VAV1-targeting degrader and use thereof

Abstract

The present application relates to a VAV1-targeting degrader and the use thereof. Particularly, the present application relates to a compound of general formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and the use of the compound of general formula (I) or the pharmaceutical composition thereof in the preparation of a drug for preventing and / or treating VAV1-mediated diseases, wherein each substituent in general formula (I) is the same as defined in the description.

Description

A VAV1 targeted degrader and its uses Technical Field

[0001] This application relates to a VAV1-targeting degrader, its stereoisomer, a pharmaceutically acceptable salt, and its use in the preparation of medicaments for treating VAV1-mediated related diseases. Background Technology

[0002] Molecular glues are a class of small molecules that influence protein function by inducing proximity between target proteins and effector macromolecules, thereby altering protein-protein interactions. The main mechanism of action of molecular glues involves inducing proximity between target proteins and ubiquitin ligases, ensuring the successful degradation of the target protein by the ubiquitin-proteasome system.

[0003] The VAV family is a group of signal transduction proteins that serve as phosphorylation-dependent GDP / GTP exchange factors (GEFs) and adaptor molecules for Rho subfamily GTPases. It consists of three members: VAV1, VAV2, and VAV3. VAV1, a member of the VAV family, is primarily expressed in human hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells. As a bifunctional protein, VAV1 possesses both GEF activity and scaffold protein function. By degrading VAV1 protein, VAV1 molecules can simultaneously inhibit its GEF activity and scaffold protein function, thereby blocking multiple important signaling pathways of T cells and B cells, more comprehensively suppressing immune responses, and reducing inflammation or autoimmune activity.

[0004] Currently, treatment options for autoimmune diseases and chronic inflammatory diseases remain limited. VAV1 molecular gel has a unique mechanism and broad potential applications. It can be safely administered orally to treat a variety of autoimmune diseases (multiple sclerosis, rheumatoid arthritis, ulcerative colitis, myasthenia gravis, chronic lymphocytic leukemia, psoriasis, cutaneous lupus, axial spondylitis, and graft-versus-host disease, etc.), thus meeting unmet clinical needs. Summary of the Invention

[0005] This application provides a compound of VAV1-targeting degrader, its stereoisomer or a pharmaceutically acceptable salt thereof, its preparation method, intermediates, and applications. Specifically, this application provides a compound of general formula (I), its preparation method, intermediates, a pharmaceutical composition comprising the compound of general formula (I), and the application of the compound of general formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for treating / preventing VAV1-mediated diseases. The compound exhibits excellent activity, superior physicochemical properties, ease of formulation, high bioavailability, and low toxicity.

[0006] This application provides a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1), formula (IV), formula (IV-1), formula (V), formula (VI-1), formula (III-A), formula (IV-A), formula (VA), formula (VB), formula (VII), formula (VII-1), and formula (IV-A-1), its stereoisomer or pharmaceutically acceptable salt.

[0007] in,

[0008] L 1、 L2 is selected independently from the key and -C. 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1 )C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl group is optionally further reinforced by 1-4 R groups. L replace;

[0009] In some implementations, L1 is selected from key, -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1)C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl group is optionally further reinforced by 1-4 R groups. L replace;

[0010] In some implementations, L1 is selected from key, -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-、-S-、-S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-6 cycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally further reinforced by 1-3 R groups. L replace;

[0011] In some implementations, L1 is selected from key, -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-3 alkynyl-, -N(R) L1 )C(O)-、-OC 1-4 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L replace;

[0012] In some implementations, L1 is selected from key, -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -N(R) L1 )C(O)-、-OC 1-3 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L replace;

[0013] In some embodiments, L1 is selected from the following: -C(O)NH-, -O-, -NH-, -N(CH3)-, -CH2-, -CH(CH3)-, -S-, -NHC(O)-, -S(O)2NH-, -NHS(O)2-, -CH=CH-, -C≡C-, -cyclopropyl-, -cyclobutyl-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-;

[0014] In some implementations, L1 is preferably selected from the bond, -O-CH2-; L 1-1 Selected from -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-8 cycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1 )C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, cycloalkyl, optionally further comprises 1-4 R- L replace;

[0015] In some implementations, L 1-1 Selected from -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-、-S-、-S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-6 cycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally further surrounded by 1-3 R groups.L replace;

[0016] In some implementations, L 1-1 Selected from -C(O)NH-, -O-, -NH-, -N(CH3)-, -CH2-, -CH(CH3)-, -S-, -NHC(O)-, -S(O)2NH-, -NHS(O)2-, -CH=CH-, -C≡C-, -C≡C-CH2-, -cyclopropyl-, -cyclobutyl-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, -O-CH2-, -CH2C(O)-, -C(O)CH2-;

[0017] L1 is selected from the key, -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1 )C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl group is optionally further reinforced by 1-4 R groups. L replace;

[0018] In some implementations, L2 is selected from key, -C 1-4 Alkyl-, -N(R) L1 )-、-N(R L1 )C(O)-, wherein the alkyl group is optionally further divided by 1-4 R L replace;

[0019] In some implementations, L2 is selected from key, -C 1-3 Alkyl-, -N(R) L1 )-、-N(R L1 )C(O)-, wherein the alkyl group is optionally further divided by 1-4 R L replace;

[0020] In some implementations, L2 is selected from key, -C1-2 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L replace;

[0021] In some embodiments, L2 is selected from the following groups: -C(O)-, -NHC(O)-, -CH2C(O)-, -N(cyclopropyl)-, -N(propenyl)-, -N(allyl)-, -N(propynyl)-, -N(propynyl)-, -N(CH2-cyclopropyl)-, -N(CH2CF3)-, -C≡C-, -CH(CH3)-,

[0022] R L1 Selected from H, D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, -C(O)-C 3-6 cycloalkyl, -S(O)2-C 3-6 cycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, or cycloalkyl group is optionally further substituted with 1 to 4 groups selected from D, halogen, =O, CN, OH, and NH2;

[0023] In some implementation schemes, R L1 Selected from H, D, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, -C(O)-C 3-4 cycloalkyl, -S(O)2-C 3-4 cycloalkyl, -C 1-3 Alkyl-C 3-4 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally further substituted with 1-3 groups selected from D, halogen, =O, CN, OH, and NH2;

[0024] In some implementation schemes, R L1 Selected from H, D, C 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Haloalkyl, C 1-2Halogenated alkoxy groups, C 3-4 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally further substituted with 1-3 groups selected from D, halogen, =O, CN, OH, and NH2;

[0025] In some implementation schemes, R L1 Selected from H, D, methyl, ethyl, methoxy, ethoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCH3, -OCF2CH3, vinyl, propynyl, propynyl, propynyl, 2-butynyl, cyclopropyl, cyclobutyl, -C(O)-cyclopropyl, -C(O)-cyclobutyl, -S(O)2-cyclopropyl, -S(O)2-cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl;

[0026] In some implementation schemes, R L1 Selected from H, D, methyl, ethyl, trifluoromethyl, trifluoroethyl, vinyl, propynyl, propynyl, cyclopropyl;

[0027] R L1-1 Selected from D and C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, -C(O)-C 3-6 cycloalkyl, -S(O)2-C 3-6 cycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, alkenyl, or alkynyl groups are optionally further substituted with 1 to 4 groups selected from D, halogen, =O, CN, OH, and NH2;

[0028] In some implementation schemes, R L1-1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -S(O)2-C 3-4 Cycloalkyl, wherein the alkenyl or ynyl group is optionally further substituted with 1-4 groups selected from D or halogens;

[0029] In some implementation schemes, R L1-1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C3-6 cycloalkyl, -S(O)2-C 3-4 Cyclopropyl groups substituted with cycloalkyl or CN;

[0030] In some implementation schemes, R L1-1 Selected from allyl, propargyl, cyclopropyl, -CH2-CH=C(F)2, -S(O)2-cyclopropyl;

[0031] In some implementation schemes, R L1-1 Selected from allyl, propargyl, cyclopropyl,

[0032] In some implementation schemes, R L1-1 Selected from 2-propenyl, 2-propynyl, cyclopropyl,

[0033] R L Selected from H, D, halogens, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic groups are optionally further substituted by 1-4 groups selected from D, halogen, =O, CN, OH and NH2;

[0034] In some implementation schemes, R L Selected from H, D, halogens, =O, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic groups are optionally further substituted by 1-3 groups selected from D, halogen, =O, CN, OH and NH2;

[0035] In some implementation schemes, R L Selected from H, D, halogens, =O, CN, C 1-2 Alkyl, C 1-2 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2Halogenated alkoxy groups, C 3-4 Cycloalkyl, 4-6 membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic groups are optionally further substituted by 1-3 groups selected from D, halogen, =O, CN, OH and NH2;

[0036] In some implementation schemes, R L Selected from H, D, halogens, =O, CN, C 1-2 Alkyl, C 1-2 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 4-6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group may optionally be further substituted by 1-3 groups selected from D, F, Cl, =O, CN, OH and NH2;

[0037] In some implementation schemes, R L Selected from H, D, halogens, =O, CN, C 1-2 Alkyl, C 1-2 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 3-4 cycloalkyl;

[0038] In some implementation schemes, R L Selected from H, D, F, Cl, =O, methyl, ethyl, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, vinyl, ethynyl, methoxy, ethoxy, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCH3, -OCF2CH3, cyclopropyl, aziridine, oxadiazine;

[0039] In some implementation schemes, R L Selected from H, D, F, Cl, =O, methyl, ethyl, trifluoromethyl, trifluoroethyl, vinyl, ethynyl, methoxy, cyclopropyl;

[0040] Or two R atoms located on the same carbon atom L Together with the carbon atom it is attached to, they form C 3-8Cycloalkyl groups, 4-8 heterocyclic groups, wherein the cycloalkyl groups or heterocyclic groups are optionally further composed of 1-4 groups selected from D, halogens, =O, CN, OH, NH2, C. 1-2 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The group substituted by the halogenated alkoxy group;

[0041] In some implementations, two R atoms located on the same carbon atom L Together with the carbon atom it is attached to, they form C 3-6 Cycloalkyl groups, 4-6 heterocyclic groups, wherein the cycloalkyl groups or heterocyclic groups are optionally further composed of 1-4 groups selected from D, halogens, =O, CN, OH, NH2, C. 1-2 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The group substituted by the halogenated alkoxy group;

[0042] In some implementations, two R atoms located on the same carbon atom L Together with the carbon atom it is attached to, they form C 3-4 Cycloalkyl; the ring C is selected from non-existent, phenyl, C 3-15 cycloalkyl groups, 5-15 membered heterocyclic groups;

[0043] In some implementations, ring C is selected from those that do not exist;

[0044] In some implementations, the cyclic C is selected from phenyl;

[0045] In some implementations, ring C is selected from C 3-15 cycloalkyl groups, 5-15 membered heterocyclic groups;

[0046] Ring C1 is selected from C 3-10 Cycloalkyl, 5-6 membered heteroaryl, 4-10 membered heterocycloalkyl;

[0047] In some implementations, ring C1 is selected from C 3-6 Monocycloalkyl, C 6-10 cycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Spirocycloalkyl, five-membered heteroaryl, six-membered heteroaryl, 4-8-membered monocyclic heterocycloalkyl, 6-10-membered fused heterocycloalkyl, 5-10-membered bridged heterocycloalkyl, 5-10-membered spirocycloalkyl;

[0048] In some implementations, ring C1 is selected from... Cyclone C2 is selected from 8-10 fused heterocyclic groups, 8-10 bicyclic heterocyclic groups, and C 10-15 Tricyclic cycloalkyl groups, 10-15 membered tricyclic heterocyclic groups;

[0049] In some embodiments, ring C2 is selected from benzopenta-heteroaryl, benzohexa-heteroaryl, benzopenta-heterocycloalkyl, benzohexa-heterocycloalkyl, C 10-15 Tricyclic cycloalkyl, 10-15 membered tricyclic heterocyclic alkyl, 10-15 membered tricyclic heteroaryl;

[0050] In some implementations, ring C2 is selected from...

