is as described in this application; X g Selected from halogens (e.g., -Cl).

[0334] Compounds of general formula IIA-1 and general formula IIA-2 are coupled together to give compound of general formula IIA-3, and then compounds of general formula IIA-3 and general formula IIA-4 are coupled together to give compound of general formula IIA.

[0335] Compounds of general formula IIA-1 and general formula IIA-4 are coupled together to give compound of general formula IIA-6, and then compounds of general formula IIA-6 and general formula IIA-2 are coupled together to give compound of general formula IIA.

[0336] Compounds of general formula IIA-6 and general formula IIA-7 are coupled to give compound of general formula IIA-8. Compound of general formula IIA-8 is deprotected to give compound of general formula IIA-9. Compounds of general formula IIA-9 and general formula IIA-10 are reduced amination to give compound of general formula IIA.

[0337] Compounds of general formula IIA-1 and general formula IIA-7 are coupled together to give compound of general formula IIA-11; compound of general formula IIA-11 and compound of general formula IIA-4 are coupled together to give compound of general formula IIA-8; compound of general formula IIA-8 is deprotected to give compound of general formula IIA-9; and compound of general formula IIA-9 and compound of general formula IIA-10 are reduced amination to give compound of general formula IIA.

[0338] In some embodiments, intermediate XII-A and intermediate XII-B undergo a coupling reaction under catalytic and alkaline conditions to obtain compound XII.

[0339] In some implementations, the catalyst is selected from XPhos Pd G3.

[0340] In some implementations, the base is selected from cesium fluoride.

[0341] In some implementations, the coupling reaction is carried out under nitrogen protection.

[0342] This application uses the following abbreviations Boc represents tert-butoxycarbonyl; DCM represents dichloromethane; THF represents tetrahydrofuran; XPhos Pd G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); PdCl2(dppf) represents [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; LHMDS represents bis(trimethylsilylamino)lithium; DIPEA represents N,N-diisopropylethylamine; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; EA represents ethyl acetate; DMF represents N,N-dimethylformamide; HOBt represents 1-hydroxybenzotriazole. DC 50 The values ​​represent the drug concentration at which the degradation rate reaches 50%; Dmax represents the maximum degradation rate; TFA represents trifluoroacetic acid; DMSO represents dimethyl sulfoxide; MeOH represents methanol; DCE represents 1,2-dichloroethane; IPA represents isopropanol; TBS represents tert-butyldimethylsilyl; Trt represents triphenylmethyl; and IBX represents 2-iodobenzoic acid.

[0343] For clarity, the invention is further illustrated by examples, but these examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. Detailed Implementation

[0344] Example 1 of intermediate preparation:

[0345] Step 1: Synthesis of intermediate 1w-2 In a reaction flask, 1w-1 (1.7 g, see WO2023109471, Preparation of ethyl 6-azaspiro[3.4]octane-7-carboxylate), dichloromethane (20 mL), triphenylchloromethane (3.88 g), and triethylamine (3.88 mL) were added sequentially, and the mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography to obtain intermediate 1w-2 (2.1 g). Step 2: Synthesis of intermediate 1w-3 In a reaction flask, 1w-2 (320 mg) and tetrahydrofuran (5 mL) were added sequentially. Under ice bath conditions, LiAlH4 (57 mg) was added, and the mixture was reacted in an ice bath for 1 h. After the reaction was complete, 1 mL of water was added dropwise to the reaction solution, followed by 1 mL of 15% sodium hydroxide aqueous solution. Then, 10 mL of dichloromethane was added for dilution, and the mixture was stirred for 10 min. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain intermediate 1w-3 (300 mg).

[0346] Step 3: Synthesis of intermediate 1w-4 In a reaction flask, intermediate 1w-3 (300 mg), THF (10 mL), and triethylamine (0.325 mL) were added, followed by the slow addition of trifluoroacetic anhydride (0.163 mL). The mixture was reacted overnight at 70 °C. After the reaction was complete, the reaction solution was cooled to room temperature, quenched by the slow addition of 15% NaOH solution, extracted with EA, and the organic phase was washed with saturated ammonium chloride and dried over anhydrous sodium sulfate. The concentrate yielded intermediate 1w-4 (210 mg).

[0347] Step 4: Synthesis of intermediate 1w-5 Intermediate 1w-4 (167g), DMSO (1 L), and IBX (305g) were added to the reaction flask, and the reaction was carried out at 30°C for 2 hours. After the reaction was completed, EA was added for dilution, the mixture was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 1w-5 (137g).

[0348] Step 5: Synthesis of intermediate 1w-6 Intermediate 1w-5 (137 g), N-phenylbis(trifluoromethanesulfonyl)imide (133 g), and tetrahydrofuran (2 L) were added to a reaction flask. The mixture was purged with nitrogen and cooled to 0 °C. Then, bis(trimethylsilylamino)lithium (402 mL, 1 M toluene solution) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 h. After the reaction was complete, the reaction solution was quenched in saturated ammonium chloride solution, extracted with EA, and the EA layer was collected, dried, concentrated, and purified by column chromatography to obtain intermediate 1w-6 (110 g).

[0349] Step 6: Synthesis of intermediate 1w-7 Intermediate 1w-6 (110 g), dipentylene glycol diborone (58.1 g), bis(triphenylphosphine)palladium dichloride (7.52 g), potassium acetate (42 g), and dioxane (1.5 L) were added to a reaction flask. Under nitrogen protection, the reaction was carried out at 100 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate and water were added, the organic layer was separated, dried, concentrated, and purified by column chromatography to obtain intermediate 1w-7 (59.3 g).

[0350] Step 7: Synthesis of intermediate 1wa Intermediate 1w-7 (59.3 g), ethyl acetate (600 mL), and 4M dioxane hydrochloride solution (155 mL) were added to the reaction flask and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was then slurried with petroleum ether to obtain intermediate 1wa (30.3 g).

[0351] Example 2: Synthesis of intermediate Z1K

[0352] Step 8: Preparation of intermediate Z1i To a single-necked flask, 1wa (0.62 g), DCM (10 mL), 3-(1H-1,2,3-triazol-1-yl)propionic acid (0.26 g), DIPEA (0.91 mL), and HATU (0.95 g) were added sequentially, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was quenched with citric acid, extracted with EA, and the organic layer was washed first with sodium bicarbonate solution, then with sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness to obtain intermediate Z1i (0.55 g).

[0353] MS(ESI, [M+H)) + ) m / z 359.13 Step 9: Preparation of intermediate Z1K Add Z1i (1.7 g), Z1j (2.4 g, refer to the preparation process of intermediate T in WO2025049820), PdCl2 (dppf) (0.39 g), cesium fluoride (2.1 g), and 1,4-dioxane / water = 5 / 1 (v:v, 40 mL) to a single-necked flask in sequence. Heat the mixture to 100°C under N2 protection. o C. After the reaction was complete, the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation, and the intermediate Z1K (2.1 g) was purified by silica gel column chromatography.

[0354] MS(ESI, [M+H)) + ) m / z 485.21 Example 1XY: Synthesis of compound 1XY

[0355] Step 1: Preparation of compound 1XY To a single-necked flask, intermediate Z1K (90 mg), XPhos Pd G3 (31.4 mg), water (2 mL), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperazine (50.5 mg), cesium fluoride (85 mg), and 1,4-dioxane (10.00 mL) were added sequentially. The reaction was carried out at 100°C under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature. The solvent was removed by vacuum distillation, and the solution was purified by silica gel column chromatography to obtain compound 1XY (37 mg).

[0356] MS(ESI, [M+H)) + ) m / z : 625.34.

[0357] 1H NMR (500 MHz, DMSO) δ 12.11 (dd, J = 12.1, 2.2 Hz, 1H), 8.11 (dd, J =18.1, 1.0 Hz, 1H), 7.68 (dd, J = 16.3, 1.0 Hz, 1H), 7.52 (dd, J = 8.8, 2.4 Hz,2H), 7.08 – 7.01 (m, 2H), 6.97 (dd, J = 25.3, 6.1 Hz, 1H), 6.84 (dt, J = 3.9, 2.0Hz, 1H), 6.27 – 6.21 (m, 1H), 4.64 (dt, J = 20.4, 6.8 Hz, 2H), 4.30 (dd, J =18.0, 1.9 Hz, 2H), 3.69 (d, J = 44.5 Hz, 2H), 3.26 – 2.93 (m, 12H), 2.48 (d, J =5.2 Hz, 4H), 2.24 (s, 3H), 2.06 – 1.82 (m, 6H). Example 1: Synthesis of Compound 1

[0358]

[0359]

[0360] Step 1: Preparation of intermediate 1m To a single-necked flask, add 1 L (1.4 g, refer to the preparation process of intermediate FK in WO2025049820), pinacol diboronate (0.809 g), PdCl2 (dppf) (0.194 g), potassium acetate (0.782 g), and 1,4-dioxane (20 mL) in sequence. Under N2 protection, heat the mixture to 90°C. o C reaction. After the reaction was complete, the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation, and the solution was purified by silica gel column chromatography to obtain intermediate 1m (0.75 g).

[0361] MS(ESI, [M+H)) + ) m / z 574.95 Step 2: Preparation of intermediate 1u 1 t (7 g) and N-phenylbis(trifluoromethanesulfonyl)imide (11 g) were added to anhydrous THF (200 mL), and LHMDS (32 mL, 1 M in THF) was added dropwise at -78 °C. After the addition was complete, the reaction was allowed to proceed for 30 min, and then the reaction was allowed to continue at room temperature. After the reaction was completed, a saturated solution of ammonium chloride was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography to obtain intermediate 1 u (4 g).

[0362] Step 3: Preparation of intermediate 1v 1u (4 g), neopentyl glycol diboronate (2.4 g), palladium dichloride bis(triphenylphosphine) (378 mg), potassium acetate (2.1 g), and 1,4-dioxane (40 mL) were mixed and reacted at 100 °C for 2 h. After the reaction was completed, ethyl acetate and saturated brine were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain intermediate 1v (2.4 g).

[0363] Step 4: Preparation of intermediate 1w 1 v (300 mg) and trifluoroacetic acid (3 mL) were reacted at room temperature for 1 h. After the reaction was completed, the mixture was concentrated to give intermediate 1 w (310 mg).

[0364] Step 5: Preparation of intermediate 1x 1w (310 mg) was added to DCM (10 mL), along with 3-(1-pyrazolyl)propionic acid (132 mg), DIPEA (0.45 mL), and HATU (490 mg). The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was quenched with citric acid, extracted with EA, and the organic layer was washed first with sodium bicarbonate, then with sodium chloride solution, and then dried over anhydrous sodium sulfate. The filtrate was then concentrated to dryness to obtain intermediate 1x (257 mg).

[0365] MS (ESI) m / z [M+H] + 358.3 Step 6: Preparation of intermediate 1y 1 g (60 mg, referring to the preparation method of intermediate C in WO2025049820), 1 m (108 mg), PdCl2 (dppf) (13 mg), cesium fluoride (86 mg), and 1,4-dioxane / water = 5 / 1 (v:v = 5 mL) were added to the reaction flask, and the reaction was carried out at 100 °C. After the reaction was completed, the reaction solution was quenched with a saturated ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain intermediate 1y (101 mg).

[0366] MS (ESI) m / z [M+H] + 687.2 Step 7: Preparation of Compound 1 1y (50 mg), 1x (31 mg), XPhos Pd G3 (6 mg), cesium fluoride (33 mg), and 1,4-dioxane / water = 5 / 1 (v:v 5 mL) were added to a reaction flask, and the reaction was carried out at 120 °C. After the reaction was completed, the reaction solution was quenched with a saturated ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain compound 1 (41 mg).

[0367] MS (ESI) m / z [M+H] + 896.3 1 H NMR (500 MHz, DMSO- d 6) δ 12.22 (d, J = 14.7 Hz, 1H), 10.85 (s, 1H), 7.71 (dd, J = 16.7, 2.3 Hz, 1H), 7.40 (dd, J = 35.6, 1.8 Hz, 1H), 7.32 (q, J = 7.5Hz, 1H), 7.03 (dd, J = 22.2, 6.3 Hz, 2H), 6.71 (d, J = 8.1 Hz, 1H), 6.68 – 6.63(m, 1H), 6.59 (d, J = 14.2 Hz, 1H), 6.29 – 6.14 (m, 2H), 5.14 (d, J = 6.8 Hz, 1H), 4.38 (dt, J = 20.0, 6.8 Hz, 2H), 4.34 – 4.22 (m, 3H), 3.82 (s, 3H), 3.67(d, J = 50.9 Hz, 2H), 3.28 (t, J = 4.8 Hz, 4H), 3.23 – 2.93 (m, 11H), 2.81 (ddd, J= 18.0, 13.2, 5.3 Hz, 1H), 2.58 – 2.52 (m, 1H), 2.19 – 2.10 (m, 2H), 2.07 –1.83 (m, 7H). Example 2: Synthesis of Compound 2

[0368] Step 1: Preparation of compound 2d Following the method described in step 6 of Example 1, intermediate 1m was replaced with intermediate 2c (refer to the preparation process of intermediate OP in WO2025049820) to synthesize compound 2d (1.0g).

[0369] MS(ESI, [M+H)) + m / z: 605.51 Step 2: Preparation of Compound 2 Following the method described in step 7 of Example 1, intermediate 2 (50 mg) was synthesized by replacing intermediate 1y with intermediate 2d.

[0370] MS(ESI, [M+H)) + m / z: 814.75 1 H NMR (500 MHz, DMSO- d 6) δ 12.18 (d, J = 13.6 Hz, 1H), 10.82 (s, 1H), 7.71 (dd, J = 16.3, 2.3 Hz, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.48 – 7.35 (m, 3H), 7.10 – 6.95 (m, 4H), 6.87 (q, J = 2.8 Hz, 1H), 6.30 – 6.15 (m, 2H), 4.44 – 4.24(m, 4H), 3.82 (dd, J = 11.8, 4.9 Hz, 1H), 3.73 (s, 1H), 3.62 (s, 1H), 3.49 (d, J = 11.0 Hz, 2H), 3.02 (dt, J = 47.8, 6.9 Hz, 8H), 2.86 – 2.62 (m, 4H), 2.53 (s,1H), 2.21 (qd, J= 12.5, 4.5 Hz, 1H), 2.07 – 1.83 (m, 11H). Example 3: Synthesis of Compound 3

[0371] Step 1: Preparation of intermediate 3a 1,2,3-triazole (3.0 g), tert-butyl acrylate (5.5 g), and pyridine (0.34 g) were added to a reaction flask, and the reaction was carried out at 90 °C for 6 h. After the reaction was completed, part of the solvent was concentrated, water and ethyl acetate were added, the organic phase was separated, washed with saturated brine, concentrated, and purified by silica gel column chromatography to obtain compound 3a (4.0 g).

[0372] MS(ESI, [M+H)) + m / z: 198.23 Step 2: Preparation of intermediate 3b 3a (4.0 g), dichloromethane (30 mL), and trifluoroacetic acid (15 mL) were added to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the solvent was directly concentrated to obtain compound 3b (6.0 g).

[0373] MS(ESI, [M+H)) + m / z: 142.13 Step 3: Preparation of intermediate 3c Add 1w (0.62 g), DCM (10 mL), 3b (0.26 g), DIPEA (0.91 mL), and HATU (0.95 g) sequentially to a single-necked flask and react at room temperature. After the reaction is complete, quench the reaction solution with citric acid, extract with EA, wash the organic layer with sodium bicarbonate solution, then wash with sodium chloride solution, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain intermediate 3c (0.55 g).

[0374] MS(ESI, [M+H)) + ) m / z 359.13 Step 4: Preparation of Compound 3 Following the method described in step 7 of Example 1, intermediate 2d was used instead of intermediate 1y, and intermediate 3c was used instead of intermediate 1x to synthesize compound 3 (30 mg).