[0051] Ring C A Selected from five-membered heteroaryl, 4-8-membered monocyclic heterocyclic alkyl, C 3-8 Monocyclic cycloalkyl, C 6-8 Bridged cycloalkyl groups, cuboalkyl groups;

[0052] In some implementation schemes, ring C A Selected from five-membered heteroaryl, 4-6-membered monocyclic heterocyclic alkyl, C 3-6 Monocyclic cycloalkyl, C 6-8 Bridged cycloalkyl groups, cuboalkyl groups;

[0053] In some implementation schemes, ring C A Selected from

[0054] In some implementation schemes, ring C A Selected from five-membered aromatic compounds;

[0055] In some implementation schemes, ring C A Selected from

[0056] In some implementation schemes, ring C A Selected from

[0057] Ring D is selected from non-existent, phenyl, C 3-10 Cycloalkyl, 4-15 membered heterocycloalkyl, 4-10 membered heteroaryl;

[0058] In some implementations, ring D is selected from those that do not exist;

[0059] In some implementations, ring D is selected from C. 3-10 Cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl;

[0060] In some implementations, ring D is selected from...

[0061] Each R C and R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-10 Cycloalkyl, -O- (4-8 membered heterocyclic), -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -S(O)2-NHC 3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)NHOH, -C(O)NHOC 1-4 Alkyl groups, -C(O)NHCN, -C(S)NHC 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)NH (4-8 membered heterocyclic group), -C(O)- (4-8 membered heterocyclic group), -N=S(O)(C 1-3 Alkyl)2, -C 1-4Alkyl-(4-8 membered heterocyclic group), -C 1-4 Alkyl-(3-8 membered cycloalkyl), -C(O)NR L1 -C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further reinforced by 1-4 R groups. X replace;

[0062] In some implementations, each R C and R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, -C 1-4 Alkyl-(4-8 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0063] In some implementations, each R CEach is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further reinforced by 1-4 R X replace;

[0064] In some implementations, each R C Each is independently selected from H, D, =O, =S, =NH, halogens, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further reinforced by 1-4 R X replace;

[0065] In some implementations, each R C Each is independently selected from H, D, =O, =S, =NH, halogens, and C. 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Haloalkyl, C 1-2 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-4 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-2 Haloalkyl, -SF5, -P(O)(C 1-2 Alkyl)2、-S(O)-C 3-4 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-4 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-4 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-4 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further reinforced by 1-4 R X replace;

[0066] In some implementations, each R CEach is independently selected from H, D, F, Cl, =O, =S, =NH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCH FCH3, -OCF2CH3, cyclopropyl, aziridine, oxacyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -SCF3, -SCHF2, -SCH2F, -SCH2CF3, -SF5, -P(O)(CH3)2, -P(O)(CH2CH3)2, -S(O)2-cyclopropyl, -S(O)2-cyclobutyl, -C(O)-cyclopropyl, -C(O)-cyclobutyl, -N=S(O)(CH3)2

[0067] In some implementations, each R C Each is independently selected from D, F, Cl, =O, =S, =NH, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, and cyclopropyl.

[0068] In some implementations, each R C Each is independently selected from =O, C 1-2 Alkyl, C 2-4 alkynyl group;

[0069] In some implementations, each R D Each is independently selected from H, D, halogens, CN, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-8 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Halogenated alkyl groups, -SF5, -P(O)(CH3)2, -S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -C 1-2 Alkyl-(4-6 membered heterocyclic group), -NR L1 -(5-6 heteroaryl groups), -C(O)NHOH, -C(O)NHOC 1-4 Alkyl groups, -C(O)NHCN, -C(S)NHC 3-6 cycloalkyl, -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -S(O)2-NHC 3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -C(O)NH (4-8 membered heterocyclic group), -C(O)- (7-8 membered binary heterocyclic group), -C(O)NR L1 -C 1-4 Alkyl groups, wherein the alkyl, alkenyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, or heteroaryl groups are optionally further surrounded by 1-4 R groups. X replace;

[0070] In some implementations, each R D Each is independently selected from H, D, halogens, CN, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-8 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Halogenated alkyl groups, -SF5, -P(O)(CH3)2, -S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -C 1-2 Alkyl-(4-6 membered heterocyclic group), -NR L1 -(5-6 heteroaryl groups), -C(O)NHOH, -C(O)NHOC 1-4 Alkyl groups, -C(O)NHCN, -C(S)NHC 3-6 cycloalkyl, -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -S(O)2-NHC 3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -C(O)NH (4-8 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, or heteroaryl group is optionally further surrounded by 1-4 R groups. X replace;

[0071] In some implementations, each R D Each is independently selected from D, halogens, =O, =S, =NH, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-8 cycloalkyl, -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -S(O)2-NHC 3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -C(O)NHOH, -C(O)NHOC 1-2 Alkyl groups, -C(O)NHCN, -C(S)NHC 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)NH (4-8 membered heterocyclic group), -C(O)- (4-8 membered heterocyclic group), -C 1-4 Alkyl-(4-8 membered heterocyclic group), -C 1-4Alkyl-(3-8 membered cycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0072] In some implementations, each R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -C 1-4 Alkyl-(4-8 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0073] In some implementations, each R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Halogenated alkyl groups, -SF5, -P(O)(CH3)2, -S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -C 1-2 Alkyl-(4-6 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0074] In some implementations, each R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Haloalkyl, C 1-2 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-4 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-2 Halogenated alkyl groups, -SF5, -P(O)(CH3)2, -S(O)-C 3-4 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-4 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-4 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-4 cycloalkyl, -C(O)NHC 3-6Cycloalkyl, -C(O)- (4-6 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0075] In some implementations, each R D Each is independently selected from H, D, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -C 1-4 Alkyl-(4-8 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0076] In some implementation schemes, R D Each is independently selected from D, F, Cl, =O, =S, =NH, CN, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, -OCD3, -ethynyl-cyclopropyl, -vinyl-cyclopropyl, -O-cyclobutyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NHCN, -C(O)NHOCH3, -C(S)NH-cyclopropyl, -C(S)NH-cyclobutyl, -O-cyclopropyl, Or difluoromethyl, -C(O)N(CH3)CH2CHF2;

[0077] In some implementations, each R D Each is independently selected from D, F, Cl, =O, =S, =NH, methyl, ethyl, vinyl, ethynyl, methoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCH3, -OCF2CH3, cyclopropyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl

[0078] In some implementation schemes, R is preferred. D Each is independently selected from -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NHOCH3, -O-cyclopropyl,

[0079] In some implementation schemes, R D Each is independently selected from D, F, Cl, =O, =S, =NH, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl. -O-cyclobutyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -O-cyclopropyl

[0080] In some implementation schemes, R D Each is independently selected from D, F, Cl, =O, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl. -O-cyclobutyl, -O-cyclopropyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl;

[0081] Or two Rs C R D Together with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further surrounded by 1-4 R groups. X replace;

[0082] Or any two R C R DTogether with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups;

[0083] In some implementations, any two R C R D Together with the atoms it is attached to, it forms a phenyl group, C 3-7 Cycloalkyl, 5-7-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups chosen from D, F, Cl, =O, CN, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Deuterated alkoxy, C 3-4 Substituted with cycloalkyl or 4-6 membered heterocyclic groups;

[0084] In some implementations, any two R C R D Together with the atoms it is attached to, it forms a phenyl group, C 3-7Cycloalkyl, 5-7-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected from 1-4 groups selected from D, F, Cl, =O, CN, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -CD3, -CH2D, -CHD2, -CH2CD3, -CH2CHD2, -C The groups substituted with H2CH2D, -CHDCH3, -CD2CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCH3, -OCF2CH3, -OCD3, -OCH2D, -OCHD2, -OCH2CD3, -OCH2CHD2, -OCH2CH2D, -OCHDCH3, -OCD2CH3, cyclopropyl, cyclobutyl, oxetyl, and aziridine groups;

[0085] In some implementations, any two R C R D Together with the atoms it is attached to, it forms a phenyl group, C 3-7 cycloalkyl, 5-7-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from methyl, ethyl, vinyl, ethynyl, =O, The groups are replaced;

[0086] R B Selected from H, or, when L1 is not a bond or C1 is not a benzene ring, R B With R C Together with the atoms it is attached to, it forms a phenyl group, C 5-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups;

[0087] In some implementation schemes, R B Selected from H;

[0088] In some implementations, when L1 is not a bond or C1 is not a benzene ring, R B With R C Together with the atoms it is attached to, it forms a phenyl group, C 5-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups;

[0089] In some implementations, when L1 is not a bond or C1 is not a benzene ring, R B With R C Together with the atoms it is attached to, it forms a phenyl group, C 5-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, F, Cl, =O, CN, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Deuterated alkoxy, C 3-4 Substituted with cycloalkyl or 4-6 membered heterocyclic groups;

[0090] In some implementations, when L1 is not a bond or C1 is not a benzene ring, R B With R C Together with the atoms it is attached to, it forms a phenyl group, C 5-8Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected from 1-4 groups selected from D, F, Cl, =O, CN, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -CD3, -CH2D, -CHD2, -CH2CD3, -CH2CHD2, -C The groups substituted with H2CH2D, -CHDCH3, -CD2CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCH3, -OCF2CH3, -OCD3, -OCH2D, -OCHD2, -OCH2CD3, -OCH2CHD2, -OCH2CH2D, -OCHDCH3, -OCD2CH3, cyclopropyl, cyclobutyl, oxetyl, and aziridine groups;

[0091] R C1 Selected from C 1-6 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, R E The alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0092] R E Selected from 4-8 membered heterocyclic groups, wherein the heterocyclic group contains at least one P atom and optionally is further surrounded by 1-4 R atoms. X replace;

[0093] In some implementation schemes, R E Selected from 4-6 membered heterocyclic groups, wherein the heterocyclic group contains at least one P atom and optionally is further surrounded by 1-2 R atoms. X replace;

[0094] In some implementation schemes, R C1 Selected from C 1-4 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC1-4 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -N=S(O)(C 1-2 Alkyl)2, R E The alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further reinforced with 1-2 R groups. X replace;

[0095] In some implementation schemes, R C1 Selected from -OCF3, -OCHF2, -OCH2F, -O-cyclopropyl, -O-cyclobutyl, -SCF3, -SCHF2, -SCH2F, -SF5, -P(O)(CH3)2, -S(O)2-cyclopropyl, -S(O)2-cyclobutyl, -N=S(O)(CH3)2, -

[0096] Or any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups;

[0097] In some implementations, any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-7 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, F, Cl, =O, CN, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Deuterated alkoxy, C 3-4 Substituted with cycloalkyl or 4-6 membered heterocyclic groups;

[0098] In some implementations, any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-6 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-3 groups selected from D, F, Cl, =O, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Substituted with cycloalkyl or 4-6 membered heterocyclic groups;

[0099] In some implementations, any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-6 Cycloalkyl, 5-7-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected from 1-3 groups selected from D, F, Cl, =O, CN, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -CD3, -CH2D, -CHD2, -CH2CD3, -CH2CHD2, -C The groups substituted with H2CH2D, -CHDCH3, -CD2CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCH3, -OCF2CH3, -OCD3, -OCH2D, -OCHD2, -OCH2CD3, -OCH2CHD2, -OCH2CH2D, -OCHDCH3, -OCD2CH3, cyclopropyl, cyclobutyl, oxetyl, and aziridine groups;

[0100] n3 is 2, and both R C2 Together with the carbon atoms it is attached to, they form 7-8 membered heterocycles, C 7-8Cycloalkyl, wherein the heterocyclic or cycloalkyl group is optionally further substituted with 1-4 Rx;

[0101] In some implementations, n3 is 2, and the two Rs C2 Together with the carbon atoms it is attached to, they form 7-8 membered heterocycles, C 7-8 Cycloalkyl, wherein the heterocyclic or cycloalkyl group is optionally further substituted with 1-4 Rx;

[0102] X1 and X2 are each independently selected from C and N. When both X1 and X2 are C, L1 is not a bond.