[0375] MS(ESI, [M+H)) + ) m / z 815.59 1 H NMR (500 MHz, DMSO- d6) δ 12.18 (s, 1H), 10.82 (s, 1H), 8.11 (d, J =18.2 Hz, 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 7.9Hz, 2H), 7.11 – 7.01 (m, 3H), 6.98 (dd, J = 8.3, 2.1 Hz, 1H), 6.87 (t, J = 3.0Hz, 1H), 6.27 (d, J = 12.0 Hz, 1H), 4.64 (dt, J = 20.5, 6.8 Hz, 2H), 4.31 (d, J =18.4 Hz, 2H), 3.82 (dd, J = 11.8, 4.9 Hz, 1H), 3.74 (s, 1H), 3.65 (s, 1H), 3.57(s, 1H), 3.49 (d, J = 11.3 Hz, 2H), 3.18 (t, J = 6.8 Hz, 3H), 3.10 (t, J = 6.9 Hz, 4H), 2.82 (t, J = 11.2 Hz, 2H), 2.79 – 2.71 (m, 1H), 2.66 (ddd, J = 17.1, 12.0,5.2 Hz, 1H), 2.53 (s, 1H), 2.21 (qd, J = 12.5, 4.4 Hz, 1H), 2.03 (dd, J = 9.8,4.3 Hz, 4H), 1.98 – 1.85 (m, 7H). Example 4: Synthesis of Compound 4

[0376] Step 1: Preparation of Compound 4 Following the method described in step 7 of Example 1, intermediate 3c was used instead of intermediate 1x to synthesize compound 4 (35 mg).

[0377] MS(ESI, [M+H))+ m / z: 897.7 1 H NMR (500 MHz, DMSO- d 6) δ 12.26 – 12.19 (m, 1H), 10.85 (s, 1H), 8.11(d, J = 17.8 Hz, 1H), 7.68 (d, J = 15.8 Hz, 1H), 7.32 (q, J = 7.4 Hz, 1H), 7.04 (dd, J = 27.2, 6.6 Hz, 2H), 6.75 – 6.64 (m, 2H), 6.59 (d, J = 14.1 Hz, 1H), 6.25 (d, J = 8.5 Hz, 1H), 5.14 (d, J = 6.8 Hz, 1H), 4.64 (dt, J = 20.2, 6.8 Hz, 2H), 4.30 (d, J = 18.8 Hz, 3H), 3.82 (s, 3H), 3.73 (s, 1H), 3.65 (s, 1H), 3.28 (t, J =4.5 Hz, 4H), 3.23 – 3.00 (m, 12H), 2.81 (ddd, J = 18.0, 13.1, 5.4 Hz, 1H), 2.60– 2.53 (m, 1H), 2.20 – 2.11 (m, 1H), 2.07 – 1.87 (m, 7H). Example 5: Synthesis of Compound 5

[0378] Step 1: Preparation of intermediate 5a To a single-necked flask, 1w (100 mg), 1-cyano-1-cyclopropanecarboxylic acid (40.9 mg), DMF (5 mL), HOBt (85 mg), and HATU (182 mg) were added sequentially, and the mixture was reacted at room temperature. After the reaction was complete, the reaction solution was quenched with citric acid, extracted with EA, and the organic layer was washed first with sodium bicarbonate solution, then with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain intermediate 5a (80 mg).

[0379] Step 2: Preparation of Compound 5 Following the method described in step 7 of Example 1, intermediate 5 (30 mg) was synthesized by replacing intermediate 1x with intermediate 5a.

[0380] MS(ESI, [M+H)) + ) m / z 867.50 1 H NMR (500 MHz, DMSO- d 6) δ 12.24 (s, 1H),10.85 (s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.11 – 6.97 (m, 2H), 6.75 – 6.64 (m,2H), 6.59 (d, J = 14.1 Hz, 1H), 6.31 (s, 1H), 5.14 (d, J = 6.8 Hz, 1H), 4.62 (s,1H), 4.28 (dt, J = 12.1, 6.0 Hz, 2H), 3.82 (s, 5H), 3.28 (d, J = 6.1 Hz, 4H), 3.18 (s, 2H), 3.12 (t, J = 4.9 Hz, 5H), 3.05 (s, 2H), 2.81 (ddd, J = 18.1, 13.2,5.3 Hz, 1H), 2.57 (t, J = 3.4 Hz, 1H), 2.55 – 2.52 (m, 1H), 2.17 – 1.91 (m,8H), 1.68 (s, 2H), 1.53 (s, 2H). Example 6: Synthesis of Compound 6

[0381] Step 1: Preparation of intermediate 6a At -20 °C, 88.0 g of NaOMe was added dropwise to a MeOH solution of 2-chloro-4-bromobenzaldehyde (29 g) and ethyl azide (63 g) in 300 mL. After the addition was complete, the mixture was stirred at this temperature for 0.5 h, and then the temperature was raised to room temperature for 2 h. After the reaction was complete, the reaction solution was quenched in a saturated ammonium chloride solution, extracted with ethyl acetate, washed with a saturated sodium chloride solution, concentrated, and purified by silica gel column chromatography to obtain compound 6a (14 g).

[0382] MS(ESI, [M+H)) + m / z: 330.12 Step 2: Preparation of intermediate 6b Add 14 g of 6a and 140 mL of xylene to the reaction flask and react at 150 °C for 1 h. After the reaction is complete, cool the reaction solution to 0 °C, filter, collect the filter cake, and dry it to obtain compound 6b (4.2 g).

[0383] MS(ESI, [M+H)) + m / z: 288.31 Step 3: Preparation of intermediate 6c Intermediate 6b (4.2 g), methanol (30 mL), and water (10 mL) were added to a reaction flask, followed by lithium hydroxide (1.71 g). The reaction was carried out at 40 °C for 10 h. After the reaction was completed, hydrochloric acid (4N) was added to adjust the pH to 5, and EA was added for extraction. The organic layer was collected and concentrated to obtain compound 6c (3.8 g).

[0384] MS(ESI, [M+H)) + m / z: 274.22 Step 4: Preparation of intermediate 6d 6c (3.8 g), N,N-diisopropylethylamine (8.95 g), 1-hydroxybenzotriazole (3.18 g), dimethylamine hydrochloride (1.5 g), and DMF were added to a reaction flask, followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (6.8 g). The reaction was carried out at room temperature for 2 h. After the reaction was complete, water was added, the mixture was filtered, the filter cake was collected, and dried to obtain compound 6d (3.6 g).

[0385] MS(ESI, [M+H)) + m / z: 301.32 Step 5: Preparation of intermediate 6e Intermediate 6d (0.15 g), intermediate 3c (0.25 g), cesium fluoride (0.24 g), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.08 g), dioxane (2 mL), and water (0.4 mL) were added to a reaction flask, and the mixture was reacted at 100 °C for 2 h. After the reaction was complete, the reaction solution was purified by silica gel column chromatography to obtain intermediate 6e (0.12 g).

[0386] MS(ESI, [M+H)) + m / z: 467.33 Step 6: Preparation of intermediate 6f Intermediate 6e (0.12 g), 4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester (0.25 g), potassium phosphate (0.16 g), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.04 g), dioxane (2 mL), and water (0.4 mL) were added to a reaction flask, and the mixture was microwaved at 120 °C for 2 h. After the reaction was completed, the reaction solution was purified by silica gel column chromatography to obtain intermediate 6f (0.11 g).

[0387] MS(ESI, [M+H)) + m / z: 693.41 Step 7: Preparation of 6g of intermediate Intermediate 6f (0.05 g), trifluoroacetic acid (1 mL), and dichloromethane (1 mL) were added to a reaction flask and reacted at room temperature for 1 h. After the reaction was complete, saturated sodium bicarbonate solution and ethyl acetate were added for extraction. The organic phase was dried and the solvent was concentrated to obtain intermediate 6 g (0.05 g).

[0388] MS(ESI, [M+H)) + m / z: 593.46 Step 8: Preparation of Compound 6 Intermediate 6 g (0.05 g), intermediate 6 h (0.04 g, referring to the preparation method of intermediate K in WO2025049820), isopropanol (3 mL), and 1,2-dichloroethane (3 mL) were added to a reaction flask, followed by sodium triacetoxyborohydride (0.04 g). The reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction system was quenched with saturated sodium bicarbonate solution, and then extracted with dichloromethane. The organic layer was separated, washed with saturated sodium chloride solution, and collected. Compound 6 (0.04 g) was obtained by silica gel column chromatography.

[0389] MS(ESI, [M+H)) + m / z: 892.03 1 H NMR (500 MHz, DMSO) δ 11.63 (d, J = 22.9 Hz, 1H), 11.08 (s, 1H), 8.12 (d, J = 9.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.36(d, J = 10.5 Hz, 1H), 7.19 (d, J= 4.8 Hz, 1H), 7.10 – 6.98 (m, 4H), 6.93 – 6.83(m, 2H), 6.41 (d, J = 21.8 Hz, 1H), 5.34 (dd, J = 12.9, 5.4 Hz, 1H), 4.66 (dt, J =14.5, 6.8 Hz, 2H), 4.34 (d, J = 8.1 Hz, 2H), 3.67 (d, J = 41.0 Hz, 2H), 3.34 (s,3H), 3.26 – 3.02 (m, 11H), 2.90 (ddd, J = 17.3, 13.4, 5.4 Hz, 1H), 2.76 – 2.60(m, 4H), 2.54 (t, J = 5.0 Hz, 4H), 2.37 (t, J = 7.2 Hz, 2H), 2.03 (q, J = 7.4 Hz, 4H), 1.91 (d, J = 5.0 Hz, 4H), 1.81 (p, J = 7.5 Hz, 2H). Example 7 Synthesis of Compound 7

[0390] Step 1: Preparation of intermediate 7a 1 g (0.2 g) of intermediate, 0.25 g (4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester), 0.26 g (potassium carbonate), 0.09 g (1,1'-bis(diphenylphosphino)ferrocene palladium dichloride), 2 mL (dioxane), and 0.4 mL (water) were added to a reaction flask, and the mixture was reacted at 100 °C for 2 h. After the reaction was completed, the reaction solution was purified by silica gel column chromatography to obtain intermediate 7a (0.27 g).

[0391] MS(ESI, [M+H)) + m / z: 501.32 Step 2: Preparation of intermediate 7b Intermediate 7a (0.1 g), intermediate 3c (0.09 g), cesium fluoride (0.09 g), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (0.03 g), dioxane (2 mL), and water (0.4 mL) were added to the reaction flask, and the reaction was carried out at 100 °C for 2 h. After the reaction was completed, the reaction solution was purified by silica gel column chromatography to obtain intermediate 7b (0.05 g).

[0392] MS(ESI, [M+H)) + m / z: 711.43 Step 3: Preparation of intermediate 7c Following the method described in step 7 of Example 6, intermediate 7b was used instead of intermediate 6f to synthesize compound 7c (0.06 g).

[0393] MS(ESI, [M+H)) + m / z: 611.51 Step 4: Preparation of Compound 7 Following the method described in step 8 of Example 6, intermediate 7c was used instead of intermediate 6g to synthesize compound 7 (0.05 g).

[0394] MS(ESI, [M+H)) + m / z: 910.71 1 H NMR (500 MHz, DMSO) δ 12.15 – 12.08 (m, 1H), 11.08 (s, 1H), 8.11(d, J = 18.1 Hz, 1H), 7.68 (d, J = 16.4 Hz, 1H), 7.56 – 7.49 (m, 2H), 7.10 – 6.88(m, 6H), 6.84 (q, J = 2.5 Hz, 1H), 6.24 (d, J = 11.4 Hz, 1H), 5.34 (dd, J = 12.9, 5.4 Hz, 1H), 4.64 (dt, J = 20.3, 6.8 Hz, 2H), 4.30 (d, J = 18.1 Hz, 2H), 3.69 (d, J= 44.4 Hz, 2H), 3.34 (s, 3H), 3.25 – 3.15 (m, 7H), 3.09 (t, J = 6.8 Hz, 4H), 2.90 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.76 – 2.62 (m, 4H), 2.57 (d, J = 30.0Hz, 4H), 2.37 (s, 2H), 2.08 – 1.98 (m, 4H), 1.96 – 1.79 (m, 6H). Example 8: Synthesis of Compound 8

[0395] Step 1: Preparation of intermediate 8b Add 3c (1.7 g), 8a (2.4 g, refer to the preparation process of intermediate T in WO2025049820) sequentially to a single-necked flask, PdCl2 (dppf) (0.39 g), cesium fluoride (2.1 g), and 1,4-dioxane / water = 5 / 1 (v:v, 40 mL). Heat the mixture to 100°C under N2 protection. o C reaction. After the reaction was complete, the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation, and the solution was purified by silica gel column chromatography to obtain intermediate 8b (2.1 g).

[0396] MS(ESI, [M+H)) + ) m / z 485.21 Step 2: Preparation of intermediate 8d To a single-necked flask, add 8c (200 mg, refer to the preparation process of intermediate T in WO2025049820), pinacol diboronate (136 mg), PdCl2 (dppf) (32 mg), potassium acetate (130 mg), and 1,4-dioxane (5 mL) in sequence. Under N2 protection, heat the mixture to 90°C. o C reaction. After the reaction was complete, the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation, and the solution was purified by silica gel column chromatography to obtain intermediate 8d (180 mg).

[0397] MS(ESI, [M+H)) + ) m / z 539.33 Step 3: Preparation of Compound 8 Compound 8 (80 mg), 8d (106 mg), Xphos Pd G3 (14 mg), cesium fluoride (75 mg), and 1,4-dioxane / water = 5 / 1 (v:v, 5 mL) were added sequentially to a single-necked flask, and the reaction was carried out at 110 °C. After the reaction was completed, the reaction solution was quenched with a saturated ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain compound 8 (41 mg).

[0398] MS (ESI) m / z [M+H] + 861.23 1 H NMR (500 MHz, DMSO- d 6) δ 12.13 (d, J = 11.8 Hz, 1H), 10.86 (s, 1H), 8.12 (d, J = 18.8 Hz, 1H), 7.69 (d, J = 15.7 Hz, 1H), 7.57 – 7.53 (m, 2H), 7.11(d, J = 8.4 Hz, 2H), 6.99 (dd, J = 25.7, 6.1 Hz, 1H), 6.86 (q, J = 2.5 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 14.2 Hz, 1H), 6.25 (d, J = 11.3 Hz, 1H), 5.14 (d, J = 6.9 Hz, 1H), 4.64 (dt, J = 20.0, 6.8 Hz, 2H), 4.31 (d, J = 18.1 Hz,3H), 3.82 (s, 3H), 3.74 (s, 1H), 3.65 (s, 1H), 3.36 (dd, J = 5.7, 3.0 Hz, 4H), 3.19 (t, J = 6.8 Hz, 4H), 3.09 (t, J = 5.2 Hz, 8H), 2.82 (ddd, J= 18.0, 13.2, 5.4Hz, 1H), 2.59 – 2.52 (m, 1H), 2.14 (d, J = 13.0 Hz, 1H), 2.09 – 1.98 (m, 3H), 1.96 – 1.84 (m, 4H). Examples 9 and 10: Synthesis of compounds 9 and 10

[0399] Compound 4 (110 mg) was separated by chiral HPLC (column: whelk-o1, 5 μm, 21*250 mm; mobile phase A: 70% ethanol-dichloromethane (1:2), mobile phase B: 30% n-hexane) to obtain compounds 9 (45 mg) and 10 (45 mg).

[0400] Compound 9: MS(ESI, [M+H]) + m / z: 897.45 1 H NMR (500 MHz, DMSO- d 6) δ 12.22 (d, J = 12.5 Hz, 1H), 10.85 (s, 1H), 8.16 – 8.06 (m, 1H), 7.68 (d, J = 15.5 Hz, 1H), 7.32 (q, J = 7.3 Hz, 1H), 7.09 –6.96 (m, 2H), 6.71 (d, J = 8.1 Hz, 1H), 6.66 (s, 1H), 6.59 (d, J = 14.2 Hz, 1H), 6.25 (d, J = 8.5 Hz, 1H), 5.14 (d, J = 6.8 Hz, 1H), 4.64 (dt, J = 20.3, 6.8 Hz, 2H), 4.29 (dd, J = 18.7, 13.7 Hz, 3H), 3.82 (s, 3H), 3.73 (s, 1H), 3.65 (s,1H), 3.28 (t, J = 4.8 Hz, 4H), 3.22 – 2.95 (m, 12H), 2.81 (ddd, J= 18.1, 13.2,5.4 Hz, 1H), 2.59 – 2.52 (m, 1H), 2.20 – 2.08 (m, 1H), 2.09 – 1.81 (m, 7H). Compound 10: MS (ESI, [M+H]) + m / z: 897.38 1 H NMR (500 MHz, DMSO- d 6) δ 12.22 (d, J = 12.5 Hz, 1H), 10.85 (s, 1H), 8.16 – 8.06 (m, 1H), 7.68 (d, J = 15.5 Hz, 1H), 7.32 (q, J = 7.3 Hz, 1H), 7.09 –6.96 (m, 2H), 6.71 (d, J = 8.1 Hz, 1H), 6.66 (s, 1H), 6.59 (d, J = 14.2 Hz, 1H), 6.25 (d, J = 8.5 Hz, 1H), 5.14 (d, J = 6.8 Hz, 1H), 4.64 (dt, J = 20.3, 6.8 Hz, 2H), 4.29 (dd, J = 18.7, 13.7 Hz, 3H), 3.82 (s, 3H), 3.73 (s, 1H), 3.65 (s,1H), 3.28 (t, J = 4.8 Hz, 4H), 3.22 – 2.95 (m, 12H), 2.81 (ddd, J = 18.1, 13.2,5.4 Hz, 1H), 2.59 – 2.52 (m, 1H), 2.20 – 2.08 (m, 1H), 2.09 – 1.81 (m, 7H). Example 11 Synthesis of Compound 11

[0401] Step 1: Preparation of intermediate 11a 1-Boc-4-(4-bromophenoxy)piperidine (5 g), TFA (25 mL), and DCM (50 mL) were mixed and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was directly evaporated to dryness to obtain intermediate 11a (7.9 g).

[0402] MS(ESI, [M+H)) + ) m / z 256.2 Step 2: Preparation of intermediate 11b 11a (7.4 g), 3,4-difluoro-6-nitrobenzene ether (2.6 g), DIPEA (9.5 g), and DMSO (70 mL) were added to a reaction flask and mixed. The mixture was reacted at 100 °C for 2 h. After the reaction was complete, the reaction solution was quenched in a saturated ammonium chloride solution, extracted with ethyl acetate, washed with a saturated sodium chloride solution, and concentrated to obtain intermediate 11b (5.6 g).

[0403] MS(ESI, [M+H)) + ) m / z 425.3 Step 3: Preparation of intermediate 11c Add 11b (5 g), reduced iron powder (6.5 g), ammonium chloride (6.5 g), ethanol (120 mL), and water (30 mL) to a reaction flask and mix. React at 90°C for 2 h. After the reaction is complete, filter to remove insoluble solids. Concentrate the filtrate, dilute with water, extract twice with EA, combine the organic layers, wash with saturated sodium chloride solution, and concentrate to obtain intermediate 11c (5 g).

[0404] MS(ESI, [M+H)) + ) m / z 395.3 Step 4: Preparation of intermediate 11d 11c (4.6 g), 3-bromopiperidine-2,6-dione (4.5 g), sodium bicarbonate (3 g), and DMF (50 mL) were added to a reaction flask and mixed. The mixture was reacted at 90 °C for 3 h. The reaction solution was quenched in a saturated ammonium chloride solution, extracted with ethyl acetate, washed with a saturated sodium chloride solution, and concentrated to obtain intermediate 11d (6.5 g).

[0405] MS(ESI, [M+H)) + ) m / z 506.5 Step 5: Preparation of intermediate 11e Referring to step 1 of Example 1, intermediate 11d (500 mg) was used to replace 1l to obtain intermediate 11e (390 mg).

[0406] MS(ESI, [M+H)) + ) m / z 554.4 Step 5: Preparation of Compound 11 Referring to step 3 of Example 8, intermediate 11e (170 mg) was replaced with 8d to obtain compound 11 (105 mg).

[0407] MS(ESI, [M+H)) + ) m / z 876.39 1 H NMR (500 MHz, DMSO- d 6) δ 12.15 (d, J = 11.3 Hz, 1H), 10.84 (s, 1H), 8.11 (d, J = 18.2 Hz, 1H), 7.68 (d, J = 15.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.11(d, J = 8.3 Hz, 2H), 7.04 – 6.97 (m, 1H), 6.85 (d, J = 3.8 Hz, 1H), 6.66 (d, J =8.1 Hz, 1H), 6.56 (d, J = 14.2 Hz, 1H), 6.25 (d, J = 12.2 Hz, 1H), 5.11 (d, J = 6.8Hz, 1H), 4.64 (dt, J = 19.8, 6.8 Hz, 3H), 4.34 – 4.24 (m, 3H), 3.80 (s, 3H), 3.74 (s, 1H), 3.65 (s, 1H), 3.24 – 3.03 (m, 10H), 2.91 (t, J = 10.0 Hz, 2H), 2.80 (td, J = 13.0, 6.6 Hz, 1H), 2.16 – 1.80 (m, 13H). Example 12: Synthesis of Compound 12

[0408] Step 1: Preparation of intermediate 12b Referring to step 3 of Example 8, 8b was replaced with intermediate 6e and 8d was replaced with intermediate 12a to obtain intermediate 12b (0.15 g).

[0409] MS(ESI, [M+H)) + ) m / z 723.51 Step 2: Preparation of intermediate 12c Following the method described in step 7 of Example 6, intermediate 6f was replaced with intermediate 12b to synthesize compound 12c (0.15 g).

[0410] MS(ESI, [M+H)) + ) m / z 623.45 Step 3: Preparation of Compound 12 Following the method described in step 8 of Example 6, intermediate 12 (40 mg) was synthesized by replacing intermediate 6 g with intermediate 12c.

[0411] MS(ESI, [M+H)) + ) m / z : 922.14 1 H NMR (500 MHz, DMSO- d 6) δ 11.47 (d, J = 25.7 Hz, 1H), 11.08 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 10.4 Hz, 1H), 7.19(d, J = 8.3 Hz, 1H), 7.11 – 6.98 (m, 3H), 6.91 (d, J = 8.1 Hz, 1H), 6.70 – 6.57(m, 2H), 6.48 (dd, J = 6.4, 2.2 Hz, 1H), 6.33 (d, J = 14.4 Hz, 1H), 5.34 (dd, J =12.9, 5.4 Hz, 1H), 4.65 (dt, J = 16.9, 6.9 Hz, 2H), 4.32 (d, J= 11.7 Hz, 2H), 3.76 – 3.59 (m, 5H), 3.29 – 2.98 (m, 13H), 2.90 (td, J = 15.4, 5.3 Hz, 1H), 2.68 (pt, J = 14.4, 7.1 Hz, 4H), 2.54 (t, J = 4.8 Hz, 4H), 2.37 (t, J = 7.1 Hz,2H), 2.09 – 1.76 (m, 11H). Example 13: Synthesis of Compound 13

[0412] Step 1: Preparation of intermediate 13a Following the method described in step 1 of Example 12, intermediate 6e was replaced with intermediate 8b to synthesize compound 13a (0.1 g).

[0413] MS(ESI, [M+H)) + ) m / z 741.56 Step 2: Preparation of intermediate 13b Following the method described in step 7 of Example 6, intermediate 6f was replaced with intermediate 13a to synthesize compound 13b (0.1 g).

[0414] MS(ESI, [M+H)) + ) m / z 641.42 Step 3: Preparation of Compound 13 Following the method described in step 8 of Example 6, intermediate 13 (40 mg) was synthesized by replacing intermediate 6g with intermediate 13b and intermediate 6h with intermediate 13c (refer to the preparation process of intermediate x in WO2023278759).

[0415] MS(ESI, [M+H)) + ) m / z 926.23 1 H NMR (500 MHz, DMSO- d 6) δ 11.94 (d, J = 14.4 Hz, 1H), 11.09 (s, 1H), 8.11 (d, J = 16.1 Hz, 1H), 7.68 (d,J = 16.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H),7.04 – 6.93 (m, 3H), 6.86 (dd, J = 23.2, 6.2 Hz, 1H), 6.68 (s, 1H), 6.64 – 6.58(m, 1H), 6.47 (d, J = 4.8 Hz, 1H), 6.20 (d, J = 5.9 Hz, 1H), 5.38 (dd, J = 12.7, 5.5 Hz, 1H), 4.64 (dt, J = 21.3, 6.8 Hz, 2H), 4.28 (d, J = 20.5 Hz, 2H), 3.72 (t, J = 5.8 Hz, 4H), 3.63 (d, J = 9.6 Hz, 4H), 3.26 (s, 4H), 3.22 – 2.99 (m, 10H), 2.94 – 2.85 (m, 1H), 2.76 – 2.59 (m, 8H), 2.00 (d, J = 9.1 Hz, 4H), 1.97 – 1.85(m, 3H). Example 14: Synthesis of Compound 14

[0416] Step 1: Preparation of intermediate 14b Following the method described in step 3 of Example 6, intermediate 6b was replaced with intermediate 14a to synthesize compound 14b (1.5 g).

[0417] MS(ESI, [M+H)) + ) m / z 270.2 Step 2: Preparation of intermediate 14c Following the method described in step 4 of Example 6, intermediate 6c was replaced with intermediate 14b to synthesize compound 14c (1.4 g).

[0418] MS(ESI, [M+H)) + ) m / z 297.4 Step 3: Preparation of intermediate 14d Intermediate 14c (1.4 g) and DCM (20 mL) were added sequentially to a reaction flask. Boron tribromide (7.07 mL) was added under ice bath conditions, and the mixture was reacted at room temperature. The reaction solution was slowly poured into water to quench the reaction, and the pH was adjusted to weakly alkaline by adding sodium bicarbonate aqueous solution. The mixture was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain compound 14d (1.3 g).

[0419] MS(ESI, [M+H)) + ) m / z : 283.1 Step 4: Preparation of intermediate 14e Intermediate 14d (0.7 g), DMF (5 mL), 1-Boc-3-iodozacyclobutane (1.05 g), and Cs₂CO₃ (2.4 mg) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. The reaction solution was cooled to room temperature, and ethyl acetate and water were added to the system for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain compound 14e (0.65 g).

[0420] MS(ESI, [M+H)) + ) m / z : 438.3 Step 5: Preparation of intermediate 14f Intermediate 14e (600 mg) and 4M dioxane hydrochloride (10 mL) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was complete, saturated sodium bicarbonate solution and ethyl acetate were added for extraction, and the solvent was removed by vacuum distillation to obtain compound 14f (0.58 g).

[0421] MS(ESI, [M+H)) + ) m / z 338.2 Step 6: Preparation of 14g of intermediate Intermediate 14f (600 mg), intermediate 3b (498 mg), DCM (10 mL), DIPEA (1.678 mL), and HATU (913 mg) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. The reaction solution was evaporated to dryness and purified by silica gel column chromatography to give 14 g (380 mg) of compound.

[0422] MS(ESI, [M+H)) + ) m / z : 461.2 Step 7: Preparation of intermediates over 14 hours 14 g (200 mg) of intermediate, 202 mg (4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester), 63.4 mg (PdCl2(dppf)), 198 mg (CsF), and dioxane / water = 5 / 1 (v:v, 5 mL) were added sequentially to the reaction flask. Under N2 protection, the mixture was heated to 110 °C. o C reaction. The reaction solution was evaporated to dryness and purified by silica gel column chromatography to give compound 14h (250 mg).

[0423] MS(ESI, [M+H)) + ) m / z 643.3 Step 8: Preparation of intermediate 14i Following the method described in step 7 of Example 6, intermediate 14h was used instead of intermediate 6f to synthesize compound 14i (0.1 g).

[0424] MS(ESI, [M+H)) + ) m / z 543.2 Step 9: Synthesis of Compound 14 Following the method described in step 8 of Example 6, intermediate 14 (60 mg) was synthesized by replacing intermediate 6 g with intermediate 14i.

[0425] MS(ESI, [M+H)) + ) m / z 842.35 1 H NMR (500 MHz, DMSO- d 6) δ 11.45 (d, J = 2.2 Hz, 1H), 11.08 (s, 1H), 8.09(s, 1H), 7.70 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.11 – 7.03 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 6.90 (dd, J = 8.2, 1.5 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.72 –6.63 (m, 2H), 5.34 (dd, J = 12.9, 5.4 Hz, 1H), 5.07 (tt, J= 6.6, 3.9 Hz, 1H), 4.58 (t, J = 6.9 Hz, 2H), 4.52 (dd, J = 9.6, 6.4 Hz, 1H), 4.30 (dd, J = 10.6, 6.5Hz, 1H), 4.12 (dd, J = 9.6, 3.8 Hz, 1H), 3.85 (dd, J = 10.5, 3.9 Hz, 2H), 3.34(s, 4H), 3.23 (s, 4H), 3.17 (d, J = 4.6 Hz, 4H), 2.90 (ddd, J = 16.8, 13.4, 5.4Hz, 1H), 2.78 (td, J = 6.9, 3.1 Hz, 2H), 2.76 – 2.62 (m, 4H), 2.62 – 2.52 (m,4H), 2.37 (s, 2H), 2.01 (ddd, J = 10.5, 6.7, 4.3 Hz, 1H), 1.82 (d, J = 8.8 Hz, 2H). Example 15: Synthesis of Compound 15

[0426] Step 1: Preparation of intermediate 15a Following the method described in step 1 of Example 7, the intermediate 4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester was replaced with intermediate 4-formylphenylboronic acid pinacol ester to synthesize compound 15a (0.4 g).

[0427] MS(ESI, [M+H)) + ) m / z 345.17 Step 2: Preparation of intermediate 15b Following the method described in step 2 of Example 7, intermediate 15a was used instead of intermediate 7a to synthesize compound 15b (0.38 g).

[0428] MS(ESI, [M+H)) + ) m / z 555.33 Step 3: Preparation of Compound 15 Intermediate 15b (50 mg), intermediate z1 (58.0 mg, refer to the preparation process of intermediate 19 in WO2023088406), MeOH (5 ml), and sodium cyanoborohydride (17.00 mg) were added sequentially to a reaction flask, and the mixture was reacted at 60 °C. The reaction solution was evaporated to dryness and purified by silica gel column chromatography to obtain compound 15 (30 mg).

[0429] MS(ESI, [M+H)) + ) m / z : 824.21 1 H NMR (500 MHz, DMSO- d 6) δ 12.20 (d, J = 11.3 Hz, 1H), 11.07 (s, 1H), 8.11 (d, J = 18.5 Hz, 1H), 7.75 – 7.63 (m, 3H), 7.57 (d, J = 8.1 Hz, 1H), 7.51(d, J = 7.7 Hz, 2H), 7.14 – 7.01 (m, 2H), 6.88 (s, 1H), 6.27 (d, J = 12.4 Hz, 1H), 4.64 (dt, J = 20.3, 6.8 Hz, 2H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.32 (d, J =17.1 Hz, 2H), 3.89 – 3.70 (m, 5H), 3.65 (s, 1H), 3.18 (dd, J = 9.6, 5.4 Hz, 4H), 3.07 (dt, J = 27.4, 6.4 Hz, 6H), 2.86 (t, J = 5.9 Hz, 2H), 2.77 (ddd, J =17.2, 11.8, 5.3 Hz, 1H), 2.67 – 2.56 (m, 1H), 2.49 – 2.43 (m, 1H), 2.24 –2.14 (m, 1H), 2.10 – 1.83 (m, 6H). Example 16: Synthesis of Compound 16

[0430] Step 1: Preparation of Compound 16 Following the method described in step 3 of Example 15, intermediate z1 was replaced with intermediate z2 (refer to the preparation process of intermediate 18 in WO2023088406) to synthesize compound 16 (40 mg).