[0103] n4 is 2, and both R C3 Together with the carbon atom it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 4-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally further substituted by 1-4 Rx;

[0104] R D1 Selected from =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic group), wherein the alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0105] In some implementation schemes, R D1 Selected from =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6Cycloalkyl, -C(O)- (4-6 membered heterocyclic group), wherein the alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0106] In some implementation schemes, R D1 Selected from =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-2 Halogenated alkoxy groups, -OC 3-4 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-2 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-4 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-4 Cycloalkyl, -C(O)- (4-6 membered heterocyclic group), wherein the alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0107] In some implementation schemes, R D1 Selected from =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =cyclobutyl, =cyclopentyl, =azacyclobutyl, =oxacyclobutyl, -OCF3, -OCHF2, -OCH2F, -O-cyclopropyl, -O-cyclobutyl, -SCF3, -SCHF2, -SCH2F, -SF5, -P(O)(CH3)2, -S(O)2-cyclopropyl, -S(O)2-cyclobutyl,

[0108] In some implementation schemes, R D1 Selected from =S;

[0109] R X Each is independently selected from D, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 cycloalkyl, = ( 4-6 (heterocyclic alkyl), C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group, -C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl groups are optionally further selected from 1 to 4 groups selected from D, halogen, =O, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Substituted with cycloalkyl groups;

[0110] In some implementation schemes, R X Each is independently selected from D, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamine group, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-4 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl groups are optionally further selected from 1 to 4 groups selected from D, halogen, =O, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Substituted with cycloalkyl groups;

[0111] R X Each is independently selected from D, F, Cl, hydroxyl, cyano, amino, =O, =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Deuterated alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-3 Alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further substituted by 1-4 groups selected from D, halogen, =O, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, or cyclopropyl.

[0112] In some implementation schemes, R X Each is independently selected from D, F, Cl, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Deuterated alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Alkylamine group, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -S(O)2-C 1-2 Alkyl, -C 1-2 Alkyl-C 1-2 Alkoxy;

[0113] In some implementation schemes, R XEach group is independently selected from D, F, Cl, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2, =cyclobutyl, =cyclopentyl, =azacyclobutyl, =oxacyclobutyl, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -CD3, -CH2D, -CHD2, -CH2CD3, -CH2CH D2, -CH2CH2D, -CHDCH3, -CD2CH3, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCH3, -OCF2CH3, -OCD3, -OCH2D, -OCHD2, -OCH2CD3, -OCH2CHD2, -OCH2CH2D, -OCHDCH3, -OCD2CH3, -CH2NH2, -CH2-OCH3, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, -S(O)2-CH3;

[0114] In some implementation schemes, R X Each is independently selected from D, F, Cl, hydroxyl, cyano, =O, methyl, ethyl, methoxy, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -CHFCH3, -CF2CH3, -CH2-OCH3, cyclopropyl, cyclobutyl, -S(O)2-CH3, =CH2, =CF2;

[0115] In some implementation schemes, R X Each is independently selected from D, F, Cl, methyl, ethyl, methoxy, -CH2-OCH3;

[0116] In some embodiments, Rx is selected from D, F, Cl, hydroxyl, cyano, methyl, ethyl, CH2CH2F, CH2CF3, CF3, CH2F, CHF2, cyclopropyl, vinyl, ethynyl, methoxy, -CH2-OCH3, =O, =S, =CH2, =CF2, -S(O)2-CH3;

[0117] In some implementation schemes, R X Each is independently selected from D, methyl, ethyl, vinyl, ethynyl, methoxy, -CH2-OCH3, =O, =S, =CH2, =CF2.

[0118] In some implementation schemes, Selected from

[0119] In some implementation schemes, Selected from *The site is the connection point with the right loop D;

[0120] or Selected from

[0121] Selected from *The site is the connection point with the right loop D;

[0122] In some implementation schemes, Selected from *The site is the connection point with the right loop D;

[0123] In some implementation schemes, Selected from

[0124] In some implementation schemes, Selected from

[0125] In some implementation schemes, Selected from

[0126] n is an integer selected from 0 to 5;

[0127] In some implementations, n is selected from integers between 0 and 4;

[0128] In some implementations, n is selected from integers between 0 and 2;

[0129] In some implementation schemes, n is selected from 1 or 2;

[0130] n1 is an integer selected from 1 to 2;

[0131] In some implementations, n1 is selected from 1;

[0132] In some implementations, n1 is selected from 2;

[0133] n2 is an integer selected from 0 to 2;

[0134] In some implementations, n2 is selected from integers between 0 and 1;

[0135] In some implementations, n2 is selected from 0;

[0136] In some implementations, n2 is selected from 1;

[0137] m is selected from integers between 0 and 5;

[0138] In some implementations, m is selected from integers between 0 and 3;

[0139] In some implementations, m is selected from integers from 1 to 3;

[0140] In some implementations, m is selected from 1;

[0141] In some implementations, m is selected from 3;

[0142] m1 is selected from integers between 0 and 1;

[0143] In some implementations, m1 is selected from 0;

[0144] In some implementations, m1 is selected from 1;

[0145] The conditions are: (1) Not for *The site is the connection point between ring C1 and the right ring D;

[0146] (2) When ring C2 is selected from 9-10 member heterocyclic groups, ring C2 contains at least one S atom or m1 is not 0;

[0147] (3) When Selected from At that time, L2 is not -CH2- or -CH2CH2-;

[0148] (4) The compound is not

[0149] The specific first technical solution involves a compound represented by general formula (I) or (IA), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0150] L1 and L2 are each independently selected from the key and -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-,-C(O)N(R) L1 )-、-N(R L1C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1 )C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl group is optionally further reinforced by 1-4 R groups. L replace;

[0151] R L1 Selected from H, D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, -C(O)-C 3-6 cycloalkyl, -S(O)2-C 3-6 cycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, or cycloalkyl group is optionally further substituted with 1 to 4 groups selected from D, halogen, =O, CN, OH, and NH2;

[0152] R L Selected from H, D, halogens, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic groups are optionally further substituted by 1-4 groups selected from D, halogen, =O, CN, OH and NH2;

[0153] Or two R atoms located on the same carbon atom L Together with the carbon atom it is attached to, they form C 3-8Cycloalkyl groups, 4-8 heterocyclic groups, wherein the cycloalkyl groups or heterocyclic groups are optionally further composed of 1-4 groups selected from D, halogens, =O, CN, OH, NH2, C. 1-2 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The group substituted by the halogenated alkoxy group;

[0154] The ring C is selected from non-existent, phenyl, C 3-15 cycloalkyl groups, 4-15 membered heterocyclic groups;

[0155] Ring D is selected from non-existent, phenyl, C 3-10 Cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl;

[0156] Each R C and R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-10 Cycloalkyl, -O- (4-8 membered heterocyclic), -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -S(O)2-NHC 3-6Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)NHOH, -C(O)NHCN, -C(O)NHOC 1-4 Alkyl group, -C(S)NHC 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)NH (4-8 membered heterocyclic group), -C(O)- (4-8 membered heterocyclic group), -N=S(O)(C 1-3 Alkyl)2, -C 1-4 Alkyl-(4-8 membered heterocyclic group), -C 1-4 Alkyl-(3-8 membered cycloalkyl), -C(O)NR L1 -C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further reinforced by 1-4 R groups. X Replace; in some implementations, each R C and R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, -C 1-4 Alkyl-(4-8 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0157] Or any two R C R D Together with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further surrounded by 1-4 R groups. X replace;

[0158] Or any two R C R D Together with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups;

[0159] R B Selected from H, or, when L1 is not a bond or C1 is not a benzene ring, R B With R C Together with the atoms it is attached to, it forms a phenyl group, C 5-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups;

[0160] R X Each is independently selected from D, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 cycloalkyl, = ( 4-6 (heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group, -C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl groups are optionally further selected from 1 to 4 groups selected from D, halogen, =O, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Substituted with cycloalkyl groups;

[0161] n is an integer selected from 0 to 5;

[0162] m is selected from integers between 0 and 5;

[0163] The condition is Selected from At that time, L1 is not a key.

[0164] The second specific technical solution relates to a compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein general formula (I) is further shown as general formulas (II), (II-1), (III), (III-1), (IV), (IV-1), (V), (VI-1), (III-A), (IV-A), (VA), (VB), (VII), (VII-1), (IV-A-1):

[0165] L 1-1 Selected from -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-8 cycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1 )C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, cycloalkyl, optionally further comprises 1-4 R- L replace;

[0166] L1 is selected from the key, -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-3 alkynyl-, -N(R) L1 )C(O)-、-OC 1-4 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L replace;

[0167] L2 is selected from the key, -C 1-4 Alkyl-, -N(R) L1 )-、-N(R L1 )C(O)-, wherein the alkyl group is optionally further divided by 1-4 R L replace;

[0168] R C1 Selected from C 1-6 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, R E The alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0169] R E Selected from 4-8 membered heterocyclic groups, wherein the heterocyclic group contains at least one P atom and optionally is further surrounded by 1-4 R atoms. X replace;

[0170] Or any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups;

[0171] Ring D is selected from C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl;

[0172] Ring C1 is selected from C 3-10 Cycloalkyl, 5-6-membered heteroaryl, 4-15-membered heterocycloalkyl, 9-10-membered heteroaryl;

[0173] Ring C A Selected from five-membered heteroaryl, 4-8-membered monocyclic heterocyclic alkyl, C 3-8 Monocyclic cycloalkyl, C 6-8 Bridged cycloalkyl groups, cuboalkyl groups;

[0174] n3 is 2, and both R C2 Together with the carbon atoms it is attached to, they form 7-8 membered heterocycles, C7-8 Cycloalkyl, wherein the heterocyclic or cycloalkyl group is optionally further substituted with 1-4 Rx;

[0175] X1 and X2 are each independently selected from C and N. When both X1 and X2 are C, L1 is not a bond.

[0176] n4 is 2, and both R C3 Together with the carbon atom it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 4-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally further substituted by 1-4 Rx;

[0177] Cyclone C2 is selected from 8-10 fused heterocyclic groups, 8-10 bicyclic heterocyclic groups, and C 10-15 Tricyclic cycloalkyl groups, 10-15 membered tricyclic heterocyclic groups;

[0178] R D1 Selected from =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic group), wherein the alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0179] Each R C Each is independently selected from H, D, =O, =S, =NH, halogens, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0180] Each R D Each is independently selected from H, D, halogens, CN, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-8 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Halogenated alkyl groups, -SF5, -P(O)(CH3)2, -S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -C 1-2 Alkyl-(4-6 membered heterocyclic group), -NR L1 -(5-6 heteroaryl groups), -C(O)NHOH, -C(O)NHOC 1-4 Alkyl groups, -C(O)NHCN, -C(S)NHC 3-6 cycloalkyl, -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -S(O)2-NHC 3-6Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -C(O)NH (4-8 membered heterocyclic group), -C(O)- (7-8 membered binary heterocyclic group), -C(O)NR L1 -C 1-4 Alkyl groups, wherein the alkyl, alkenyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, or heteroaryl groups are optionally further surrounded by 1-4 R groups. X Replace; in some implementations, each R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Halogenated alkyl groups, -SF5, -P(O)(CH3)2, -S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -C 1-2 Alkyl-(4-6 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace;

[0181] R X Each group is independently selected from D, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups, C 1-4 Alkylamine group, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl groups are optionally further selected from 1 to 4 groups selected from D, halogen, =O, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Substituted with cycloalkyl groups;

[0182] R L1-1 Selected from D and C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, -C(O)-C 3-6 cycloalkyl, -S(O)2-C 3-6 cycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, alkenyl, or alkynyl groups are optionally further substituted with 1 to 4 groups selected from D, halogen, =O, CN, OH, and NH2;

[0183] n1 is an integer selected from 1 to 2;

[0184] n2 is an integer selected from 0 to 2;

[0185] m1 is selected from integers between 0 and 1;

[0186] The conditions are: (1) Not for *The site is the connection point between ring C1 and the right ring D;

[0187] (2) When ring C2 is selected from 9-10 member heterocyclic groups, ring C2 contains at least one S atom or m1 is not 0;

[0188] (3) When Selected from At that time, L2 is not -CH2- or -CH2CH2-;

[0189] (4) The compound is not

[0190] The definition of the functional groups is consistent with any of the technical solutions mentioned above.