[0431] MS(ESI, [M+H)) + ) m / z 824.33 1 H NMR (500 MHz, DMSO- d 6) δ 12.19 (d, J = 11.8 Hz, 1H), 11.07 (s, 1H), 8.11 (d, J = 19.1 Hz, 1H), 7.74 – 7.64 (m, 3H), 7.60 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 7.7 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 7.09 (dd, J = 25.1, 6.0 Hz, 1H), 6.88 (s, 1H), 6.27 (d, J = 12.2 Hz, 1H), 4.64 (dt, J = 21.3, 6.8 Hz, 2H), 4.55(dd, J = 11.9, 5.0 Hz, 1H), 4.32 (d, J = 17.8 Hz, 2H), 3.84 (d, J = 6.9 Hz, 4H), 3.69 (d, J = 44.8 Hz, 2H), 3.26 – 2.99 (m, 10H), 2.86 (d, J = 6.1 Hz, 2H), 2.76(ddd, J = 17.2, 11.9, 5.3 Hz, 1H), 2.66 – 2.55 (m, 1H), 2.49 – 2.43 (m, 1H), 2.24 – 2.10 (m, 1H), 2.03 (s, 3H), 1.96 – 1.86 (m, 3H). Example 17 Synthesis of Compound 17

[0432] Step 1: Preparation of intermediate 17a Add p-bromoiodobenzene (1 g), 3-(dimethoxymethyl)azacyclobutane (0.87 g), cuprous iodide (0.14 g), L-proline (81 mg), potassium carbonate (1.4 g), and DMSO (5 mL) to a reaction flask and mix. React at 90 °C for 3 h. After the reaction is complete, quench the reaction mixture in a saturated ammonium chloride solution, extract with ethyl acetate, wash with a saturated sodium chloride solution, and concentrate to obtain intermediate 17a (0.5 g).

[0433] MS(ESI, [M+H)) + ) m / z 286.2 Step 2: Preparation of intermediate 17b Referring to step 1 of Example 1, intermediate 17a (480 mg) was replaced with 1l to obtain intermediate 17b (260 mg).

[0434] MS(ESI, [M+H)) + ) m / z 334.3 Step 3: Preparation of intermediate 17c Referring to step 1 of Example 7, intermediate 17b (140 mg) was replaced with 4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester to obtain intermediate 17c (175 mg).

[0435] MS(ESI, [M+H)) + ) m / z 446.4 Step 4: Preparation of intermediate 17d Referring to step 2 of Example 7, intermediate 17c (100 mg) replaces 7a to obtain intermediate 17d (75 mg).

[0436] MS(ESI, [M+H)) + ) m / z 656.4 Step 5: Preparation of intermediate 17e Intermediate 17d (72 mg) and formic acid (2 mL) were added to the reaction flask and mixed, and reacted at 50 °C for 3 h. After the reaction was completed, the reaction solution was concentrated to obtain intermediate 17e (70 mg).

[0437] MS(ESI, [M+H)) + ) m / z 610.3 Step 6: Preparation of Compound 17 A DCE / IPA solution of intermediate 17e (70 mg), intermediate z3 (50 mg, refer to the preparation procedure of intermediate 20 in WO2023088406), sodium acetate (30 mg), and sodium triacetoxyborohydride (40 mg) in 5:1 (v:v, 2 mL) was added to a reaction flask and reacted at room temperature. After the reaction was completed, the reaction solution was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain compound 17 (36 mg).

[0438] MS(ESI, [M+H)) + ) m / z 893.42 1 H NMR (500 MHz, DMSO- d 6) δ 12.09 (d, J = 12.1 Hz, 1H), 11.08 (s, 1H), 8.11 (d, J = 17.9 Hz, 1H), 7.68 (d, J = 16.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.4, 2.4 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 24.6, 6.1Hz, 1H), 6.83 (s, 1H), 6.55 (d, J = 8.2 Hz, 2H), 6.23 (d, J = 11.4 Hz, 1H), 4.64(dt, J = 20.1, 6.8 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.30 (d, J = 17.9 Hz,2H), 4.05 – 3.96 (m, 2H), 3.73 (s, 1H), 3.65 (s, 1H), 3.55 (s, 2H), 3.21 –3.00 (m, 13H), 2.87 – 2.57 (m, 8H), 2.22 – 2.16 (m, 1H), 2.05 – 1.88 (m, 6H), 1.23 (d, J= 4.9 Hz, 1H). Example 18 Synthesis of Compound 18

[0439] Step 1: Preparation of intermediate 18a Following the method described in step 6 of Example 17, intermediate z3 was replaced with intermediate z4 (refer to the preparation process of intermediate 16 in WO2023088406) to synthesize compound 18a (64 mg).

[0440] MS(ESI, [M+H)) + ) m / z : 865.3 Step 2: Preparation of Compound 18 Intermediate 18a (64 mg), methanol (5 mL) and methanesulfonic acid (22 mg) were added to the reaction flask. After reacting for 5 min, the reaction solution was concentrated to obtain compound 18 (86 mg).

[0441] MS(ESI, [M+H)) + ) m / z : 865.21 1 H NMR (500 MHz, DMSO- d 6) δ 12.12 (d, J = 11.5 Hz, 1H), 11.13 (s, 1H), 10.94 (s, 1H), 8.12 (d, J = 17.4 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.70 (d, J =16.2 Hz, 1H), 7.58 – 7.41 (m, 3H), 6.95 (dd, J = 24.9, 6.1 Hz, 1H), 6.83 (s,1H), 6.62 (d, J = 8.2 Hz, 2H), 6.24 (d, J = 12.0 Hz, 1H), 5.23 (s, 1H), 5.05 (s,1H), 4.90 (s, 1H), 4.30 (d, J = 17.2 Hz, 2H), 4.13 (t, J = 7.7 Hz, 2H), 3.87 (s,2H), 3.76 (dd, J= 14.3, 7.6 Hz, 3H), 3.65 (s, 1H), 3.37 – 2.94 (m, 4H), 2.80(ddd, J = 17.4, 12.2, 5.3 Hz, 1H), 2.70 – 2.59 (m, 1H), 2.55 (dd, J = 12.4, 4.3Hz, 1H), 2.36 (s, 10H), 2.27 – 2.17 (m, 1H), 2.12 – 1.83 (m, 7H). Example 19 Synthesis of Compound 19

[0442] Step 1: Preparation of intermediate 19a Referring to step 1 of Example 17, 4-iodophenylboronic acid pinacol ester was used to replace p-bromoiodobenzene and 3-(dimethoxymethyl)azacyclobutane was used to replace 3-(dimethoxymethyl)azacyclobutane to synthesize intermediate 19a (0.7 g).

[0443] MS(ESI, [M+H)) + ) m / z 276.3 Step 2: Preparation of intermediate 19b Referring to step 1 of Example 7, intermediate 19a was replaced with 4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester to obtain intermediate 19b (250 mg).

[0444] MS(ESI, [M+H)) + ) m / z 388.2 Step 3: Preparation of intermediate 19c Referring to step 2 of Example 7, intermediate 19b replaces 7a to obtain intermediate 19c (120 mg).

[0445] MS(ESI, [M+H)) + ) m / z 598.4 Step 4: Preparation of intermediate 19d Intermediate 19c (300 mg), DCM (10 mL), and DIPEA (0.526 mL) were added sequentially. Under ice bath conditions and N2 protection, pyridine trioxide (240 mg) dissolved in DMSO (1 mL) was added to the reaction solution, and the mixture was reacted at room temperature. The reaction solution was extracted with dilute hydrochloric acid and ethyl acetate, the organic phase was collected, and then extracted with saturated sodium chloride aqueous solution. The mixture was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 19d (100 mg).

[0446] MS(ESI, [M+H)) + ) m / z 596.1 Step 5: Preparation of Compound 19 Following the method described in step 3 of Example 15, intermediate 19 (30 mg) was synthesized by replacing intermediate 15b with intermediate 19d and intermediate z1 with intermediate z3.

[0447] MS(ESI, [M+H)) + ) m / z 879.35 1 H NMR (500 MHz, DMSO- d 6) δ 12.09 (d, J = 12.1 Hz, 1H), 11.08 (s, 1H), 8.11 (d, J = 17.6 Hz, 1H), 7.69 (d, J = 15.8 Hz, 1H), 7.61 – 7.47 (m, 3H), 7.21(d, J = 8.2 Hz, 1H), 6.95 (dd, J = 24.7, 6.0 Hz, 1H), 6.85 (s, 1H), 6.60 (d, J =8.1 Hz, 2H), 6.24 (d, J = 11.6 Hz, 1H), 4.64 (dt, J = 20.1, 6.8 Hz, 2H), 4.55(dd, J = 11.9, 5.0 Hz, 1H), 4.30 (d, J = 17.9 Hz, 2H), 4.05 (t, J = 7.0 Hz, 2H),3.74 (s, 1H), 3.66 (d, J= 7.4 Hz, 3H), 3.55 – 3.43 (m, 1H), 3.33 (s, 1H), 3.19(d, J = 6.5 Hz, 6H), 3.09 (d, J = 8.9 Hz, 6H), 2.82 – 2.74 (m, 1H), 2.66 – 2.52(m, 5H), 2.24 – 2.13 (m, 1H), 2.03 (s, 3H), 1.92 (d, J = 22.8 Hz, 3H). Example 20 Synthesis of Compound 20

[0448] Step 1: Preparation of intermediate 20a Referring to step 1 of Example 17, 4-(dimethoxymethyl)-piperidine (1 g) was replaced with 3-(dimethoxymethyl)azacyclobutane to obtain intermediate 20a (450 mg).

[0449] MS(ESI, [M+H)) + ) m / z 314.3 Step 2: Preparation of intermediate 20b Referring to step 1 of Example 1, intermediate 20a (400 mg) was replaced with 1 l to obtain intermediate 20b (250 mg).

[0450] MS(ESI, [M+H)) + ) m / z 362.5 Step 3: Preparation of intermediate 20c Referring to step 1 of Example 7, intermediate 20b (220 mg) was replaced with 4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester to obtain intermediate 20c (190 mg).

[0451] MS(ESI, [M+H)) + ) m / z 474.4 Step 4: Preparation of intermediate 20d Referring to step 2 of Example 7, intermediate 20c (100 mg) replaces 7a to obtain intermediate 20d (60 mg).

[0452] MS(ESI, [M+H)) + ) m / z 684.4 Step 5: Preparation of intermediate 20e Referring to step 5 of Example 17, intermediate 20d (550 mg) replaced 17d to obtain intermediate 20e (45 mg).

[0453] MS(ESI, [M+H)) + ) m / z 638.3 Step 6: Preparation of Compound 20 Referring to step 6 of Example 17, intermediate 20e (50 mg) was used to replace 17e to obtain compound 20 (27 mg).

[0454] MS(ESI, [M+H)) + ) m / z 921.45 1 H NMR (500 MHz, DMSO- d 6) δ 12.11 (d, J = 12.3 Hz, 1H), 11.08 (s, 1H),8.11 (d, J = 17.5 Hz, 1H), 7.69 (d, J = 15.8 Hz, 1H), 7.57 – 7.50 (m, 3H),7.19 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.00 – 6.93 (m, 1H), 6.86 (p, J = 2.0 Hz, 1H), 6.24 (d, J = 11.4 Hz, 1H), 4.69 – 4.61 (m, 2H), 4.58 –4.53 (m, 1H), 4.30 (d, J = 17.8 Hz, 2H), 3.80 (d, J = 12.0 Hz, 2H), 3.74 (s,1H), 3.65 (s, 1H), 3.22 – 3.03 (m, 11H), 2.77 (dt, J = 19.4, 8.2 Hz, 3H), 2.72 – 2.58 (m, 5H), 2.37 (s, 2H), 2.19 (dd, J = 9.3, 4.3 Hz, 1H), 2.05 –1.86 (m, 9H), 1.76 (s, 1H), 1.25 (d, J = 11.9 Hz, 3H). Example 21 Synthesis of Compound 21

[0455] Step 1: Preparation of intermediate 21a Referring to step 1 of Example 17, 1-bromo-2-fluoro-4-iodobenzene was replaced with p-bromoiodobenzene, and 4-(dimethoxymethyl)-piperidine was replaced with 3-(dimethoxymethyl)azacyclobutane to obtain intermediate 21a (12.2 g).

[0456] MS(ESI, [M+H)) + ) m / z 332.1 Step 2: Preparation of intermediate 21b Referring to step 1 of Example 1, intermediate 21a replaces 1l to obtain intermediate 21b (0.79 g).

[0457] MS(ESI, [M+H)) + ) m / z 380.3 Step 3: Preparation of intermediate 21c Referring to step 1 of Example 7, intermediate 21b (220 mg) was replaced with 4-[4-(N-Boc)piperazin-1-yl]phenylboronic acid pinacol ester, and intermediate 1 g was replaced with 8b, to obtain intermediate 21c (140 mg).

[0458] MS(ESI, [M+H)) + ) m / z 702.4 Step 4: Preparation of intermediate 21d Referring to step 5 of Example 17, intermediate 21c replaces 17d to obtain intermediate 21d (45 mg).

[0459] MS(ESI, [M+H)) + ) m / z 656.4 Step 5: Preparation of Compound 21 Referring to step 6 of Example 17, intermediate 21d replaces 17e to obtain compound 21 (55 mg).

[0460] MS(ESI, [M+H)) + ) m / z 939.45 1 H NMR (500 MHz, DMSO- d 6) δ 12.11 (d, J = 13.5 Hz, 1H), 11.08 (s, 1H), 8.11 (dd, J = 17.3, 1.0 Hz, 1H), 7.68 (dd, J= 15.9, 1.0 Hz, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.37 (dt, J = 8.7, 4.7 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 6.0Hz, 1H), 6.93 (d, J = 6.0 Hz, 1H), 6.90 – 6.83 (m, 2H), 6.60 (dd, J = 6.1, 3.0Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 4.64 (dt, J = 21.0, 6.8 Hz, 2H), 4.55 (dd, J =11.9, 5.0 Hz, 1H), 4.30 (d, J = 17.7 Hz, 2H), 3.84 (d, J = 12.1 Hz, 2H), 3.69 (d, J = 43.9 Hz, 2H), 3.24 – 2.96 (m, 15H), 2.88 – 2.57 (m, 8H), 2.22 – 2.15 (m,1H), 2.06 – 1.69 (m, 10H). Example 22 Synthesis of Compound 22

[0461] Step 1: Preparation of intermediate 22b Intermediate 22a (0.5 g) (refer to the preparation process of intermediate 8n in WO2024037616), tetrahydrofuran (10 mL) and acrylamide (0.13 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and potassium tert-butoxide (1 M tetrahydrofuran solution, 1.5 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, the extract was concentrated, and purified by silica gel column chromatography to obtain intermediate 22b (0.45 g).

[0462] MS(ESI, [M+H]+) m / z: 301.23 Step 2: Preparation of intermediate z5 Intermediate 22b (0.2 g), DMSO (5 mL) and IBX (0.56 g) were added sequentially to the reaction flask. The reaction was carried out at 80 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and the extract was concentrated to obtain intermediate z5 (0.18 g).

[0463] MS(ESI, [M+H)) + ) m / z 299.32 Step 3: Preparation of Compound 22 Following the method described in step 8 of Example 6, intermediate 7c was used instead of intermediate 6g, and intermediate z5 was used instead of intermediate 6h to synthesize compound 22 (30 mg).