[0191] Specifically, the third technical solution refers to the compounds shown in the aforementioned general formulas (II), (II-1), (III), (III-1), (IV), (IV-1), (V), (VI-1), (III-A), (IV-A), (VA), (VB), (VII), and (IV-A-1), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0192] L 1-1 Selected from -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-、-S-、-S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-6 cycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally further surrounded by 1-3 R groups. L Replacement; preferred L 1-1 Selected from -C(O)NH-, -O-, -NH-, -N(CH3)-, -CH2-, -CH(CH3)-, -S-, -NHC(O)-, -S(O)2NH-, -NHS(O)2-, -CH=CH-, -C≡C-, -C≡C-CH2-, -cyclopropyl-, -cyclobutyl-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, -O-CH2-, -CH2C(O)-, -C(O)CH2-;

[0193] L1 is selected from the key, -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -N(R) L1 )C(O)-、-OC 1-3 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L Substitution; preferably L1 is selected from the bond, -O-CH2-;

[0194] L2 is selected from the key, -C 1-3 Alkyl-, -N(R) L1 )-、-N(RL1 )C(O)-, wherein the alkyl group is optionally further divided by 1-4 R L Substitution; preferably L2 is selected from bond, -C(O)-, -NHC(O)-, -CH2C(O)-, -N(cyclopropyl)-, -N(CH2CF3)-, -C≡C-, -CH(CH3)-;

[0195] R L1 Selected from H, D, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, -C(O)-C 3-4 cycloalkyl, -S(O)2-C 3-4 cycloalkyl, -C 1-3 Alkyl-C 3-4 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally further substituted with 1-3 groups selected from D, halogen, =O, CN, OH, and NH2; preferably R. L1 Selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, vinyl, propynyl, cyclopropyl;

[0196] R L Selected from H, D, halogens, =O, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further substituted by 1-3 groups selected from D, halogen, =O, CN, OH, and NH2; preferably R L Selected from H, D, F, Cl, =O, methyl, ethyl, trifluoromethyl, trifluoroethyl, vinyl, ethynyl, methoxy, cyclopropyl;

[0197] R C Each is independently selected from D, F, Cl, =O, =S, =NH, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl.

[0198] Ring D is selected from C 3-10 Cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl; preferably ring D is selected from... Preferred ring D is selected from

[0199] R D Each is independently selected from D, F, Cl, =O, =S, =NH, CN, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, -OCD3, -ethynyl-cyclopropyl, -vinyl-cyclopropyl, -O-cyclobutyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NHCN, -C(O)NHOCH3, -C(S)NH-cyclopropyl, -C(S)NH-cyclobutyl, -O-cyclopropyl, Or difluoromethyl, -C(O)N(CH3)CH2CHF2; In some implementations, R D Each is independently selected from D, F, Cl, =O, =S, =NH, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl. -O-cyclobutyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -O-cyclopropyl

[0200] R C1 Selected from C 1-4 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -N=S(O)(C 1-2 Alkyl)2, R E The alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further reinforced with 1-2 R groups. X Replacement; preferred R C1 Selected from -OCF3, -OCHF2, -OCH2F, -O-cyclopropyl, -O-cyclobutyl, -SCF3, -SCHF2, -SCH2F, -SF5, -P(O)(CH3)2, -S(O)2-cyclopropyl, -S(O)2-cyclobutyl, -N=S(O)(CH3)2,

[0201] R E Selected from 4-6 membered heterocyclic groups, wherein the heterocyclic group contains at least one P atom and optionally is further surrounded by 1-2 R atoms. X replace;

[0202] Or any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-6 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-3 groups selected from D, F, Cl, =O, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Substituted with cycloalkyl or 4-6 membered heterocyclic groups;

[0203] Ring C1 is selected from C 3-6 Monocycloalkyl, C 6-10 cycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Spirocycloalkyl, five-membered heteroaryl, six-membered heteroaryl, 4-8-membered monocyclic heterocycloalkyl, 6-10-membered fused heterocycloalkyl, 5-10-membered bridged heterocycloalkyl, 5-10-membered spirocycloalkyl; preferably, ring C1 is selected from...

[0204] Ring C A Selected from five-membered heteroaryl, 4-8-membered monocyclic heterocyclic alkyl, C 3-8 Monocyclic cycloalkyl, C 6-8 Bridged cycloalkyl, cuboalkyl; preferably cycloC A Selected from

[0205] The C2 ring is selected from benzo[5] heteroaryl, benzo[6] heteroaryl, benzo[5] heterocycloalkyl, benzo[6] heterocycloalkyl, 8-10 bicyclic heterocyclic, C 10-15 Tricyclic cycloalkyl, 10-15 membered tricyclic heterocyclic alkyl, 10-15 membered tricyclic heteroaryl; preferably, ring C2 is selected from...

[0206] R XEach is independently selected from D, F, Cl, hydroxyl, cyano, amino, =O, =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Deuterated alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-3 Alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further substituted by 1-4 groups selected from D, halogen, =O, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, or cyclopropyl.

[0207] R L1-1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -S(O)2-C 3-4 Cycloalkyl, wherein the alkenyl or ynyl group is optionally further substituted with 1-4 groups selected from D or halogens;

[0208] n is an integer selected from 0 to 2;

[0209] m is selected from integers between 0 and 3;

[0210] The definition of the functional groups is consistent with any of the technical solutions mentioned above.

[0211] Specifically, the fourth technical solution refers to the compounds shown in the aforementioned general formulas (II), (III), (IV), (IV-1), (V), (VI-1), (III-A), (III-1), (IV-A), (VA), (VB), (VII), and (IV-A-1), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0212] Selected from

[0213] Selected from *The site is the connection point with the right loop D;

[0214] or Selected from

[0215] or Selected from

[0216] Selected from *The site is the connection point with the right loop D;

[0217] Selected from *The site is the connection point with the right loop D;

[0218] or Selected from

[0219] Selected from

[0220] Selected from

[0221] Selected from

[0222] Rx is selected from D, F, Cl, hydroxyl, cyano, methyl, ethyl, CH2CH2F, CH2CF3, CF3, CH2F, CHF2, cyclopropyl, vinyl, ethynyl, methoxy, -CH2-OCH3, =O, =S, =CH2, =CF2. -S(O)2-CH3;

[0223] R L1-1 Selected from allyl, propargyl, cyclopropyl, -CH2-CH=C(F)2, -S(O)2-cyclopropyl or CN-substituted cyclopropyl;

[0224] The definition of the functional groups is consistent with any of the technical solutions mentioned above.

[0225] Specifically, in the fifth technical solution, the compound of the aforementioned general formula (IV-A-1), its stereoisomers, or its pharmaceutically acceptable salts, wherein,

[0226] Ring C A Selected from five-membered heteroaryl groups; preferably cyclic C A Selected from Preferred C A Selected from Preferred C A Selected from Preferred C A Selected from Preferred C A Selected from

[0227] L2 is selected from the key, -C 1-2 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L Substitution; preferably L2 is selected from the bond;

[0228] R L Selected from H, D, halogens, =O, CN, C 1-2 Alkyl, C 1-2 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 3-4 cycloalkyl;

[0229] Each R D Each is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-8 Cycloalkyl, -O- (4-8 membered heterocyclic), -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -S(O)2-NHC3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)NHOH, -C(O)NHCN, -C(S)NHC 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)NH (4-8 membered heterocyclic group), -C(O)- (4-8 membered heterocyclic group), -C 1-4 Alkyl-(4-8 membered heterocyclic group), -C 1-4 Alkyl-(3-8 membered cycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X Replace; preferably each R D Each is independently selected from H, D, halogen, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-8 cycloalkyl, -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -S(O)2-NHC 3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -C(O)NHOH, -C(O)NHCN, -C(O)NHOC 1-4 Alkyl group, -C(S)NHC 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)NH (4-8 membered heterocyclic groups), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -C 1-4 Alkyl-(4-8 membered heterocyclic group), -C 1-4 Alkyl-(3-8 membered cycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X Replacement; preferred R DEach is independently selected from D, F, Cl, CN, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, -OCD3, -ethynyl-cyclopropyl, -vinyl-cyclopropyl, -O-cyclobutyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NHCN, -C(O)NHOCH3, -C(S)NH-cyclopropyl, -C(S)NH-cyclobutyl, -O-cyclopropyl, Or difluoromethyl, -C(O)N(CH3)CH2CHF2;

[0230] In some implementation schemes, R is preferred. D Each is independently selected from -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NHOCH3, -O-cyclopropyl,

[0231] R X Each is independently selected from D, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group, -C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl groups are optionally further selected from 1 to 4 groups selected from D, halogen, =O, CN, OH, NH2, C. 1-3 Alkyl, C 1-3Alkoxy, C 3-6 The cycloalkyl group is substituted; preferably R X Each is independently selected from D, F, Cl, hydroxyl, cyano, amino, =O, =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Deuterated alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-3 Alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further substituted with 1-4 groups selected from D, halogen, =O, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, or cyclopropyl; preferably Rx is selected from D, F, Cl, hydroxyl, cyano, methyl, ethyl, CH2CH2F, CH2CF3, CF3, CH2F, CHF2, cyclopropyl, vinyl, ethynyl, methoxy, -CH2-OCH3, =O, =S, =CH2, =CF2. -S(O)2-CH3;

[0232] m is selected from integers between 0 and 4; preferably m is selected from 0, 1, or 2.

[0233] n is selected from an integer between 0 and 2; preferably, n is selected from 0, 1, or 2.

[0234] Specifically, in the sixth technical solution, the compound, its stereoisomer, or its pharmaceutically acceptable salt is selected from the compounds listed in Tables 1 and 2:

[0235] Table 1:

[0236] Table 2:

[0237] This application further provides a pharmaceutical composition comprising a therapeutically effective dose of the compound as described above, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0238] Furthermore, the pharmaceutical composition or pharmaceutical preparation of this application contains 1-1500 mg of the compound described in any of the foregoing schemes, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0239] In some embodiments of this application, the above-described pharmaceutical composition can be formulated using one or more pharmaceutically acceptable carriers in a conventional manner. The carrier refers to a carrier conventional in the pharmaceutical field, such as: diluents like water; binders like cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers like starch, etc.; disintegrants like calcium carbonate, sodium bicarbonate, etc.; lubricants like calcium stearate or magnesium stearate, etc. Additionally, other excipients such as sweeteners, flavorings, or colorings may be added to the composition.

[0240] In some embodiments of this application, the pharmaceutical composition may be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or via an external implantation device. Oral administration is preferred.

[0241] When taken orally, the compounds of this application can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions.

[0242] This application further provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the treatment / prevention of VAV1-mediated diseases.

[0243] This application further provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective dose of any of the compounds shown, their stereoisomers, or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof, or a pharmaceutical composition thereof. The disease is preferably an autoimmune disease, preferably rheumatoid arthritis, multiple sclerosis, inflammatory gastroenteritis, etc., and the therapeutically effective dose is preferably 1-1500 mg. In some embodiments, the mammals described in this application include humans.

[0244] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0245] This application relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound described in this application or its stereoisomers or pharmaceutically acceptable salts, as well as a carrier and / or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, etc. The compound of this application or its stereoisomers or pharmaceutically acceptable salts in the amounts of g, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg.

[0246] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present application, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg, wherein the disease is selected from autoimmune diseases, preferably rheumatoid arthritis, multiple sclerosis, and inflammatory gastroenteritis.

[0247] A method for treating a disease in mammals. The method comprises administering a drug, the compound of this application, its stereoisomer or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient, to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100- 1000mg / day, 200-1000mg / day, 25-800mg / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day. In some embodiments, the daily dose includes, but is not limited to, 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, and 1500mg / day.

[0248] This application relates to a kit that may include a single-dose or multi-dose composition containing the compound of this application or its stereoisomer or pharmaceutically acceptable salt, wherein the amount of the compound of this application or its stereoisomer or pharmaceutically acceptable salt is the same as that in the above-described pharmaceutical composition.

[0249] In this application, the amount of the compound of this application or its stereoisomers or pharmaceutically acceptable salts is converted in each case as a free base.

[0250] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0251] Detailed description of the invention

[0252] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. In case of any discrepancy, the definitions provided in this application shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0253] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C... 1-6 Alkyl, C2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0254] The term "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, etc.

[0255] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include: vinyl, 1-propenyl, 2-propenyl, 2-methylpropenyl, 1-, 2-, or 3-butenyl, etc. The alkenyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C. 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0256] The term "alkenyl" refers to a straight-chain or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, alkenyl groups contain 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include alkenyl groups. The alkenyl groups may optionally be substituted with substituents.

[0257] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl; the alkynyl group may optionally be substituted with substituents.

[0258] The term "ethynyl" refers to a straight-chain or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), typically containing 2-6 carbon atoms, and more commonly 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, and butynyl, wherein the ethynyl group may optionally be substituted with substituents.

[0259] The term "carbocyclic" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbocyclic ring, encompassing aryl and cycloalkyl groups. The carbocyclic ring can be monocyclic, bicyclic, or polycyclic, including bridged rings, fused rings, and spirocyclic rings, as well as combinations thereof. Carbocyclic rings typically have 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting embodiments, monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc., and bicyclic bridged rings include... Etc., double-ring parallel rings include etc., double-ring spiral rings include In addition, the carbon ring can be optionally replaced by substituents.

[0260] The term "heterocycle" or "heterocyclic group" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing one to four heteroatoms selected from N, O, Se, P, Si, boron, or S and their oxidation states. It includes heteroaryl and heterocyclic alkyl groups. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles, or combinations thereof. They are typically 3- to 12-membered heterocycles, 5- to 12-membered heterocycles, or 5- to 7-membered heterocycles. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, piperazine, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, and 1,3-dithiayl. Dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazoyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazoyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, In addition, heterocyclic rings can be optionally substituted by substituents.

[0261] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 Alkyne group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C... 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0262] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl groups. The cycloalkyl group can be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic or a 12- to 18-membered quaternary system, wherein the tricyclic and quaternary systems include bridged rings, fused rings, and spirocyclic rings, as well as combinations thereof. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12+). 3-12 cycloalkyl groups, more preferably cycloalkyl groups having 3 to 8 carbon atoms (i.e., C14-C ... 3-8 Cycloalkyl groups, more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C164-C ... 3-6 (Cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0263] The term "spirocycloalkyl" refers to a polycyclic group in which the monocyclic rings share a single carbon atom (called the spiro atom). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Spirocycloalkyl. The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C14). 6-14 Spirocycloalkyl, more preferably spirocycloalkyl having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Spirocycloalkyl. Based on the number of spiroatoms shared between rings, spirocycloalkyl is classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocycloalkyl.

[0264] The term "fused cycloalkyl" or "tert-cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20Fused cyclic alkyl groups. They may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused cyclic alkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Fused cyclic alkyl groups, more preferably fused cyclic alkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Fused cyclic alkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused cyclic alkyl groups based on the number of constituent rings. Bicyclic or tricyclic fused cyclic alkyl groups are preferred, and ternary / quadrivalent, ternary / quinary, ternary / sixary, quadrivalent / quadrivalent, quadrivalent / quinary, quadrivalent / sixary, quinary / trivalent, quinary / quadrivalent, quinary / quinary, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, or quinary / sixary bicyclic fused cyclic alkyl groups are more preferred.

[0265] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Bridged cycloalkyl groups. They contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, the bridged cycloalkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Bridged cycloalkyl groups, more preferably bridged cycloalkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Bridged cycloalkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups based on the number of rings, with bicyclic or tricyclic bridged cycloalkyl groups being preferred. Example structures are shown below:

[0266] The cycloalkyl group can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl group. The cycloalkyl group can be optionally substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C... 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0267] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic alkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic alkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3-20 membered heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from the heteroatoms of nitrogen, oxygen, boron (B), S, Si, selenium (Se), P, P(O)2, SO2 and S(O), but excluding the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heterocyclic alkyl group can be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic or a 12- to 18-membered quaternary system, wherein the tricyclic and quaternary systems include bridged rings, fused rings, and spirocyclic rings, as well as combinations thereof. The heterocyclic alkyl group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocyclic alkyl groups), wherein it contains 1 to 4 heteroatoms selected from N, O, B, P, Si, Se and S atoms; more preferably it has 4 to 8 ring atoms (i.e., 4-8 membered heterocyclic alkyl groups), wherein it contains 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms; even more preferably it has 3 to 6 ring atoms (i.e., 3-6 membered heterocyclic alkyl groups), wherein it contains 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms; and most preferably it has 4 to 6 ring atoms (i.e., 4-6 membered heterocyclic alkyl groups), wherein it contains 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocyclic alkyl groups include: azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, acrylonitrile, oxacyclopentyl, azirropentyl, tetrahydropyrrolyl, butyrolactam, valeronyl, or caprolactam, etc. Example structures are as follows: Non-limiting examples of the 10- to 15-membered tricyclic heterocyclic alkyl groups include

[0268] Non-limiting examples of the polycyclic heterocyclic alkyl groups include spirocyclic alkyl groups, fused heterocyclic alkyl groups, and bridged heterocyclic alkyl groups.

[0269] The term "spiroheteroalkyl" refers to a polycyclic heterocyclic alkyl group that shares a single atom (called a spiro atom) between monocyclic rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20-membered spiroheteroalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from heteroatoms of nitrogen, oxygen, sulfur, phosphorus, selenium, boron, Si, P(O)₂, SO₂, and S(O), but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. The spiroheteroalkyl group is preferably a spiroheteroalkyl group having 6 to 14 ring atoms (i.e., 6-14-membered spiroheteroalkyl), more preferably a spiroheteroalkyl group having 7 to 10 ring atoms (i.e., 7-10-membered spiroheteroalkyl). The spiroheterocyclic alkyl group is classified into monospiroheterocyclic alkyl, bispiroheterocyclic alkyl, or polyspiroheterocyclic alkyl based on the number of spiro atoms shared between the rings. It is preferred to be monospiroheterocyclic alkyl or bispiroheterocyclic alkyl, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospiroheterocyclic alkyl.

[0270] The term "fused heterocyclic alkyl" or "fused heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which each ring shares an adjacent pair of atoms with the other rings in the system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered fused heterocyclic alkyl groups), where one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from heteroatoms of nitrogen, oxygen, sulfur, phosphorus, selenium, boron, Si, P(O)₂, SO₂, and S(O), excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. The fused heterocyclic alkyl group is preferably a fused heterocyclic alkyl group having 6 to 14 ring atoms (i.e., 6-14 fused heterocyclic alkyl group), more preferably a fused heterocyclic alkyl group having 7 to 10 ring atoms (i.e., 7-10 fused heterocyclic alkyl group). It is classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl group according to the number of constituent rings, preferably bicyclic or tricyclic fused heterocyclic alkyl group, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 bicyclic fused heterocyclic alkyl group.

[0271] The term "bridged heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which any two rings share two non-directly connected atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20-membered bridged heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from heteroatoms of nitrogen, oxygen, sulfur, phosphorus, selenium, boron, Si, P(O)2, SO2, and S(O), but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged heterocyclic alkyl is preferably a bridged heterocyclic alkyl with 6 to 14 ring atoms (i.e., 6-14-membered bridged heterocyclic alkyl), more preferably a bridged heterocyclic alkyl with 7 to 10 ring atoms (i.e., 7-10-membered bridged heterocyclic alkyl). Based on the number of constituent rings, they are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic alkyl groups, with bicyclic bridged heterocyclic alkyl groups or tricyclic bridged heterocyclic alkyl groups being preferred.

[0272] The heterocyclic alkyl group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic alkyl group.

[0273] The heterocyclic alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linker. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, and C. 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0274] The In It refers to a heterocyclic alkyl group containing at least one nitrogen atom, wherein the heterocyclic alkyl group is as defined above.

[0275] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C64). 6-12Aryl), more preferably aryl having 6 to 10 carbon atoms (i.e., C10). 6-10 Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracene, phenanthryl, etc.

[0276] The aryl group can be fused to a cycloalkyl or heterocycloalkyl ring to form a fused aromatic ring system, wherein the ring connected to the parent structure is an aryl ring. The fused aromatic ring system is preferably a 6-10-membered aryl-3-8-membered cycloalkyl or a 6-10-membered aryl-4-8-membered heterocycloalkyl, more preferably a phenyl-4-8-membered cycloalkyl or a phenyl-4-8-membered heterocycloalkyl, and even more preferably a phenyl-4-6-membered cycloalkyl or a phenyl-4-6-membered heterocycloalkyl. Non-limiting examples include: indolyl, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thiophene, quinazolinyl, benzothiazolyl, carbazole, thiophenepyridyl, pyridothiophenyl, pyridopyrroleyl, etc. Example structures are as follows:

[0277] The aryl group can be optionally substituted or unsubstituted. When substituted, the substituent can be replaced at any usable linker. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C... 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0278] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14-membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, O, sulfur, phosphorus, selenium, boron, Si, P(O)2, SO2, and S(O), preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group). Non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyridazinyl, etc.

[0279] The heteroaryl group can be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring to form a fused heteroaryl ring system, wherein the ring connected to the parent structure can be a heteroaryl ring or an aryl ring. The fused heteroaryl ring system is preferably 5-6 membered heteroaryl-5-6 membered heteroaryl, 5-10 membered heteroaryl-C6-10 aryl, or C6-10 aryl-5-10 membered heteroaryl, more preferably 5-6 membered heteroaryl-5-6 membered heteroaryl, 5-6 membered heteroaryl-phenyl, or phenyl-5-6 membered heteroaryl. Non-limiting examples include: indole, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, thiophene-phenyl, quinazolinyl, benzothiazolyl, carbazole, thiophene-pyridyl, pyridothiophene, pyridopyrrole, etc. Example structures are as follows:

[0280] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any usable linker. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C... 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0281] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups, more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups, preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linking point, preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0282] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12-C ... 1-3 Alkylthioyl). Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc. The alkylthioyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C... 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0283] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0284] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-Trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl. The alkyl halogroup may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0285] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 2-Dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy. The haloalkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linker. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C... 1-6 Alkyl, C 2-6 alkenyl, ynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl compounds.

[0286] The term "thiol" refers to -SH.

[0287] The term "hydroxyl group" refers to -OH.

[0288] The term "nitro" refers to -NO2.

[0289] The term "amino" refers to -NH2.

[0290] The term "cyano" refers to -CN.

[0291] The term "carboxyl group" refers to -C(O)OH.

[0292] The term "oxo" or "oxo group" refers to =O.

[0293] The term "carbonyl" refers to C=O.

[0294] The term "aminoacyl" refers to -C(O)NH2.

[0295] The term “deuterated alkyl” refers to an alkyl group that is substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0296] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0297] The term "deuterium" or "D" is a stable, non-radioactive isotope of hydrogen with a mass of protium ( ). 1 It has about twice the mass of H and is the most common hydrogen isotope.