[0464] MS(ESI, [M+H)) + ) m / z 893.22 1 H NMR (500 MHz, DMSO- d 6) δ 11.94 (d, J = 14.4 Hz, 1H), 11.09 (s, 1H), 8.14 – 8.08 (m, 1H), 7.72 – 7.65 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.03 – 6.92(m, 3H), 6.86 (dd, J = 23.2, 6.1 Hz, 1H), 6.68 (s, 1H), 6.63 – 6.58 (m, 1H), 6.48 (d, J = 4.7 Hz, 1H), 6.20 (d, J = 5.9 Hz, 1H), 5.38 (dd, J = 12.7, 5.4 Hz, 1H), 4.64 (dt, J = 21.4, 6.8 Hz, 2H), 4.28 (d, J = 20.5 Hz, 2H), 3.72 (t, J = 5.8Hz, 4H), 3.63 (d, J = 9.8 Hz, 4H), 3.26 (s, 3H), 3.21 – 3.01 (m, 9H), 2.94 –2.85 (m, 1H), 2.72 – 2.60 (m, 7H), 2.00 (d, J= 9.5 Hz, 4H), 1.96 – 1.85 (m,3H). Example 23 Synthesis of Compound 23

[0465] Step 1: Preparation of intermediate z6b Intermediate Z6a (100 g), diethyl carbonate (335 g), toluene (1500 mL), and sodium hydride (113 g) were added sequentially to a reaction flask. The reaction was carried out at 120 °C. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z6b (139 g).

[0466] MS(ESI, [M+H)) + ) m / z 249.10 Step 2: Preparation of intermediate z6c Intermediate z6b (60 g), trifluoroacetic acid (600 mL) and triethylsilane (56 g) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was directly concentrated and purified by silica gel column chromatography to obtain intermediate z6c (27 g).

[0467] MS(ESI, [M+H)) + ) m / z 235.13 Step 3: Preparation of intermediate z6d Intermediate Z6C (70 g) and tetrahydrofuran (1000 mL) were added sequentially to the reaction flask. The mixture was cooled to 0°C, and lithium aluminum hydride (18 g) was added in portions. The reaction was carried out at 25°C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z6D (34 g).

[0468] MS(ESI, [M+H)) + ) m / z 193.12 Step 4: Preparation of intermediate z6e Intermediate Z6D (33 g) and dichloromethane (2000 mL) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and boron tribromide (2 M, dichloromethane solution, 257 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate Z6E (27 g).

[0469] MS(ESI, [M+H]+) m / z: 179.23 Step 5: Preparation of intermediate Z6F Intermediate z6e (161 g), dichloromethane (2500 mL), triethylamine (366 g), and 4-dimethylaminopyridine (11 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and acetic anhydride (256 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate z6f (247 g).

[0470] MS(ESI, [M+H)) + ) m / z 263.12 Step 6: Preparation of intermediate z6g Intermediate z6f (216 g), ethanol (2100 mL), water (1000 mL) and sodium hydroxide (165 g) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, the extract was concentrated, and purified by silica gel column chromatography to obtain intermediate z6g (181 g).

[0471] MS(ESI, [M+H)) + ) m / z 263.12 Step 7: Preparation of intermediate z6h Intermediate z6 g (290 g), o-dichlorobenzene (1500 mL) and anhydrous aluminum chloride (295 g) were added sequentially to the reaction flask. The reaction was carried out at 150 °C. After the reaction was completed, saturated citric acid aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, the extract was concentrated, and purified by silica gel column chromatography to obtain intermediate z6 h (216 g).

[0472] MS(ESI, [M+H)) + ) m / z : 221.11 Step 8: Preparation of intermediate z6i Intermediate z6h (166 g), dichloromethane (1600 mL), imidazole (103 g), and tert-butyldimethylchlorosilane (284 g) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. 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 silica gel column chromatography to obtain intermediate z6i (258 g).

[0473] MS(ESI, [M+H)) + ) m / z 335.20 Step 9: Preparation of intermediate z6j Intermediate z6i (279 g), toluene (2900 mL) and diethyl carbonate (493 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and sodium hydride (167 g) was added in portions. The reaction was carried out at 120 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, the extract was concentrated, and purified by silica gel column chromatography to obtain intermediate z6j (271 g).

[0474] MS(ESI, [M+H)) + ) m / z 361.18 Step 10: Preparation of intermediate z6k Intermediate z6j (105 g), ethanol (800 mL) and 50% hydroxylamine aqueous solution (106 g) were added sequentially to the reaction flask. The reaction was carried out at 70 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate z6k (80 g).

[0475] MS(ESI, [M+H)) + ) m / z 376.19 Step 11: Preparation of intermediate z6l Intermediate Z6K (105 g), ethanol (1100 mL), and sulfuric acid (41 g) were added sequentially to the reaction flask. The reaction was carried out at 70 °C. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z6L (80 g).

[0476] MS(ESI, [M+H)) + ) m / z 290.31 Step 12: Preparation of intermediate z6m Intermediate Z6L (21 g), tetrahydrofuran (500 mL), and acrylamide (5.09 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and potassium tert-butoxide (1 M, tetrahydrofuran solution, 67 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z6M (18 g).

[0477] MS(ESI, [M+H]+) m / z: 315.13 Step 13: Preparation of intermediate z6 Intermediate z6m (1 g), DMSO (10 mL) and IBX (2.6 g) were added sequentially to the reaction flask. The reaction was carried out at 80 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and the extract was concentrated to obtain intermediate z6 (0.9 g).

[0478] MS(ESI, [M+H)) + ) m / z 313.21 Step 14: Preparation of intermediate 23a Following the method described in step 1 of Example 12, 4-(N-methylamino)phenylboronic acid pinacol ester was used to replace intermediate 12a and 8b was used to replace 6e to synthesize compound 23a (0.1 g).

[0479] MS(ESI, [M+H)) + ) m / z 556.3 Step 15: Preparation of Compound 23 Intermediate 23a (40 mg), intermediate Z6 (112 mg), trifluoroacetic acid (131 mg), triethylsilane (134 mg), and acetonitrile (5 mL) were added to a reaction flask, followed by sodium triacetoxyborohydride (153 mg). The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction system was quenched with saturated sodium bicarbonate solution, and then extracted with dichloromethane. The organic layer was separated, washed with saturated sodium chloride solution, collected, and subjected to silica gel column chromatography to obtain compound 23 (30 mg).

[0480] MS(ESI, [M+H)) + ) m / z 852.35 1 H NMR (500 MHz, DMSO- d 6) δ 12.07 (d, J = 12.3 Hz, 1H), 11.06 (s, 1H), 8.10 (d, J = 19.0 Hz, 1H), 7.68 (d, J = 18.8 Hz, 1H), 7.51 (dd, J = 19.6, 8.0 Hz, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.98 – 6.82 (m, 4H), 6.23 (d, J = 10.7 Hz, 1H), 4.63 (dt, J = 21.2, 6.6 Hz, 2H), 4.54 (dd, J = 11.7, 5.0 Hz, 1H), 4.30 (d, J = 18.1Hz, 2H), 3.69 (d, J= 44.0 Hz, 2H), 3.44 (d, J = 7.3 Hz, 2H), 3.21 – 3.02 (m,11H), 2.92 – 2.73 (m, 3H), 2.62 (dd, J = 27.3, 16.9 Hz, 3H), 2.29 (s, 1H), 2.18(s, 1H), 2.12 – 1.84 (m, 8H), 1.56 (s, 1H). Example 24 Synthesis of Compound 24

[0481] Step 1: Preparation of intermediate z7a CCl4 (6750 mL), 2,3-dimethyl anisole (450 g), 2,2-azobisisobutyronitrile (18.45 g), and N-bromosuccinimide (1194 g) were added sequentially to a reaction flask. The mixture was heated to 80 °C and refluxed. After the reaction was complete as monitored by TLC, the reaction solution was filtered, the solvent was removed from the filtrate by vacuum distillation, petroleum ether was added and the mixture was stirred, filtered, and the filter cake was collected to obtain intermediate Z7a (833 g).

[0482] Steps 2 and 3: Preparation of intermediate z7c At 0°C, a solution of intermediate z7a (69 g) and diethyl 1,3-propanone dicarboxylate (57.0 g) in DCM (350 mL) was slowly added dropwise to a mixture of tetrabutylammonium iodide (52.0 g) in sodium bicarbonate solution (1 M, 1178 mL) and DCM (500 mL) with stirring. The reaction was carried out at room temperature. After the reaction was completed, the mixture was extracted with dichloromethane. The extract was concentrated and then slurried with methyl tert-butyl ether. The mixture was filtered, and the filtrate was concentrated to obtain z7b. Then, ethanol (1000 mL) and potassium hydroxide (1 M, 1173 mL) were added to the crude product, and the reaction was carried out at 85°C. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane. The organic phase was concentrated and purified by column chromatography to obtain intermediate z7c (24 g).

[0483] Step 4: Preparation of intermediate z7d 0 o Under C, N2 protection, a 1M, 157 mL solution of potassium tert-butoxide in THF was slowly added dropwise to a 450 mL solution of (methoxymethyl)triphenylphosphine chloride (49.7 g) in THF. After the addition was complete, the mixture was kept at 0°C. oThe reaction was stirred at C for 0.5 h, then intermediate Z7C (23 g) was added, and the reaction was brought to room temperature. After the reaction was completed, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by column chromatography to obtain intermediate Z7D (28.6 g).

[0484] Step 5: Preparation of intermediate z7e Intermediate Z7D (28.8 g), THF (200 mL), and 2M hydrochloric acid (130 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate to separate the organic phase. After concentration, intermediate Z7E (25.9 g) was obtained.

[0485] Following the method described in Preparation Example z22 or z33 of WO2023125944, perform the following steps 6-14: Step 6: Preparation of intermediate z7f Following the method described in step 6 of preparation examples z22 or z33, intermediate z7f (25.6 g) was synthesized by replacing intermediate z22f with intermediate z7e.

[0486] Step 7: Preparation of intermediate z7g Following the method described in step 5 of preparation examples z22 or z33, intermediate z7g (14.42g) was synthesized by replacing intermediate z22e with intermediate z7g.

[0487] Steps 8-14: Preparation of intermediate Z7N Following the method described in steps 7-14 of preparation examples z22 or z33, intermediate z7g was used instead of intermediate z22g to synthesize compound z7n (2.20g).

[0488] Compound z7n: ​​MS (ESI, [MH]) - m / z: 304.3 Step 15: Synthesis of intermediate 24a 8b (500 mg), pinacol diboronate (524 mg), dioxane (10 mL), Xphos-Pd-G3 (87 mg), and potassium carbonate (304 mg) were added sequentially to the reaction flask. The reaction was carried out at 90 °C. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 24a (609 mg).

[0489] MS(ESI, [M+H)) + ) m / z 577.3 Step 16: Synthesis of intermediate 24b Z7N (500 mg), 2,6-dimethylpyridine (530 mg), and dichloromethane (50 mL) were added sequentially to the reaction flask. The mixture was cooled to 0°C, and trifluoromethanesulfonic anhydride (698 mg) was added dropwise. The reaction was carried out at 0°C. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the extract was concentrated. p-bromophenol (300 mg), acetonitrile (20 mL), and potassium carbonate (719 mg) were added to the residue. The mixture was carried out at 65°C. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the extract was concentrated. The extract was purified by silica gel column chromatography to obtain intermediate 24b (447 mg).

[0490] MS(ESI, [M+H)) + ) m / z : 458.1 Step 17: Synthesis of intermediate 24c 24b (440 mg), acrylamide (530 mg), and tetrahydrofuran (100 mL) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and 0.86 mL of 1 M potassium tert-butoxide tetrahydrofuran solution was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 24c (109 mg).

[0491] MS(ESI, [M+H)) + ) m / z 483.1 Step 18: Synthesis of Compound 24 Intermediate 24c (130 mg), intermediate 24a (109 mg), dioxane (10 mL), water (2 mL), PdCl2 (dppf) (16 mg), and cesium fluoride (103 mg) were added sequentially to the reaction flask. The reaction was carried out at 90 °C. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain compound 24 (60 mg).

[0492] MS(ESI, [M+H)) + ) m / z 853.38 1 H NMR (500 MHz, DMSO- d 6) δ 12.14 (d, J = 11.5 Hz, 1H), 11.08 (d, J = 3.5Hz, 1H), 8.10 (dd, J= 18.5, 1.0 Hz, 1H), 7.68 (dd, J = 16.6, 1.0 Hz, 1H), 7.61 –7.52 (m, 3H), 7.23 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.98 (dd, J =25.3, 6.1 Hz, 1H), 6.83 (q, J = 2.2 Hz, 1H), 6.25 (d, J = 11.8 Hz, 1H), 4.64 (dt, J = 20.3, 6.8 Hz, 2H), 4.55 (ddd, J = 11.9, 5.0, 2.3 Hz, 1H), 4.30 (d, J = 18.0Hz, 2H), 3.91 (d, J = 6.1 Hz, 2H), 3.73 (s, 1H), 3.64 (s, 1H), 3.44 (dd, J =14.5, 7.0 Hz, 1H), 3.21 – 3.15 (m, 4H), 3.12 – 2.99 (m, 6H), 2.87 (t, J = 13.3Hz, 1H), 2.77 (ddd, J = 17.2, 12.0, 5.3 Hz, 1H), 2.65 – 2.57 (m, 1H), 2.31 –2.13 (m, 4H), 2.05 – 1.86 (m, 6H), 1.23 (s, 3H). Example 25 Synthesis of Compound 25

[0493] Step 1: Preparation of intermediate 25a Sodium hydride (39.4 g) and DMA (500 mL) were added sequentially to a single-necked flask, and the temperature of the reaction solution was lowered to 0-5℃. 3,3-bis(bromomethyl)oxetane (50 g) and N-BOC-glycine ethyl ester (72.0 g) were dissolved in DMA (500 mL) and slowly added dropwise to the sodium hydride solution. After the addition was complete, the mixture was transferred to room temperature for further reaction. Once the reaction was complete, the reaction solution was slowly poured into an ice-cold ammonium chloride aqueous solution to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by silica gel column chromatography to obtain intermediate 25a (38 g).

[0494] Step 2: Preparation of intermediate 25b Intermediate 25a (36 g) and TFA / DCM = 2 / 1 (v:v, 300 mL) were added sequentially to a single-necked flask, and the mixture was reacted at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure to obtain intermediate 25b (40 g). Step 3: Preparation of intermediate 25c To a single-necked flask, intermediate 25b (40 g), benzyl bromide (48.3 g), acetonitrile (1 L), and potassium carbonate (98 g) were added sequentially. The mixture was heated to 80 °C to react. The reaction solution was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was purified by silica gel column chromatography to obtain intermediate 25c (10 g).

[0495] MS(ESI, [M+H)) + ) m / z 276.22 Step 4: Preparation of intermediate 25d To a single-necked flask, intermediate 25c (10 g) and THF (100 mL) were added sequentially. Under ice bath conditions and N2 protection, lithium aluminum hydride (0.62 g) was slowly added, and the mixture was reacted at 0°C. After the reaction was complete, 0.7 mL of water, 0.7 g of 15% sodium hydroxide aqueous solution, and then 2.1 g of water were added to the reaction solution under ice bath conditions. The mixture was stirred at room temperature for 30 min. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain intermediate 25d (7.2 g).

[0496] MS(ESI, [M+H)) + ) m / z 234.36 Step 5: Preparation of intermediate 25e Intermediate 25d (7 g), triethylamine (9.11 g), and THF (100 mL) were added to a reaction flask, followed by the slow addition of trifluoroacetic anhydride (9.45 g). After the addition was complete, the temperature was raised to 60 °C for the reaction. Upon completion of the reaction, a 15% sodium hydroxide aqueous solution and EA were added to the reaction system for extraction. The EA layer was collected, washed with saturated ammonium chloride solution and saturated sodium chloride solution, and the organic layer was concentrated to dryness to obtain intermediate 25e (8 g).

[0497] MS(ESI, [M+H)) + ) m / z 234.33 Step 6: Preparation of intermediate 25f Add intermediate 25e (8 g), di-tert-butyl dicarbonate (11.23 g), 20% Pd / C (2 g), 20% Pd(OH)2 (2 g), and methanol (100 mL) to the reaction flask. Replace the solution with hydrogen balloons 2-3 times and react overnight at 30°C. After the reaction is complete, filter the solution. Wash the filter cake with methanol and purify the filtrate by silica gel column chromatography to obtain intermediate 25f (5.2 g).

[0498] Step 7: Preparation of 25g of intermediate Intermediate 25f (5 g), DCM (50.00 mL), and DIPEA (15.94 g) were added sequentially to a reaction flask. Under N2 protection and an ice bath, pyridine trioxide (9.81 g) was slowly added, and the mixture was allowed to react at room temperature. After the reaction was complete, the reaction solution was extracted with dilute hydrochloric acid and ethyl acetate. The organic phase was then extracted with saturated sodium bicarbonate, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain intermediate 25 g (4.3 g).

[0499] Step 8: Preparation of intermediates over 25 hours Referring to step 2 of Example 1, 1t was replaced with intermediate 25g (3.7g) to obtain intermediate 25h (3g).

[0500] Step 9: Preparation of intermediate 25i Referring to step 3 of Example 1, intermediate 25h (3.0g) replaces 1u to obtain intermediate 25i (1.6g).

[0501] Step 10: Preparation of intermediate 25j Referring to step 1 of Example 8, intermediate 25i (0.3g) replaces 3c to obtain intermediate 25j (0.36g).

[0502] MS(ESI, [M+H)) + ) m / z 464.25 Step 11: Preparation of intermediate 25k Referring to step 4 of Example 1, intermediate 25j (0.36g) replaces 1v to obtain intermediate 25k (0.3g).

[0503] MS(ESI, [M+H)) + ) m / z 364.15 Step 12: Preparation of intermediate 25L Referring to step 5 of Example 1, intermediate 25k (0.3g) was replaced with 1w, and intermediate 3b (0.19g) was replaced with 3-(1-pyrazolyl)propionic acid to obtain intermediate 25l (0.28g).

[0504] MS(ESI, [M+H)) + ) m / z 487.22 Step 13: Preparation of intermediate 25m Referring to step 3 of Example 8, intermediate 25l (80 mg) replaces 8b, and intermediate 20b (65 mg) replaces 8d to obtain intermediate 25m (100 mg).

[0505] MS(ESI, [M+H)) + ) m / z 686.31 Step 14: Preparation of intermediate 25n Referring to step 5 of Example 17, intermediate 25m (100 mg) was replaced with 17d to obtain intermediate 25n (90 mg).

[0506] MS(ESI, [M+H)) + ) m / z 640.42 Step 15: Preparation of Compound 25 Referring to step 6 of Example 17, intermediate 25n (90 mg) was used to replace 17e to obtain compound 25 (30 mg).

[0507] MS(ESI, [M+H)) + ) m / z : 923.25. 1 H NMR (500 MHz, DMSO- d 6) δ 12.15 (d, J = 11.8 Hz, 1H), 11.08 (s, 1H), 8.12 (d, J = 29.0 Hz, 1H), 7.69 (d,J = 19.7 Hz, 1H), 7.54 (t, J = 8.0 Hz, 3H), 7.19 (d, J = 8.1 Hz, 1H), 7.04 (dd, J = 21.2, 10.4 Hz, 3H), 6.87 (s, 1H), 6.48(d, J = 13.6 Hz, 1H), 4.60 (dtd, J = 29.4, 14.9, 5.4 Hz, 5H), 4.47 (d, J = 6.2 Hz, 1H), 4.35 (dd, J = 14.9, 7.7 Hz, 3H), 3.97 (d, J = 31.5 Hz, 2H), 3.80 (d, J = 11.8Hz, 2H), 3.28 – 3.22 (m, 2H), 3.22 – 3.14 (m, 4H), 3.13 – 2.97 (m, 6H), 2.80 – 2.59 (m, 8H), 2.43 – 2.27 (m, 2H), 2.26 – 2.11 (m, 1H), 1.92 – 1.85 (m, 2H), 1.76 (s, 1H), 1.41 – 1.17 (m, 3H). Example 26 Synthesis of Compound 26

[0508] Step 1: Preparation of intermediate 26b Add 26a (1 g), 4-hydroxypiperidine (0.62 g), cuprous iodide (0.14 g), L-proline (81 mg), potassium carbonate (1.4 g), and DMSO (5 mL) to a reaction flask and mix. React at 90 °C for 3 h. After the reaction is complete, quench the reaction mixture in a saturated ammonium chloride solution, extract with ethyl acetate, wash with a saturated sodium chloride solution, and concentrate to obtain intermediate 26b (0.5 g).

[0509] MS(ESI, [M+H)) + ) m / z 304.31. Step 2: Preparation of intermediate 26c Referring to step 3 of Example 8, intermediate 26b (85 mg) replaced 8d to obtain intermediate 26c (110 mg).

[0510] MS(ESI, [M+H)) + ) m / z 626.31 Step 3: Preparation of intermediate 26d Referring to step 4 of Example 19, intermediate 26c (100 mg) replaces 19c to obtain intermediate 26d (90 mg).

[0511] MS(ESI, [M+H)) + ) m / z 624.23 Step 4: Preparation of Compound 26 Referring to step 6 of Example 17, intermediate 26d (90 mg) replaced 17e to obtain compound 26 (33 mg).

[0512] MS(ESI, [M+H)) + ) m / z : 907.44. 1 H NMR (500 MHz, DMSO) δ 12.11 (d, J = 12.2 Hz, 1H), 11.08 (s, 1H), 8.11 (d, J = 18.0 Hz, 1H), 7.68 (d, J = 16.5 Hz, 1H), 7.61 – 7.45 (m, 3H), 7.20 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 6.96 (dd, J = 25.1, 6.1Hz, 1H), 6.87 – 6.83 (m, 1H), 6.24 (d, J = 11.7 Hz, 1H), 4.64 (dt, J = 20.4,6.8 Hz, 2H), 4.55 (dd, J = 11.9, 5.0 Hz, 1H), 4.30 (d, J = 17.7 Hz, 2H), 3.69 (d, J = 44.3 Hz, 2H), 3.25 – 2.95 (m, 12H), 2.91 – 2.56 (m, 8H), 2.08 – 1.85(m, 6H), 1.72 (d, J = 83.7 Hz, 4H). Example 27 Synthesis of Compound 27

[0513] Step 1: Synthesis of intermediate 27a 1 g (200 mg) of intermediate, sodium tert-butoxide (241 mg), tris(dibenzylindeneacetone)palladium(0) (115 mg), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (165 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (117 mg) and 1,4-dioxane (5 mL) were added sequentially to the reaction flask. The reaction was carried out at 100 °C. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 27a (230 mg).

[0514] MS(ESI, [M+H)) + ) m / z : 479.21. Step 2: Synthesis of intermediate 27b Intermediate 27a (230 mg), intermediate 3c (258 mg), Xphos-Pd-G3 (81 mg), cesium fluoride (219 mg), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to the reaction flask. The reaction was carried out at 100 °C. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 27b (286 mg).

[0515] MS(ESI, [M+H)) + ) m / z : 689.39. Step 3: Synthesis of intermediate 27c Intermediate 27b (130 mg) and trifluoroacetic acid (1 mL) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution. After extraction and concentration with ethyl acetate, intermediate 27c (77 mg) was obtained.

[0516] MS(ESI, [M+H)) + ) m / z 589.34. Step 4: Synthesis of Compound 27 Intermediate 27c (65 mg), intermediate Z5 (35 mg), sodium acetate (54 mg), sodium triacetoxyborohydride (117 mg), isopropanol (5 mL), and dichloroethane (25 mL) were added to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain compound 27 (60 mg).

[0517] MS(ESI, [M+H)) + ) m / z : 871.43 1 H NMR (500 MHz, DMSO- d 6) δ 11.90 (d, J = 11.7 Hz, 1H), 11.07 (s, 1H),8.14 – 8.07 (m, 1H), 7.68 (d, J = 14.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.26(d, J = 8.1 Hz, 1H), 6.72 (q, J = 2.1 Hz, 1H), 6.33 (dd, J = 15.3, 5.2 Hz, 1H), 6.14 (d, J = 12.9 Hz, 1H), 4.63 (dt, J = 17.8, 6.8 Hz, 2H), 4.56 (dd, J = 11.8, 5.0Hz, 1H), 4.23 (d, J = 17.8 Hz, 2H), 3.71 (s, 1H), 3.62 (s, 1H), 3.17 (d, J = 5.2Hz, 14H), 2.96 – 2.71 (m, 5H), 2.60 (dd, J = 12.9, 4.4 Hz, 3H), 2.45 (s, 4H), 2.21 – 2.14 (m, 1H), 2.05 – 1.96 (m, 3H), 1.90 (td, J = 12.2, 4.6 Hz, 3H), 1.75(d, J = 14.8 Hz, 4H), 1.65 (s, 2H). Example 28 Synthesis of Compound 28

[0518] Step 1: Synthesis of intermediate 28a Referring to step 1 of Example 27, tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (165 mg) was replaced with tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate to obtain intermediate 28a (225 mg).

[0519] MS(ESI, [M+H)) + ) m / z : 493.31. Step 2: Synthesis of intermediate 28b Referring to step 2 of Example 27, intermediate 28a (225mg) was used to replace 27a to obtain intermediate 28b (254mg).

[0520] MS(ESI, [M+H)) + ) m / z : 703.11. Step 3: Synthesis of intermediate 28c Referring to step 3 of Example 27, intermediate 28b (130 mg) was used to replace 27b to obtain intermediate 28c (81 mg).

[0521] MS(ESI, [M+H)) + ) m / z : 603.34. Step 4: Synthesis of Compound 28 Referring to step 4 of Example 27, intermediate 28c (81 mg) replaced 27c, and intermediate z8 (40 mg, see WO2024037616 Preparation of compound 26f) replaced z5, to obtain compound 28 (53 mg).

[0522] MS(ESI, [M+H)) + ) m / z 885.45 1 H NMR (500 MHz, DMSO- d 6) δ 11.89 (d, J = 12.1 Hz, 1H), 11.09 – 11.05(m, 1H), 8.11 (dd, J = 15.5, 1.0 Hz, 1H), 7.68 (dd, J = 13.4, 0.9 Hz, 1H), 7.61(d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.35 (dd, J = 15.2, 5.3 Hz, 1H), 6.15 (d, J= 12.4 Hz, 1H), 4.68 – 4.54 (m, 3H), 4.28 –4.20 (m, 2H), 3.71 (s, 1H), 3.63 (s, 1H), 3.25 – 3.14 (m, 7H), 3.07 (s, 6H), 2.89 (d, J = 13.6 Hz, 2H), 2.86 – 2.71 (m, 3H), 2.64 – 2.58 (m, 1H), 2.48 –2.30 (m, 7H), 2.19 (dt, J = 8.7, 4.2 Hz, 1H), 2.04 – 1.85 (m, 6H), 1.66 (s, 4H), 1.55 (s, 4H). Example 29 Synthesis of Compound 29

[0523] Step 1: Synthesis of Compound 29 Referring to step 4 of Example 27, intermediate 28c (80 mg) replaced 27c, and intermediate z9 (40 mg, see WO2024037616 Preparation of compound 26a) replaced z5, to obtain compound 29 (45 mg).

[0524] MS(ESI, [M+H)) + ) m / z 885.45 1 H NMR (500 MHz, DMSO- d 6)δ 11.90 (d, J = 11.8 Hz, 1H), 11.07 (s, 1H), 8.11 (dd, J = 15.5, 1.0 Hz, 1H), 7.68 (dd, J = 13.4, 1.0 Hz, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 1.8 Hz, 1H), 6.35 (dd, J = 15.2,5.2 Hz, 1H), 6.18 – 6.12 (m, 1H), 4.68 – 4.53 (m, 3H), 4.24 (d, J= 18.0 Hz, 2H), 3.71 (s, 1H), 3.63 (s, 1H), 3.26 – 3.01 (m, 15H), 2.92 – 2.73 (m, 4H), 2.64 – 2.58 (m, 1H), 2.37 (d, J = 33.5 Hz, 6H), 2.18 (dq, J = 8.3, 4.3 Hz, 1H), 2.02 (q, J = 6.6 Hz, 3H), 1.95 – 1.85 (m, 3H), 1.66 (s, 4H), 1.55 (s, 4H). Example 30 Synthesis of Compound 30

[0525] Step 1: Synthesis of Compound 30 Referring to step 4 of Example 27, intermediate 28c (80 mg) replaced 27c, and intermediate z10 (40 mg, see WO2025195363 Preparation of intermediate 66d) replaced z5, to obtain compound 30 (42 mg).

[0526] MS(ESI, [M+H)) + ) m / z 913.48 1 H NMR (500 MHz, DMSO- d 6) δ 11.90 (d, J = 12.0 Hz, 1H), 11.07 (d, J = 3.4Hz, 1H), 8.11 (dd, J = 15.3, 1.0 Hz, 1H), 7.69 (dd, J = 13.2, 1.0 Hz, 1H), 7.51(d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.74 – 6.69 (m, 1H), 6.35 (dd, J =15.2, 5.2 Hz, 1H), 6.15 (d, J = 12.8 Hz, 1H), 4.64 (dt, J = 17.0, 6.8 Hz, 2H),4.53 (ddd, J= 11.8, 5.1, 2.6 Hz, 1H), 4.24 (d, J = 17.7 Hz, 2H), 3.72 (s, 1H), 3.63 (s, 1H), 3.42 – 3.33 (m, 2H), 3.20 – 2.90 (m, 14H), 2.77 (tt, J = 11.9,5.5 Hz, 2H), 2.64 – 2.56 (m, 1H), 2.46 (d, J = 12.1 Hz, 1H), 2.35 (s, 2H), 2.22– 1.86 (m, 13H), 1.65 (s, 4H), 1.54 (s, 4H), 0.97 (s, 2H). Example 31 Synthesis of Compound 31 Step 1: Synthesis of intermediate z11 Intermediate 31a (1 g, see WO 2025195363, Preparation of intermediate z39), DMSO (10 mL) and IBX (2.6 g) were added sequentially to the reaction flask. The reaction was carried out at 30 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and the extract was concentrated to obtain intermediate z11 (0.9 g).

[0527] MS(ESI, [M+H)) + ) m / z 327.21 Step 2: Synthesis of Compound 31 Referring to step 4 of Example 27, intermediate 28c (80mg) replaced 27c, and intermediate z11 (40mg) replaced z5, to obtain compound 31 (35mg).

[0528] MS(ESI, [M+H)) + ) m / z 913.49 1H NMR (500 MHz, DMSO-d6) δ 11.90 (d, J = 12.0 Hz, 1H), 11.07 (d, J =3.2 Hz, 1H), 8.14 – 8.07 (m, 1H), 7.72 – 7.65 (m, 1H), 7.51 (d, J = 8.0 Hz,1H), 7.18 (d, J = 8.1 Hz, 1H), 6.71 (q, J = 2.4 Hz, 1H), 6.35 (dd, J = 15.2,5.2 Hz, 1H), 6.18 – 6.12 (m, 1H), 4.64 (dt, J = 17.1, 6.8 Hz, 2H), 4.53 (ddd,J = 11.9, 5.0, 2.6 Hz, 1H), 4.24 (d, J = 17.9 Hz, 2H), 3.72 (s, 1H), 3.63 (s,1H), 3.41 – 3.36 (m, 1H), 3.17 (t, J = 6.8 Hz, 2H), 3.07 (d, J = 7.0 Hz, 8H),2.98 – 2.91 (m, 2H), 2.77 (tt, J = 12.2, 5.7 Hz, 2H), 2.63 – 2.58 (m, 1H),2.18 (tt, J = 9.2, 5.0 Hz, 4H), 2.06 – 1.96 (m, 5H), 1.94 – 1.86 (m, 3H),1.60 (d, J = 54.9 Hz, 9H). Example 32 Synthesis of Compound 32

[0529] Step 1: Synthesis of intermediate z12 Intermediate 32a (1 g, see WO 2025195363, Preparation of intermediate z40), DMSO (10 mL) and IBX (2.6 g) were added sequentially to the reaction flask. The reaction was carried out at 30 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and the extract was concentrated to obtain intermediate z12 (0.92 g).

[0530] MS(ESI, [M+H)) + ) m / z 327.23 Step 2: Synthesis of Compound 32 Referring to step 4 of Example 27, intermediate 28c (80mg) replaced 27c, and intermediate z12 (40mg) replaced z5, to obtain compound 32 (37mg).