[0298] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0299] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0300] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0301] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0302] The expression mn used in this article refers to the range from m to n, as well as the subranges consisting of the individual point values ​​and the individual point values ​​themselves. For example, the expression "C2-C8" or "C2-8" covers the range of 2 to 8 carbon atoms, and should be understood to also cover any subranges within it and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C10" or "C3-10" should be understood in a similar way, encompassing any subrange and point value included within it, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C10, etc. Similarly, the expression "C1-C6" or "C1-6" covers a range of 1-6 carbon atoms and should be understood to also encompass any subrange and each point value within it, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression "three to ten yuan" should be understood as encompassing any subrange and each point value within it, such as three to five yuan, three to six yuan, three to seven yuan, three to eight yuan, four to five yuan, four to six yuan, four to seven yuan, four to eight yuan, five to seven yuan, five to eight yuan, six to seven yuan, six to eight yuan, nine to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this article should also be understood in a similar manner.

[0303] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0304] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0305] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a chosen substituent from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing the optional substitution of each carbon atom in a group with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in the present case and that a stable compound is formed.

[0306] If a substituent is described as "optionally...substituted," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "unsubstituted." Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0307] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0308] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0309] The term "isomer" includes "stereoisomer" and "tautomer." A stereoisomer is a molecule whose atoms or groups of atoms are connected in the same order but arranged differently in space. Stereoisomers include cis-trans isomers and optical isomers. A tautomer is a molecule that can interconvert through a reversible chemical reaction called tautomerization, typically caused by the migration of hydrogen atoms and π bonds (double or triple bonds), resulting in a transformation from one functional group to another. Examples include the following paired compounds: aldehyde / ketone-enol, imine-enamine.

[0310] The compounds of this application may exist in specific geometric or stereoisomeric forms. All such compounds of this application, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, are within the scope of this application. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this application. All such isomers and mixtures thereof are included within the scope of this application. In some embodiments, the preferred compounds are those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this application, or racemic mixtures or mixtures of diastereomers, are also included within the scope of this application. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0311] All hydrogen atoms described in this application can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments involved in this application can also be replaced by a deuterium atom.

[0312] The compounds of this application include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0313] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0314] In the compounds of this application, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0315] The compounds in this application also include their racemates, stereoisomers, tautomers, deuterated derivatives, isotopic compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

[0316] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0317] The term "pharmaceutically acceptable salt" refers to the salt of the compound of this application, which is safe and effective when used in mammals and has the intended biological activity.

[0318] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this application or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0319] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0320] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0321] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0322] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0323] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0324] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include individuals suffering from a disease (such as the disease described herein) (referred to as patients) or healthy individuals. In this application, “non-human animal” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0325] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0326] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0327] In the context of this application, when the words “about” or “approximately” are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, to those skilled in the art, the terms “about” or “approximately” mean within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where “+ / -” means addition or subtraction.

[0328] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of this application, so that other skilled in the art can modify and implement this application in many forms to best suit the requirements of a particular purpose. Detailed Implementation

[0329] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the scope defined by the appended claims.

[0330] Example

[0331] The embodiments of this application will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this application. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0332] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers in the following solvents: deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). Tetramethylsilane (TMS) was used as the internal standard.

[0333] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0334] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0335] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0336] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0337] Abbreviation Explanation:

[0338] DMF: N,N-dimethylformamide;

[0339] RuPhos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II);

[0340] XPhos: 2-Dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl;

[0341] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride;

[0342] DDQ: 2,3-Dichloro-5,6-dicyanobenzoquinone;

[0343] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0344] Example 1:

[0345] Step 1: 1A (1 g, 3.85 mmol), 2-pyridone (367.5 mg, 3.85 mmol), potassium carbonate (2.66 g, 19.25 mmol), and cuprous iodide (73.5 mg, 0.41 mmol) were added to DMF (20 mL), purged three times with nitrogen, and reacted at 130 °C for 5 hours. The reaction proceeded to completion as monitored by TLC. The mixture was filtered, diluted with water (20 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 1B (500 mg, yield: 47.3%).

[0346] LC-MS (ESI): m / z = 275.9 [M+H] + .

[0347] Step 2: 1B (200 mg, 0.73 mmol), intermediate 1 (380 mg, 1.10 mmol, synthesized according to patent WO2024151547), potassium phosphate (771 mg, 3.65 mmol), and Pd(dppf)Cl2 (53.2 mg, 0.07 mmol) were added to DMF (10 mL), purged three times with nitrogen, and reacted at 100 °C for 16 hours. The reaction was monitored by TLC until the starting material was completely reacted. Then, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography and reversed-phase column chromatography to obtain compound 1 (55 mg, yield: 18.09%).

[0348] LC-MS (ESI): m / z = 419.1 [M+H]+ .

[0349] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.79-7.73(m,1H),7.56-7.47(m,1H),7.46-7.32(m,5H),6.55-6.48(m,1H),6.37-6.3 1(m,1H),4.42-4.30(m,1H),3.21-3.09(m,4H),2.88-2.74(m,1H),2.61-2.50(m,1H),2.41-2.26(m,1H),2.12-2.01(m,1H).

[0350] Example 2

[0351] Step 1: 2A (1 g, 2.98 mmol), 2-pyridone (284 mg, 2.98 mmol), potassium phosphate (1.58 g, 7.45 mmol), cuprous iodide (57 mg, 0.30 mmol), and (R,R)-(-)-N,N′-dimethyl-1,2-cyclohexanediamine (85 mg, 0.60 mmol) were added to DMF (30 mL), purged three times with nitrogen, and reacted at 110 °C for 5 hours. The mixture was filtered, diluted with water (20 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 2B (550 mg, yield: 60.95%).

[0352] LC-MS (ESI): m / z = 303.9 [M+H] + .

[0353] Step 2: Compound 2B (130 mg, 0.42 mmol), intermediate 1 (100 mg, 0.42 mmol), and potassium phosphate (220 mg, 1.05 mmol) were added to a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). Then, methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G3) (35 mg, 0.042 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (20 mg, 0.042 mmol) were added. After nitrogen purging, the mixture was heated to 100 °C and reacted for 3 hours. After the reaction was complete, ethyl acetate and saturated brine were added, the mixture was separated and washed with saturated brine, and the resulting organic phase was concentrated to dryness under reduced pressure using anhydrous sodium sulfate. The residue was purified by reversed-phase silica gel column chromatography to give compound 2 (25 mg, 14.90%).

[0354] LC-MS (ESI): m / z = 399.1 [M+H] + .

[0355] 1 H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.75-7.66(m,1H),7.55-7.50(m,1H),7.43-7.28(m,2H),7.24-7.17(m ,2H),7.11(d,1H),6.75-6.67(m,1H),6.38-6.26(m,1H),4.38-4.30(m,1H),2.88-2.66(m,2H),2.43-2.22(m,2H).

[0356] Example 3:

[0357] Step 1: 3A (4 g, 17.77 mmol, synthesis method according to patent CN106986886), 2-pyridone (1.69 g, 17.77 mmol), and cesium carbonate (11.58 g, 35.54 mmol) were added to DMF (40 mL), purged with nitrogen three times, and reacted at 60 °C for 16 hours. The reaction was monitored by TLC until complete. After filtration, the mixture was diluted with water (100 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 3B (1.2 g, yield: 22.5%).

[0358] LC-MS (ESI): m / z = 301.2 [M+H] + .

[0359] Step 2: Dissolve 3B (1.2 g, 4.0 mmol) in ethanol (20 mL), add iron powder (1.12 g, 20.0 mmol), ammonium chloride (2.14 g, 40.0 mmol) and water (20 mL), purge with nitrogen three times, and react at room temperature for 4 hours. Monitor the reaction of the starting material by TLC until complete. Filter, dilute with water (50 mL), extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain the target compound 3C (1.0 g, yield: 92.5%).

[0360] LC-MS (ESI): m / z = 271.2 [M+H] + .

[0361] Step 3: Dissolve 3C (1.0 g, 3.7 mmol) in acetonitrile (20 mL), add cuprous bromide (0.80 g, 5.55 mmol) and tert-butyl nitrite (0.57 g, 5.55 mmol), purge with nitrogen three times, and react at 80 °C for 4 hours. Monitor the reaction of the starting material by TLC until complete. Filter, dilute with water (50 mL), extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain the target compound 3D (0.4 g, yield: 32.3%).

[0362] LC-MS (ESI): m / z = 334.1 [M+H] + .

[0363] Step 4: 3D (0.4 g, 1.20 mmol), intermediate 1 (500 mg, 1.44 mmol, synthesized according to patent WO2024151547), potassium phosphate (760 mg, 3.60 mmol), and Pd(dppf)Cl2 (78 mg, 0.12 mmol) were added to DMF (10 mL), purged three times with nitrogen, and reacted at 100 °C for 16 hours. The reaction was monitored by TLC until complete. The mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography and reversed-phase column chromatography to obtain compound 3 (15 mg, yield: 2.6%).

[0364] LC-MS (ESI): m / z = 477.2 [M+H] + .

[0365] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.70-7.68(m,2H),7.63-7.62(m,2H),7.58-7.54(m,1H),7.48-7.41(m,3H),6.53( d,1H),6.37-6.34(m,1H),4.41-4.36(m,1H),2.85-2.76(m,1H),2.59-2.52(m,1H),2.41-2.30(m,1H),2.11-2.04(m,1H).

[0366] Example 4:

[0367] Step 1: Compound 4A (200 mg, 0.88 mmol, synthesized according to the method of patent WO2006107784A1), intermediate 1 (250 mg, 0.70 mmol), potassium phosphate (0.37 g, 1.76 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G) were prepared. 2， 69 mg (0.088 mmol) was dissolved in DMF (8 mL), and after nitrogen purging, the mixture was heated to 100 °C and reacted for 3 hours. After the reaction was complete, ethyl acetate and saturated brine were added, the mixture was separated and washed with saturated brine, and the resulting organic phase was concentrated to dryness under reduced pressure with anhydrous sodium sulfate. The residue was purified by reversed-phase silica gel column chromatography to obtain compound 4 (35 mg, 10.75%).

[0368] LC-MS (ESI): m / z = 370.1 [M+H] + .

[0369] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),7.88(s,1H),7.78-7.76(m,1H),7.42-7.33(m,4H),7.17(s,1H),4.37- 4.32(m,1H),2.83-2.74(m,1H),2.59-2.58(m,3H),2.57-2.52(m,1H),2.36-2.30(m,1H),2.09-2.04(m,1H).

[0370] Example 5:

[0371] Compound 5A (228 mg, 1 mmol), intermediate 1 (380 mg, 1.10 mmol), potassium phosphate (634 mg, 3 mmol), and Pd(dppf)Cl2 (76 mg, 0.1 mmol) were added to DMF (10 mL), purged three times with nitrogen, and reacted at 100 °C for 16 hours. The reaction was monitored by TLC until the starting material was completely reacted. The mixture was then diluted with water (20 mL), extracted with ethyl acetate (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give compound 5 (62 mg, yield: 17.2%).

[0372] LC-MS (ESI): m / z = 371.1 [M+H] + .

[0373] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.09-8.05(m,1H),7.97(d,1H),7.52-7.46(m,1H),7.46-7.35( m,3H),4.40-7.32(m,1H),2.86-2.73(m,4H),2.61-2.51(m,1H),2.41-2.28(m,1H),2.12-1.96(m,1H).

[0374] Example 6:

[0375] Step 1: 6A (5.0 g, 15.98 mmol) was dissolved in DCM (50 mL), and phosphorus tribromide (1.47 g, 5.43 mmol) was added. The reaction was carried out at room temperature for 1 hour. The reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with water (50 mL), and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 6B (3.5 g, yield: 58%).