[0531] MS(ESI, [M+H)) + ) m / z 913.49 1 H NMR (500 MHz, DMSO) δ 11.91 (d, J = 12.1 Hz, 1H), 11.07 (d, J =3.2 Hz, 1H), 8.11 (dd, J = 15.1, 0.9 Hz, 1H), 7.69 (dd, J = 13.0, 1.0 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 2.7 Hz,1H), 6.35 (dd, J = 14.8, 5.2 Hz, 1H), 6.15 (d, J = 12.8 Hz, 1H), 4.64 (dt, J= 16.6, 6.8 Hz, 2H), 4.54 (ddd, J = 11.9, 5.1, 2.9 Hz, 1H), 4.24 (d, J = 17.6Hz, 2H), 3.63 (s, 1H), 3.42 – 3.32 (m, 4H), 3.18 (t, J = 6.8 Hz, 3H), 3.07(t, J = 6.2 Hz, 7H), 2.97 (s, 3H), 2.77 (ddd, J = 17.1, 11.9, 5.3 Hz, 2H), 2.64 – 2.57 (m, 1H), 2.36 (s, 3H), 2.18 (tt, J = 9.4, 4.8 Hz, 2H), 2.06 (d, J= 38.3 Hz, 6H), 1.95 – 1.81 (m, 4H), 1.60 (d, J = 50.9 Hz, 8H). Example 33 Synthesis of Compound 33

[0532] Step 1: Synthesis of intermediate 33a Intermediate 28a (1.35 g) and 4M dioxane hydrochloride solution (30 mL) were added sequentially to the reaction flask. The reaction was carried out at 25°C. After the reaction was completed, the reaction solution was directly concentrated to obtain intermediate 33a (1.1 g).

[0533] MS(ESI, [M+H)) + ) m / z 393.18.

[0534] Step 2: Synthesis of intermediate 33b Intermediate 33a (1.1 g), triethylamine (2.83 g), and dichloromethane (50 mL) were added sequentially to the reaction flask. The mixture was cooled to 0°C and trifluoroacetic anhydride (1.18 g) was added dropwise. The reaction was carried out at 25°C. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 33b (0.64 g).

[0535] MS(ESI, [M+H]+) m / z: 489.16 Step 3: Preparation of intermediate 33c Referring to step 2 of Example 27, intermediate 33b replaces 27a, and intermediate 25i replaces 3c, to obtain intermediate 33c (697mg).

[0536] MS(ESI, [M+H)) + ) m / z 678.32 Step 4: Synthesis of intermediate 33d Intermediate 33c (700 mg) and trifluoroacetic acid (3 mL) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was directly concentrated. Intermediate 3b (238 mg), dichloromethane (50 mL), N,N-diisopropylethylamine (800 mg), HOBt (785 mg), and HATU (800 mg) were added to the residue. The reaction was carried out at 25 °C. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate 33d (769 mg).

[0537] MS(ESI, [M+H)) + ) m / z 701.31 Step 5: Synthesis of intermediate 33e Intermediate 33d (768 mg), methanol (50 mL), and potassium carbonate (303 mg) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated to obtain intermediate 33e (511 mg).

[0538] MS(ESI, [M+H)) + ) m / z 605.33 Step 6: Synthesis of Compound 33 Intermediate 33e (125 mg), sodium cyanoborohydride (32 mg), acetic acid (62 mg), methanol (50 mL), and intermediate Z11 (120 mg) were added sequentially to the reaction flask. The reaction was carried out at 50 °C. 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 silica gel column chromatography to obtain compound 33 (75 mg).

[0539] MS(ESI, [M+H)) + ) m / z 915.46 1 H NMR (500 MHz, DMSO- d 6) δ 11.94 (d, J = 12.1 Hz, 1H), 11.07 (d, J = 3.4Hz, 1H), 8.12 (d, J = 27.0 Hz, 1H), 7.69 (d, J = 17.3 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.72 (q, J = 2.5 Hz, 1H), 6.43 – 6.36 (m, 2H), 4.64 (dt, J = 14.3, 6.8 Hz, 2H), 4.58 – 4.51 (m, 3H), 4.45 (d, J = 6.1 Hz, 1H), 4.35 (d, J = 5.9 Hz, 1H), 4.27 (d, J = 9.8 Hz, 2H), 3.98 (s, 1H), 3.92 (s, 1H), 3.41 – 3.32 (m, 2H), 3.28 – 3.16 (m, 4H), 3.07 (t, J = 6.6 Hz, 8H), 2.95 (t, J =9.5 Hz, 2H), 2.81 – 2.71 (m, 2H), 2.62 (d, J = 3.9 Hz, 1H), 2.36 (s, 4H), 2.22– 1.93 (m, 6H), 1.66 (s, 4H), 1.54 (s, 4H), 0.97 (s, 2H). Example 34 Synthesis of Compound 34

[0540] Step 1: Preparation of Compound 34 Referring to step 6 of Example 33, intermediate z12 replaces z11 to obtain compound 34 (27 mg).

[0541] MS(ESI, [M+H)) + ) m / z 915.46 1 H NMR (500 MHz, DMSO- d 6) δ 11.94 (d, J = 12.2 Hz, 1H), 11.07 (d, J = 3.3Hz, 1H), 8.12 (d, J = 27.0 Hz, 1H), 7.69 (d, J = 17.3 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.39 (dd, J = 11.7, 4.4 Hz, 2H), 4.64 (dt, J = 14.3, 6.8 Hz, 2H), 4.59 – 4.50 (m, 3H), 4.45 (d, J = 6.1 Hz, 1H), 4.35 (d, J = 5.9 Hz, 1H), 4.27 (d, J = 9.6 Hz, 2H), 3.98 (s, 1H), 3.92 (s, 1H), 3.41 – 3.34 (m, 2H), 3.25 – 2.93 (m, 14H), 2.82 – 2.71 (m, 2H), 2.60 (dd, J =17.2, 3.8 Hz, 1H), 2.36 (s, 4H), 2.21 – 1.93 (m, 6H), 1.60 (d, J = 58.6 Hz, 8H), 0.97 (s, 2H). Experimental Example 1: Assay of STAT6 Degradation Activity in In Vitro Cells Collect A549-STAT6-HIBIT cells in good growth condition into centrifuge tubes and adjust the cell density to 5 × 10⁻⁶. 4 The compound was seeded at a concentration of 10 nM to 0.00061 nM using a nanoparticle pipette, with two replicates per well. A control was also included. After culturing for 24 hours, the Nano-GLo HiBiT Lytic assay reagent (Promega, 25 μL / well) was added. The cells were shaken at 400 rpm for 10 minutes at room temperature. The luminescence value was then measured using a PerkinElmer Envision Lumi 384 microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the concentration-dependent gain (DC) was calculated. 50 The experimental results are shown in Table 4. The compound of this application exhibits STAT6 degradation activity.

[0542] Table 4

[0543]

[0544] Experimental Example 2: In vitro liver microsomal stability Liver microsomal incubation samples were prepared by incubating with a mixture of PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), the test compound, and NADPH + MgCl2 solution at 37°C and 150 rpm for 1 hour. Samples prepared at 0 hours were prepared with a mixture of PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and the test compound. Acetonitrile solution containing an internal standard was added to the samples, followed by protein precipitation to prepare the supernatant, which was then diluted for LC / MS analysis. The experimental results are shown in Table 5. The compounds in this application are metabolically stable in liver microsomes.

[0545] Table 5

[0546] In vivo pharmacokinetics in Experimental Example 3 3.1 Mouse Pharmacokinetics ICR mice, weighing 20-25 g, were randomly divided into two groups after acclimatization for 3-5 days: an intravenous injection group (n=6 per group) and a gavage group (n=6 per group). The intravenous injection group received the example solution intravenously at a dose of 1 mg / kg, while the gavage group received the example solution by gavage at a dose of 10 mg / kg.

[0547] Blood was collected by gavage at 0.25 (15 min), 1, 2, 4, 8, and 24 h, and by intravenous injection at 0.083 h (5 min), 0.25 h (15 min), 1 h, 2 h, 4 h, 8 h, and 24 h. Blood was collected from the orbital cavity to prepare plasma samples for testing.

[0548] A 30 µL sample of plasma was taken and acetonitrile solution containing an internal standard was added. After protein precipitation, the supernatant was obtained, diluted, and used for LC / MS / MS analysis. A non-compartmental model was used for fitting. The results are shown in Table 6.

[0549] Table 6

[0550] The experimental results showed that in the gavage group, the AUC (0-24h) of the tested compound exceeded 10000 ng*h / mL. The compound of this application exhibits favorable in vivo pharmacokinetic properties (e.g., AUC, t...). 1 / 2 (e.g., parameters).

[0551] 3.2 Rat Pharmacokinetics SD rats, weighing 180-220 g, were randomly divided into groups of 3 rats each after acclimatization for 3-5 days. The intravenous injection group received the example solution intravenously at a dose of 0.5 mg / kg, and the gavage group received the example solution by gavage at a dose of 10 mg / kg.

[0552] Blood was collected by gavage at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 24 h, and by intravenous injection at 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 24 h. Blood was collected from the orbital rim to prepare plasma samples for testing.

[0553] Take 30 µL of the plasma sample to be tested, add acetonitrile solution containing internal standard, and obtain supernatant after protein precipitation. After dilution, use it for LC / MS / MS determination and fit it with a non-compartment model.

[0554] Experimental Example 4A: Assay of IL-4-induced TARC release activity Collect freshly revived hPBMC cells into centrifuge tubes and adjust the cell density to 2 × 10⁻⁶. 7 The compound was seeded at a concentration of 55 μL / well in a 96-well plate using a nanoparticle pipette to achieve a final concentration of 10 nM - 0.0046 nM. Two replicates were performed, and a control was also included. After pre-incubation for 3 h in a cell culture incubator, IL-4 stimulation (5 μL / well) was added, and the plate was incubated for another 24 h. The supernatant was collected by centrifugation. 15 μL of the supernatant was added to a 384-well plate, followed by 5 μL / well of the detection antibody mixture (Bioauxilium, KIT-CCL17-500). The mixture was centrifuged and incubated at room temperature for 1 h. Fluorescence was detected at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The results are shown in Table 7.

[0555] Table 7

[0556] The experimental results show that the tested compound has anti-inflammatory activity.

[0557] Experimental Example 4B: Assay of IL-4-induced TARC release activity Collect freshly revived hPBMC cells into centrifuge tubes and adjust the cell density to 2 × 10⁻⁶. 7 The compound was seeded at a concentration of 55 μL / well in a 96-well plate using a nanoparticle pipette to achieve a final concentration of 10 nM–0.0046 nM. Two replicates were performed for each concentration, and a control was also included. After pre-incubation for 3 h in a cell culture incubator, IL-4 stimulation (5 μL / well) was added, and the plate was incubated for another 24 h. The supernatant was collected by centrifugation. 15 μL of the supernatant was added to a 384-well plate, followed by 5 μL / well of the detection antibody mixture (Bioauxilium, KIT-CCL17-500). The mixture was centrifuged and incubated at room temperature for 1 h. Fluorescence was detected at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The test results are shown in Table 8.

[0558] Table 8

[0559] Experimental Example 5: Assay of IL-13-induced CD23 expression activity Freshly revived hPBMCs were collected into centrifuge tubes and sorted using the EasySep™ Human B Cell Isolation Kit (Stemcell, 17954). The cells were seeded into 96-well plates, and compounds were added using a nanoparticle pipette to achieve a final concentration of 50,000 pM - 0.019 pM, with two replicates per concentration. A control was also included. After pre-incubation for 24 h in a cell culture incubator, IL-13 was added for stimulation, and the cells were cultured for another 24 h. 200 μL / well of cell suspension was transferred to V-bottom 96-well plates, and the cells were washed once with FACS Buffer (PBS + 2% FBS). Human TruStain FcX™ was added, and the plates were blocked at 4°C for 10 minutes, followed by washing once with FACS Buffer. Add APC anti-human CD23 Antibody (biolegeno, 338514), stain at 4℃ in the dark for 30 minutes, add 100 μL FACS Buffer, centrifuge at 500g for 5 minutes, discard the supernatant, resuspend in 200 μL FACS Buffer, and perform flow cytometry to detect CD23 expression in B cells. Perform four-parameter analysis, fit a dose-response curve, and calculate IC50. 50 The results are shown in Table 9.

[0560] Table 9

[0561] The experimental results show that the tested compound has anti-inflammatory activity.

[0562] Experimental Example 6: Assay of STAT6 Protein Binding Activity Add 8 nM STAT6 (W123-T658), a His Tag protein, to 384-well plates at 2.5 μL / well using a nanoparticle pipette to achieve a final concentration of 10000 nM - 0.51 nM. Perform two replicates for each concentration. Include a control. Centrifuge to mix and incubate at room temperature for 10 minutes. Add 8 nM M-probe at 2.5 μL / well, centrifuge, and add Anti His-Tb antibody (Revvity, 61HISTLB) at 5 μL / well. Centrifuge to mix and incubate at room temperature for 1 hour. Detect fluorescence values ​​at 520 nm / 490 nm using a BMG plate reader. Perform four-parameter analysis, fit a dose-response curve, and calculate the IC50. 50 The experimental results are shown in Table 10.

[0563] Table 10

Claims

1. A compound of formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof, in, L a It does not exist or is selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 Imyethynyl, When L a No, ring E is selected from 7-15 membered heterospirocycloalkyl or 7-15 membered heterospirocycloalkenyl; When L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The acetylenic group, the R L Selected from hydrogen, deuterium, halogens, -CN, C 1-10 Alkyl or C 1-10 Heteroalkyl, with ring E selected from C 3-15 Cycloalkyl, 4-15 membered heterocyclic alkyl, C 3-15 Cycloalkenyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl or 5-15 heteroaryl groups; Each R 2 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, =O, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl; R 3 Selected from the following groups optionally substituted with one or more R': C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 Alkyl-N=, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-; R u Selected from H, -OH or C 1-12 alkyl; R v Selected independently from C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-, the C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 Alkyl groups are optionally substituted with one or more deuterium, halogen, -OH, -NH2, or -CN; Ring F is selected from C 6-12 Aryl or 5-12 heteroaryl groups; R 4 Selected from H, or optionally substituted with one or more R'' groups: R s C(O)-, R s C(O)O-、R s OC(O)-, R s S(O)-、R s S(O)2-、R s R t NC(O)-, R s C(O)NR t -、R s S(O)2NR t -or R s R t NS(O)2-; R t Each independently selected from H or C 1-12 alkyl; R s Selected independently from C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 The aryl or 5-12 heteroaryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-; Each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 4-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 4-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-; R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, -CHO, -COOH, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 3-12 The cycloalkyl or 3-12-membered heterocycloalkyl group is optionally substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2 or -CHO; j and k are independently selected from 0, 1, 2, 3, or 4; CLM is selected from the E3 ubiquitin ligase binding region; L is selected from the linking group.

2. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, each R 2 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, =O, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl S-, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; Or, each R 2 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, =O, or C. 1-3 alkyl; Or, each R 2 Each can be independently selected from -F, -OH, methyl, or =O.

3. The compound of claim 1 or 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, R 3 Selected from the following groups optionally substituted with one or more R': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl-N=, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 quinone heteroaryl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-; Or, R 3 Selected from the following groups optionally substituted with one or more R': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl-N=, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-; Or, R 3 Selected from C substituted with a 5-membered N-containing heteroaryl group 1-3 Alkyl-C(O)-.

4. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, wherein R u Selected from C 1-6 alkyl; Or, the R u Selected from methyl.

5. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, wherein R v Selected independently from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 quinone heteroaryl; Or, the R v Selected independently from C 1-3 Alkyl, C 3-4 cycloalkyl or 3-4 membered heterocyclic alkyl; Or, the R v Each is independently selected from methyl, ethyl, isopropyl, or cyclopropyl.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-5, wherein each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 quinone heteroaryl, C 3-6 cycloalkyl C 1-3 Alkyl-, 4-6 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-6 Cycloalkenyl C 1-3 alkyl-, 4-6 membered heterocyclic alkenyl C 1-3 Alkyl-, C 6-10 Aryl C 1-3 Alkyl-, 5-6-membered heteroaryl C 1-3 alkyl-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl, 5-6 membered heteroaryl C 3-6 cycloalkyl C 1-3 Alkyl-, 4-6 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-6 Cycloalkenyl C 1-3 alkyl-, 4-6 membered heterocyclic alkenyl C 1-3 Alkyl-, C 6-10 Aryl C 1-3 Alkyl-, 5-6-membered heteroaryl C 1-3 The alkyl group is optionally substituted by one or more elements selected from deuterium, halogen, -OH, -NH2 or -CN; Alternatively, each R' can be independently selected from deuterium, halogen, -OH, -NH2, -CN, C. 1-6 Alkyl, phenyl, 5-6 heteroaryl or 5-6 heteroaryl C 1-3 alkyl-, the C 1-6 The alkyl group is optionally substituted by one or more elements selected from deuterium, halogen, -OH, -NH2 or -CN; Alternatively, each R' may be independently selected from -F, -CN, 1,2,3-triazolyl, pyrazolyl, 1,2,3-triazolylethyl-, or cyanomethyl-.

7. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-6, R 4 Selected from H, or R optionally replaced by one or more R'' s C(O)- or R s R t NC(O)-; Optional, R t Selected independently from C 1-6 alkyl; Or, R t Each is independently selected from methyl groups; Optional, R s Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Or, R s Selected independently from C 1-3 alkyl; Or, R s Each is independently selected from methyl groups; Or, the R 4 Selected from hydrogen or -CON(CH3)2.

8. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, wherein each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 6-10 The aryl or 5-6 heteroaryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-; Alternatively, each R'' can be independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocyclic alkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, each R'' can be independently selected from deuterium, halogen, -OH, -NH2, or -CN.

9. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-8, wherein each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 4-7 membered heterocyclic alkyl, C 3-7 Cycloalkenyl, 4-7 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl C 1-3 Alkyl-, 4-7 membered heterocyclic alkyl C 1-3 Alkyl-, C 3-7 Cycloalkenyl C 1-3 alkyl-, 4-7 membered heterocyclic alkenyl C 1-3 Alkyl-, phenyl-C 1-3 Alkyl- or 5-6-membered heteroaryl C 1-3 alkyl-; Or, each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or C 3-6 cycloalkyl C 1-3 alkyl-; Or, each of the R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, or optionally by one or more R d Replacement C 1-4 Alkyl or C 3-6 cycloalkyl C 1-3 alkyl-; Or, each of the R 5 Selected independently from halogens or optionally by one or more R d Substituted methyl or cyclopropylmethyl-; Optional, R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, -CHO, -COOH, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-11 Cycloalkyl or 4-11 membered heterocycloalkyl, wherein the C 3-11 The cycloalkyl or 4-11 membered heterocycloalkyl group is optionally substituted with one or more of the following groups: deuterium, -CN, =O, halogen, -OH, -NH2, -NO2 or -CHO; Or, the R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkoxy, C 1-6 Alkyl NH-, or (C 1-6 Alkyl)2N-; Or, the R d Selected from deuterium, halogens, -OH, -NH2, -CN, or -NO2; or, said R 5 Selected from halogens; Or, the R 5 Selected from -F, methyl or .

10. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-9, wherein the ring F is selected from C 6-10 Aryl or 9-10 heteroaryl groups; Alternatively, the ring F is selected from 9-membered heteroaryl groups; Alternatively, the heteroaryl group in ring F is a dicyclic heteroaryl group; Alternatively, the heteroaryl group in ring F is selected from benzo5-membered heteroaryl or pyrido5-membered heteroaryl; Alternatively, ring F is selected from ,in, Indicates a single or double bond; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 Z 8 and Z 9 Each is independently selected from O, S, N, NH, Se, C, or CH; Alternatively, ring F is selected from in, Indicates a single or double bond; Z 1 Z 2 Z 7 Z 8 and Z 9 Each is independently selected from O, S, N, NH, Se, C, or CH.

11. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as described in any one of claims 1-10, wherein the structural moiety is... Selected from , , , , , , , , , , , , , , , or .

12. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-11, when L a No, ring E is selected from 9-11 member heterospirocycloalkyl or 9-11 member heterospirocycloalkenyl; Or, when L a It does not exist; ring E is selected from... , , , , , , , , , , , , , , , , , , , , , , , , or ; Or, when L a It does not exist; ring E is selected from... or .

13. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-12, wherein the L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or ethynyl group; Optionally, the R L Selected from hydrogen, deuterium, halogens, CN, C 1-6 Alkyl or C 1-6 Heteroalkyl; Or, the R L Selected from hydrogen, -F, or methyl; Or, the L a Selected from -O-, -S-, -N(CH3)-, -CH2-, -CF2-, -C(CH3)2-, =CH-, =CF-, -C(=CH2)-, -C(=CF2)- or -C≡C-.

14. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-13, wherein ring E is selected from C. 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Or, C in ring E 3-12 Selected from C 3-10 C 4-10 Or C 4-6 ; Alternatively, the 4-12 yuan in ring E can be selected from 4-7 yuan or 5-6 yuan; Or, C in ring E 6-12 Selected from C 6-10 ; Alternatively, the 5-12 yuan in ring E can be selected from 5-10 yuan or 5-6 yuan; Alternatively, ring E is selected from C. 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic alkenyl, C 6-10 Aryl or 5-6 heteroaryl.

15. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as described in any one of claims 1-14, wherein the structural moiety is... Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Or, structural parts Selected from ,or .

16. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-15, wherein the CLM is selected from the following structures: 、 、 、 、 、 、 、 ， in, u is selected from 0, 1, or 2; Ring D is independently selected from 5-25 element rings; R 7 Each independently selected from H or C 1-6 alkyl; X 11 Each of the following is independently selected from O, S, C(O), CH2, or NH; X 4 Selected independently from C(R) f ) or N; R f C atoms independently selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted with one or more substituents. 1-6 alkyl; L 1 Each is independently selected from the bond, -NH-, -O-, -S-, -CONH-, or -CON(C). 1-6 alkyl)-; Each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, =O, and optionally substituted by one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 alkyl)NH-, (C 1-10 Alkyl)2N-, Halogenated C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; n is selected from 0, 1, 2, 3, 4 or 5.

17. The compound of claim 16, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring D is selected from... , , , , ,or ,in, Ring A does not exist, or is selected from C. 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl or 5-6-membered heteroaryl groups; Cyclic C is selected from 5-6 member heteroaryl groups; X 5 Selected from C(O), CH2, or NH; X 6 Selected from O, CH2, NH or .

18. The compound of claim 17, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring A is absent or selected from C. 5-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, azircycloheptenyl, oxazircycloheptenyl, azirspirooctenyl, azirspirononenyl, azirspirodecenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl; Optionally, ring B is selected from phenyl or 6-membered heteroaryl; Alternatively, ring B is selected from phenyl or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; Alternatively, ring B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl; Optionally, the ring C is selected from 5-membered heteroaryl groups; Alternatively, the ring C is selected from a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; Alternatively, the ring C is selected from isoxazolyl, furanyl, pyrazolyl, isothiazolyl, or thiophenyl.

19. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 16-18, R 7 Each is independently selected from H or methyl.

20. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 16-19, R f Each of the following is independently selected from H, halogen, OH, NH2, CN, deuterium, or methyl; Or, R f Each is independently selected from H, F, or deuterium.

21. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 16-20, L 1 Each is independently selected from the bond, -NH-, -O-, -S-, -CONH-, or -CON(CH3)-.

22. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 16-21, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, =O, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; Or, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, =O, C 1-3 Alkyl or C 1-3 Alkoxy; Or, each R 1 It is independently selected from F, -Cl, =O, methyl or methoxy.

23. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-22, wherein the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 imide or C 2-15 Alkyne group, optionally, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the alkynyl group are independently and optionally surrounded by -O-, -NH-, or -N(C) 1-3 Alkyl)-, -S-, C 3-15 cycloalkyl, C 3-15 Cycloalkenyl, 4-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl or 5-15 member heteroaryl substitution; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 imide or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the alkynyl group are independently and optionally surrounded by -O-, -NH-, or -N(C) 1-3 Alkyl)-, -S-, C 3-11 cycloalkyl, C 3-11 Cycloalkenyl, 4-11 membered heterocyclic alkyl, 4-11 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 quinone heteroaryl substitution; Alternatively, the L is selected from C that is optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, -NH-, -N(C 1-3 Alkyl)-, -S-, C 4-9 cycloalkyl, C 4-6 Cycloalkenyl, 4-11 membered heterocyclic alkyl, C 6-10 Aryl or 6-10 member heteroaryl substitution; Optionally, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, or optionally substituted by deuterium, halogen, -OH, -NH2, or -CN, and the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; Alternatively, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, and optionally substituted with a halogen: C 1-3 Alkyl, C 1-3 Alkoxy or C 3-4 cycloalkyl; Alternatively, in the definition of L, the substituent is selected from -F, -Cl, methyl, CH3O-, CHF2O-, or CF3O-.

24. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-23, wherein the L is selected from -LNK. 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -LNK 3 -Cy 4 -LNK 4 -,in, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R... b The following groups are substituted: C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkyl, 4-12 membered heterocyclic alkenyl, C 6-10 Aryl, or 5-10 heteroaryl; LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Selected independently from the bond, -NH-, -N(C) 1-3 Alkyl group, -O-, -S-, or optionally with one or more R groups c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 1-10 Heteroalkylene, C 2-10 Heteroeneyl, or C 2-10 Hetero-ynyl group; Each R b and R c Each of the following groups, independently selected from deuterium, halogen, =O, -OH, -NH2, -CN, or optionally substituted by deuterium, halogen, -OH, -NH2, or -CN, is selected: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

25. The compound of claim 24, its stereoisomers, or pharmaceutically acceptable salts thereof, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Selected independently from the bond, -NH-, -N(C) 1-3 Alkyl group, -O-, -S-, or optionally with one or more R groups c The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 1-4 Heteroalkylene, C 2-4 Heteroeneyl, or C 2-4 Hetero-ynyl group; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the key, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-4 etyne group, or C 1-4 Heteroalkylene; Or, -LNK 1 -、LNK 2 LNK 3 and LNK 4 Each is independently selected from the following: -CH2-, -CH2CH2-, -CF2CH2-, -CH2CH2CH2-, -O-, -N(CH3)CH2- or -OCH2-; Optional, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R... b The following groups are substituted: C 4-9 cycloalkyl, C 4-6 Cycloalkenyl, 4-11 membered heterocyclic alkyl, C 6-10 Aryl or 6-10 heteroaryl groups; Or, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R... b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, piperazine, tetrahydropyridyl, azirspiroheptyl, azirspirohoctyl, azirspirononyl, azirspirodealkyl, azirspiroundecyl, diazirspirononyl, azirspirodealkyl, diazirspirodealkyl, diazirspiroundecyl, azirbicyclohexyl, azirbicyclooctyl, azirbicyclononyl, diazirbicycloheptyl, diazirbicyclooctyl, octahydrocyclopentylpyrroleyl, phenyl, tetrahydrophenyl, phenyl, naphthyl, pyridyl, or indole.

26. The compound of claim 24 or 25, its stereoisomer, or a pharmaceutically acceptable salt thereof, each R b and R c Each of the following groups, independently selected from deuterium, halogen, =O, -OH, -NH2, -CN, or optionally substituted by deuterium, halogen, -OH, -NH2, or -CN, is selected: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl) NH-, (C 1-6 Alkyl)2N-, C 3-6 cycloalkyl, or 3-6 membered heterocyclic alkyl; Or, each R b and R c Each of the following groups, independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, or optionally substituted with a halogen: C 1-3 Alkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl; Or, each R b and R c Each is independently selected from -F, -Cl, methyl, CH3O-, CHF2O-, or CF3O-.

27. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-26, wherein the compound is selected from compounds of formula II-A, II-B, VI, or VIA, their stereoisomers, or a pharmaceutically acceptable salt thereof. ， ， ,or 。 28. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-27, wherein, The compound is selected from the following compounds: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， , , , , , , , , , , , , , , , ,or .

29. A compound of formula XI, its stereoisomers, or a pharmaceutically acceptable salt thereof, in, L a It does not exist or is selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 Ethyne group; When L a No, ring E is selected from 7-15 membered heterospirocycloalkyl or 7-15 membered heterospirocycloalkenyl; When L a Selected from -O-, -S-, -N(R) L )-、-C(R L )2-、=C(R L )-、-C(=CR L 2)- or C 2-3 The acetylenic group, the R L Selected from hydrogen, deuterium, halogens, -CN, C 1-10 Alkyl or C 1-10 Heteroalkyl, with ring E selected from C 3-15 Cycloalkyl, 4-15 membered heterocyclic alkyl, C 3-15 Cycloalkenyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl or 5-15 heteroaryl groups; Each R 2 Each is independently selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, =O, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl; R 3 Selected from the following groups optionally substituted with one or more R': C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 Alkyl-N=, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, R v C(O)-, R v C(=S)-、R v S(O)-、R v S(O)2- or R u R v P(=O)-; R u Selected from H, -OH or C 1-12 alkyl; R v Selected independently from C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-, the C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 3-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 3-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 Alkyl groups are optionally substituted with one or more deuterium, halogen, -OH, -NH2, or -CN; Ring F is selected from C 6-12 Aryl or 5-12 heteroaryl groups; R 4 Selected from H, or optionally substituted with one or more R'' groups: R s C(O)-, R s C(O)O-、R s OC(O)-, R s S(O)-、R s S(O)2-、R s R t NC(O)-, R s C(O)NR t -、R s S(O)2NR t -or R s R t NS(O)2-; R t Each independently selected from H or C 1-12 alkyl; R s Selected independently from C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl groups; Each R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 6-12 The aryl or 5-12 heteroaryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl)2N-; Each R 5 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, and optionally influenced by one or more R. d The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 4-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 4-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-; R d Selected from deuterium, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, or (C 1-6 Alkyl)2N-; R 55 It does not exist, or is selected from one or more Rs. d1 The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-6 Alkyl-, 4-12 membered heterocyclic alkyl C 1-6 Alkyl-, C 3-12 Cycloalkenyl C 1-6 alkyl-, 4-12-membered heterocyclic alkenyl C 1-6 Alkyl-, C 6-12 Aryl C 1-6 Alkyl- or 5-12-membered heteroaryl C 1-6 alkyl-; Each R d1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, -CHO, -COOH, or optionally by one or more R dd The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-15 Cycloalkyl, 4-15 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-15 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl; Each R dd Each of the following is independently selected from deuterium, -CN, =O, halogen, -OH, -NH2, -NO2, -CHO, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 3-12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, R s C(O)-, R s C(O)O-、R s OC(O)-, R s S(O)-、R s S(O)2-、R s R t NC(O)-, R s C(O)NR t -、R s S(O)2NR t -or R s R t NS(O)2-; j and k are independently selected from 0, 1, 2, 3, or 4.

30. The compound of claim 29, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from compounds of formula XII, their stereoisomers, or pharmaceutically acceptable salts thereof. 。 31. A compound of formula X, its structural moiety, its derivatives, its stereoisomers, or a pharmaceutically acceptable salt thereof: in, R 2 R 3 R 4 R 5 , ring F, j, k, L a The definition of ring E is as described in claim 1 or 29.

32. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 29-31, wherein, The compound is selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 、 ； 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

33. A pharmaceutical composition comprising the compound of any one of claims 1-32, its structural moiety, its derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof.

34. Use of the compound, its structural moiety, its derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 33, in the preparation of a medicament for treating a disease; optionally, the disease is selected from inflammatory diseases.

35. A method of treating a mammalian disease, comprising administering to a mammal in need of the treatment a therapeutically effective amount of a compound of any one of claims 1-32, its structural moiety, its derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 33; optionally, the disease is selected from inflammatory diseases.

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