[0376] 1 H NMR (400MHz, Chloroform-d) δ7.65-7.60(m,1H),7.55-7.52(m,1H),7.07-7.02(m,1H),4.44(s,2H).

[0377] Step 2: 2,6-Dihydroxypyridine (600 mg, 5.4 mmol) was dissolved in DMF (20 mL), and 6B (2.0 g, 5.4 mmol) and potassium carbonate (1.49 g, 10.8 mmol) were added. The mixture was reacted at room temperature for 3 hours. The reaction was monitored by TLC until the starting material was completely reacted. The mixture was diluted with water (50 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse-phase column chromatography to obtain the target compound 6C (140 mg, yield: 6%).

[0378] LC-MS (ESI): m / z = 406.0 [M+H] + .

[0379] Step 3: Dissolve 6C (140 mg, 0.34 mmol) in 1,4-dioxane (5 mL), then add cuprous iodide (13 mg, 0.07 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (32 mg, 0.14 mmol), and cesium carbonate (220 mg, 0.68 mmol) sequentially. The mixture is purged with nitrogen three times and reacted at 100 °C for 4 hours. The reaction proceeds as monitored by TLC until complete. The mixture is diluted with water (30 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and purified by silica gel column chromatography to obtain the target compound 6D (50 mg, yield: 52%).

[0380] LC-MS (ESI): m / z = 278.0 [M+H] + .

[0381] Step 4: 6D (50 mg, 0.18 mmol), intermediate 1 (76 mg, 0.22 mmol), potassium phosphate (110 mg, 0.54 mmol), and Ruphos-Pd-G 3 (15.1 mg, 0.02 mmol) were added to 1,4-dioxane (50 mL), purged with nitrogen three times, and reacted at 100 °C for 4 hours. The reaction proceeded to completion as monitored by TLC. The mixture was diluted with water (30 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse-phase column chromatography to obtain compound 6 (27 mg, yield: 36%).

[0382] LC-MS(ESI): m / z = 421.2 [M+H] + .

[0383] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.52-8.48(m,1H),7.52-7.35(m,6H),6.27-6.20(m,1H),5.94-5.89(m,1 H),5.23(s,2H),4.40-4.32(m,1H),2.86-2.74(m,1H),2.61-2.52(m,1H),2.41-2.29(m,1H),2.14-2.00(m,1H).

[0384] Example 7:

[0385] Step 1: 7A (0.7 g, 2.85 mmol, synthesized according to the method described in Organometallics, 2013, vol. 32, #9, p. 2509-2512) was dissolved in ultra-dry tetrahydrofuran (10 mL), purged three times with nitrogen, and cooled to 0 °C. NaH (0.14 g, 3.42 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 0.5 hours. 6B (1.29 g, 3.42 mmol, synthesized according to the method described in Journal of Organic Chemistry, 2009, vol. 74, #16, p. 6181-6189) was added. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC until the starting material was completely reacted. The mixture was then diluted with water (50 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 7C (900 mg, yield: 58.38%).

[0386] LC-MS (ESI): m / z = 539.9 [M+H] + .

[0387] Step 2: 7C (900 mg, 1.67 mmol) was dissolved in dichloromethane (20 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 1.52 g, 6.68 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC until the starting material was completely reacted. Then, water (50 mL) was added for dilution, followed by extraction with dichloromethane (50 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 7D (300 mg, yield: 42.87%).

[0388] LC-MS (ESI): m / z = 419.9 [M+H] + .

[0389] Step 3: 7D (300 mg, 0.71 mmol), cesium carbonate (460 mg, 1.42 mmol), CuI (68 mg, 0.35 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (84 mg, 0.35 mmol) were dissolved in 1,4-dioxane (20 mL), purged three times with nitrogen, and reacted at 100 °C for 16 hours. The reaction was monitored by TLC until the starting material was completely reacted. Then, water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 7E (50 mg, yield: 23.96%).

[0390] LC-MS(ESI): m / z = 292.0 [M+H] + .

[0391] Step 4: Compound 7E (50 mg, 0.17 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), followed by the sequential addition of intermediate 1 (89 mg, 0.26 mmol), potassium phosphate (72 mg, 0.34 mmol), Ruphos PdG3 (14 mg, 0.017 mmol), and X-phos (16 mg, 0.034 mmol). After the addition was complete, nitrogen was introduced, and the mixture was heated to 100 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 7 (25 mg, yield: 33.5%).

[0392] LC-MS (ESI): m / z = 435.0 [M+H] + .

[0393] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.75-7.73(m,1H),7.61-7.53(m,3H),7.47-7.38(m,3H),6.63-6.61(m,1H),6.54-6.52(m,1H),4.70-4.6 7(m,1H),4.50-4.47(m,1H),4.40-4.36(m,2H),3.89-3.86(m,1H),2.84 -2.77(m,1H),2.58-2.54(m,1H),2.38-2.34(m,1H),2.09-2.06(m,1H).

[0394] Example 8:

[0395] Step 1: Compound 8A (5 g, 38.16 mmol) was dissolved in dichloromethane (75 mL) and acetic acid (75 mL), cooled to below 0 °C, and N-iodosuccinimide (21.46 g, 95.40 mmol) was slowly added in batches. The mixture was then slowly heated to room temperature and reacted for 12 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. Ethyl acetate (200 mL) and saturated brine (200 mL) were added, and the mixture was stirred and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by normal-phase silica gel column chromatography to obtain compound 8B (10 g, yield 68.45%).

[0396] Step 2: Compound 8B (5.00 g, 13.06 mmol) was dissolved in N,N-dimethylformamide (100 mL), followed by the addition of 2-hydroxypyridine (1.24 g, 13.06 mmol), cuprous iodide (250.0 mg, 1.31 mmol), potassium carbonate (4.51 g, 32.65 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.37 g, 2.61 mmol). The mixture was purged with nitrogen three times, and the temperature was raised to 110 °C and reacted overnight. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 8C (1.40 g, yield: 30.63%).

[0397] LC-MS (ESI): m / z = 351.9 [M+H] + .

[0398] Step 3: Compound 8C (200 mg, 0.57 mmol) was dissolved in 1,4-dioxane (20 mL) and water (0.5 mL). Then, intermediate 1 (0.24 g, 0.68 mmol), potassium phosphate (0.36 g, 1.71 mmol), and Ruphos Pd G3 (48.00 mg, 0.057 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 90 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to obtain compound 8 (23 mg, 9.03%).

[0399] LC-MS (ESI): m / z = 447.1 [M+H] + .

[0400] 1 H NMR(400MHz,Chloroform-d)δ8.06-7.90(m,2H),7.56-7.48(m,1H),7.44-7.35(m,2H),7.35-7.28(m,2H),7.2 1-7.13(m,1H),6.84-6.74(m,1H),6.47-6.36(m,1H),4.43-4.28(m,1H),2.87-2.65(m,2H),2.43-2.21(m,2H).

[0401] Example 9:

[0402] Step 1: 9A (0.6 g, 4.80 mmol) was added to DMF (50 mL) solvent, followed by 2,5-diiodothiophene (1.61 g, 4.80 mmol), cuprous iodide (0.18 g, 0.96 mmol), potassium phosphate (3.57 g, 16.8 mmol), and 1,10-phenanthroline (0.43 g, 2.4 mmol). Under nitrogen purging protection, the mixture was heated to 100 °C and reacted overnight. After cooling, the mixture was filtered, and the filtrate was diluted with water. The mixture was extracted three times with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 9B (0.85 g, yield: 53%).

[0403] LC-MS (ESI): m / z = 333.9 [M+H] + .

[0404] Step 2: 9B (0.45 g, 1.35 mmol) was added to DCM (30 mL), followed by the addition of Desmond-Martin oxidant (0.86 g, 2.03 mmol). The mixture was stirred overnight at room temperature, then washed with saturated sodium sulfite solution. The organic phase was then washed with saturated sodium bicarbonate solution and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain the target compound 9C (0.41 g, yield: 92%).

[0405] LC-MS (ESI): m / z = 331.8 [M+H] + .

[0406] Step 3: 9C (0.7 g, 2.11 mmol) was added to a mixed solvent of tert-butanol (40 mL) and water (10 mL), followed by the addition of 2-methyl-2-butene (1.18 g, 16.88 mmol), sodium dihydrogen phosphate (2.03 g, 16.88 mmol), and sodium chlorite (0.95 g, 10.55 mmol). The mixture was heated to 27 °C and stirred for 4 hours. The reaction of the starting material was monitored by TLC until complete. Then, 2 M hydrochloric acid was added to adjust the pH to 2-3. The mixture was then filtered, the filter cake was washed with water, and dried to obtain the target compound 9D (0.55 g, yield: 75%).

[0407] LC-MS (ESI): m / z = 347.9 [M+H] +

[0408] Step 4: Add 9D (170 mg, 0.49 mmol) to THF (15 mL), then add DMF (36 mg, 0.49 mmol), followed by thionyl chloride (580 mg, 4.9 mmol). Heat to 55 °C and stir for 2 hours. After cooling and concentration, dissolve the crude product in DCM (15 mL). Then, slowly add the crude product dropwise to a solution of cyclopropylamine (56 mg, 0.98 mmol) and triethylamine (200 mg, 1.96 mmol) in dichloromethane (15 mL) under ice bath conditions. Continue stirring for 2 hours after the addition is complete. Dilute with water, extract twice with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain the target compound 9E (150 mg, yield: 79%).

[0409] LC-MS (ESI): m / z = 387.0 [M+H] +

[0410] Step 5: Compound 9E (120 mg, 0.31 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the sequential addition of intermediate 1 (220 mg, 0.62 mmol), potassium phosphate (200 mg, 0.93 mmol), and Pd(dppf)Cl2 (23 mg, 0.031 mmol). After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to obtain compound 9 (30 mg, 20%).

[0411] LC-MS (ESI): m / z = 482.1 [M+H] +

[0412] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),9.34(d,1H),8.47-8.39(m,2H),7.61-7.54(m,1H),7.51(d,1H),7.47-7.38(m,2H),7.36(d,1H),6.72( t,1H),4.42-4.30(m,1H),2.92-2.74(m,2H),2.61-2.52(m,1H),2.42- 2.28(m,1H),2.11-2.00(m,1H),0.81-0.68(m,2H),0.58-0.50(m,2H).

[0413] Example 10:

[0414] Step 1: Compounds 10A (10.00 g, 41.33 mmol), 10B (5.17 g, 41.33 mmol), CuI (0.79 g, 4.13 mmol), 1,10-phenanthroline (0.74 g, 4.13 mmol), and potassium phosphate (13.16 g, 61.99 mmol) were added sequentially to N,N-dimethylformamide (100 mL). After nitrogen purging, the mixture was heated to 95 °C and reacted for 12 hours. After the reaction was completed, the mixture was filtered, and ethyl acetate and saturated brine were added to the filtrate. The mixture was separated, washed, and the resulting organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 10C (8.50 g, 71.86%).

[0415] LC-MS(ESI): m / z=285.9; 287.9[M+H] + .

[0416] Step 2: A 20 mL solution of boron tribromide in dichloromethane (1.00 mmol / L) was placed in a 100 mL three-necked flask and cooled to -70 °C under nitrogen protection. Compound 10C (2.00 g, 6.99 mmol) was dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction solution. After the addition was complete, the ice bath was removed, and the mixture was slowly warmed to room temperature over approximately 1 hour. The reaction solution was then slowly added to a saturated sodium bicarbonate aqueous solution under ice bath conditions, and the mixture was extracted with dichloromethane. The resulting organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 10D (0.80 g, 42.06%).

[0417] LC-MS(ESI): m / z=272.0; 273.9[M+H] + .

[0418] Step 3: 10D (0.50 g, 1.84 mmol) was dissolved in DMF (20 mL), and sodium hydride (0.11 g, 2.76 mmol) and cyclopropyl trifluoromethanesulfonate (0.70 g, 3.68 mmol) were added in portions under ice bath conditions. The mixture was then heated to 60 °C and reacted for 1 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain compound 10E (0.20 g, yield: 34.87%).

[0419] LC-MS(ESI): m / z=312.0; 314.0[M+H] + .

[0420] Step 4: Compound 10E (100 mg, 0.28 mmol) was dissolved in 1,4-dioxane (20 mL) and water (0.5 mL). Intermediate 1 (0.12 g, 0.34 mmol) (prepared according to the method described in patent WO2024151547), potassium phosphate (0.18 g, 0.84 mmol), and Ruphos Pd G3 (23.00 mg, 0.028 mmol) were added sequentially. After nitrogen purging, the mixture was heated to 90 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to obtain compound 10 (4.2 mg, 3.32%).

[0421] LC-MS (ESI): m / z = 455.0 [M+H] +

[0422] 1 H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.54-7.47(m,1H),7.40-7.36(m,1H),7.35-7.30(m,1H),7.22-7.16(m,2H),7.13-7.08(m,1H ),7.04-6.99(m,1H),6.31-6.24(m,1H),4.39-4.29(m,1H),3.78-3.72(m,1H),2.88-2.65(m,2H),2.41-2.24(m,2H),0.94-0.76(m,4H).

[0423] Example 11:

[0424] Step 1: 11A (110 mg, 0.45 mmol, synthesized according to patent WO2022261204) was added to DMF (7 mL) solvent, followed by the addition of cesium carbonate (290 mg, 0.90 mmol) and 3-bromomethyl-1-methylpyrazole (120 mg, 0.68 mmol). Under nitrogen purging protection, the mixture was heated to 60 °C and stirred for 4 hours. The mixture was diluted with water, extracted three times with EA, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 11B (75 mg, yield: 49%).

[0425] LC-MS (ESI): m / z = 336.0 [M+H] + .

[0426] Step 2: Compound 11B (75 mg, 0.22 mmol) was dissolved in 1,4-dioxane (7 mL), followed by the sequential addition of intermediate 1 (150 mg, 0.44 mmol), potassium phosphate (140 mg, 0.66 mmol), and Pd(dppf)Cl2 (16 mg, 0.022 mmol). After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to obtain compound 11 (25 mg, 23%).

[0427] LC-MS (ESI): m / z = 479.1 [M+H] +

[0428] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),7.61-7.56(m,1H),7.55(d,1H),7.42-7.31(m,3H),7.29-7.24(m,1H),7.16(d,1H),6.06(d,1H),4.91(s,2 H),4.54(t,2H),4.37-4.30(m,1H),3.76(s,3H),2.84-2.73(m,1H),2.6 6-2.60(m,2H),2.58-2.52(m,1H),2.36-2.28(m,1H),2.09-2.00(m,1H).

[0429] Example 12:

[0430] Step 1: Compound 8B (10.00 g, 26.12 mmol) was dissolved in N,N-dimethylformamide (150 mL), followed by the sequential addition of 2-hydroxy-3-methoxypyridine (3.27 g, 26.12 mmol), cuprous iodide (0.50 g, 0.26 mmol), potassium phosphate (8.32 g, 39.18 mmol), and 1,10-phenanthroline (0.94 g, 5.22 mmol). The mixture was purged with nitrogen three times, and the temperature was raised to 95 °C and reacted overnight. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 12A (6.40 g, yield: 64.47%).

[0431] LC-MS (ESI): m / z = 382.0 [M+H] + .

[0432] Step 2: Compound 12A (3g, 7.89mmol%) was placed in DCM (10mL), cooled to below -50℃ under nitrogen protection, and a boron trichloride dichloromethane solution (1.00mmol / L, 15.78mL) was slowly added. The temperature was slowly raised to -20℃ and reacted for 1 hour. After the reaction was completed, the temperature was cooled to below -40℃, methanol was added to quench the reaction, and the pH was adjusted to 7-9 with triethylamine. Then dichloromethane and distilled water were added, the mixture was separated, washed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 12B (2.70g, yield: 93.45%).

[0433] LC-MS (ESI): m / z = 367.8 [M+H] + .

[0434] Step 3: 12B (0.80 g, 2.19 mmol) was dissolved in DMF (20 mL), and sodium hydride (0.20 g, 3.29 mmol) and cyclopropyl trifluoromethanesulfonate (0.50 g, 2.63 mmol) were added in portions under ice bath conditions. The mixture was then heated to 60 °C and reacted for 1 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain compound 12C (0.35 g, yield: 39.43%).

[0435] LC-MS(ESI): m / z = 408.0 [M+H] + .

[0436] Step 4: Compound 12C (200 mg, 0.49 mmol) was dissolved in 1,4-dioxane (20 mL) and water (0.5 mL). Then, intermediate 1 (0.26 g, 0.73 mmol), potassium phosphate (0.21 g, 98 mmol), and Ruphos Pd G3 (41.00 mg, 0.049 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 90 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 12 (5 mg, 2.02%).

[0437] LC-MS (ESI): m / z = 503.0 [M+H] + .

[0438] 1H NMR(400MHz, CDCl3)δ7.98(s,1H),7.70-7.60(m,1H),7.55-7.45(m,1H),7.40-7.35(m,1H),7.34-7.28(m,2H),7.20-7.10(m,1H),7 .07-7.02(m,1H),6.40-6.32(m,1H),4.40-4.28(m,1H),3.81-3.71(m,1H),2.87-2.65(m,2H),2.42-2.25(m,2H),0.97-0.77(m,4H).

[0439] Examples 13, 14:

[0440] Step 1: Compound 13A (2 g, 15.56 mmol) was dissolved in 1,4-dioxane (20 mL) and acetic acid (20 mL). Compound 13B (2.96 g, 15.56 mmol) was added at room temperature, and the mixture was heated to 100 °C and stirred for 6 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was poured into water. The pH was adjusted to 7–8 with a saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain compound 13C (1.2 g, yield 27.34%).

[0441] LC-MS(ESI): m / z = 282.0 [M+H] + .

[0442] Step 2: Dissolve 13C (1.0 g, 3.54 mmol) in DMF (10 mL), add NaH (0.42 g, 10.62 mmol) in portions, react at 60 °C for 0.5 h, then slowly add cyclopropyl trifluoromethanesulfonate (2.69 g, 14.16 mmol), and continue the reaction at 60 °C for 1 h. After the reaction is complete, slowly pour the reaction solution into ice water, extract with ethyl acetate, concentrate the organic phase under reduced pressure, and separate the residue by silica gel column chromatography to obtain 0.5 g of a mixture of compounds 13D and 14D.

[0443] LC-MS(ESI): m / z = 322.0 [M+H] + .

[0444] Step 3: A mixture of compounds 13D and 14D (200 mg, 0.62 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL). Then, intermediate meta-1 (220 mg, 0.62 mmol), potassium phosphate (260 mg, 1.24 mmol), and Ruphos Pd G3 (52 mg, 0.062 mmol) were added sequentially. After the addition was complete, nitrogen was introduced, and the mixture was heated to 90 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compounds 13 (30 mg, 10.39%) and 14 (50 mg, 17.32%).

[0445] Compound 13: LC-MS (ESI): m / z = 465.2 [M+H] + .

[0446] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.29(s,2H),7.44-7.38(m,4H),7.35-7.26(m,2H),4.39-4.35(m,1H),3.19-3.11(m,1 H),2.81(s,1H),2.61-2.53(m,1H),2.39-2.28(m,1H),2.13(s,3H),2.09-2.05(m,1H),0.89-0.84(m,2H),0.52-0.48(m,2H).

[0447] Compound 14: LC-MS (ESI): m / z = 465.2 [M+H] + .

[0448] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.27(s,2H),7.51-7.46(m,1H),7.43-7.37(m,3H),7.34-7.26(m,2H),5.98-5.90(m,1H),5.19-5.0 6(m,2H),4.59-4.58(m,2H),4.39-4.35(m,1H),2.86-2.74(m,1H),2.57-2.52(m,1H),2.38-2.30(m,1H),2.12(s,3H),2.09-2.00(m,1H).

[0449] Example 15:

[0450] Step 1: 15A (150 mg, 0.62 mmol) was added to DMF (7 mL) solvent, followed by sodium hydride (50 mg, 1.24 mmol, 60% purity). The mixture was stirred in an ice bath for 20 minutes, then 3-bromomethyl-1-methylpyrazole (140 mg, 0.81 mmol) was added, and stirring was continued for 2 hours. The reaction mixture was then quenched with water, extracted three times with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 15B (150 mg, yield: 72%).

[0451] LC-MS (ESI): m / z = 334.0 [M+H] + And 336.0 [M+H] + .

[0452] Step 2: Compound 15B (150 mg, 0.45 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the sequential addition of intermediate 1 (310 mg, 0.90 mmol), potassium phosphate (290 mg, 1.35 mmol), and Pd(dppf)Cl2 (33 mg, 0.045 mmol). After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 15 (25 mg, 12%).

[0453] LC-MS (ESI): m / z = 477.2 [M+H] +

[0454] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),7.57-7.48(m,2H),7.43-7.31(m,4H),7.29-7.25(m,1H),6. 06(d,1H),4.92(s,2H),4.40-4.28(m,1H),3.75(s,3H),2.85-2.74(m,1H),2.73-2.63(m,2H),2.59 -2.52(m,1H),2.40-2.27(m,1H),2.26-2.18(m,2H),2.15-2.02(m,3H).

[0455] Example 16:

[0456] Step 1: Add 9D (150 mg, 0.43 mmol) to THF (15 mL), then add DMF (31 mg, 0.43 mmol), and then add thionyl chloride (510 mg, 4.3 mmol). Heat to 55 °C and stir for 2 hours. After cooling and concentration, dissolve the crude product in DCM (15 mL). Then, under ice bath conditions, slowly add the crude product dropwise to a solution of bicyclo[1.1.1]pentan-2-amine hydrochloride (77 mg, 0.65 mmol) and triethylamine (170 mg, 1.72 mmol) in dichloromethane (15 mL). After the addition is complete, continue stirring for 2 hours. Dilute with water, extract twice with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain the target compound 16A (140 mg, yield: 79%).

[0457] LC-MS(ESI): m / z = 413.0 [M+H] + .

[0458] Step 2: Compound 16A (140 mg, 0.34 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the sequential addition of intermediate 1 (240 mg, 0.68 mmol), potassium phosphate (220 mg, 1.02 mmol), and Pd(dppf)Cl2 (25 mg, 0.034 mmol). After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 16 (20 mg, 12%).

[0459] LC-MS (ESI): m / z = 508.1 [M+H] + .

[0460] 1 H NMR(400MHz, CDCl3)δ9.80(s,1H),8.70-8.50(m,1H),8.00-7.90(m,1H),7.83(d,1H),7.55-7.49(m,1H),7.35(t,1H),7.25-7.20 (m,2H),7.14-7.10(m,1H),6.60-6.50(m,1H),4.38-4.28(m,1H),2.88-2.66(m,2H),2.47(s,1H),2.39-2.25(m,2H),2.18(s,6H).

[0461] Example 17:

[0462] Step 1: Compound 17A (3.00 g, 19.59 mmol) and cyclopropylamine (3.36 g, 58.77 mmol) were added to tetrahydrofuran (30 mL), and the mixture was heated to 70 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. After stirring for 1 hour, the mixture was filtered, and the filter cake was dried to obtain 17B (3.40 g, yield: 97.40%).

[0463] LC-MS (ESI): m / z = 179.0 [M+H] + .

[0464] Step 2: Compound 8B (3.00 g, 7.84 mmol), compound 17B (1.40 g, 7.84 mmol), cuprous iodide (0.15 g, 0.78 mmol), 1,10-phenanthroline (0.14 g, 0.78 mmol), and anhydrous potassium phosphate (2.50 g, 11.76 mmol) were added to N,N-dimethylformamide (50 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 12 hours. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was separated and washed. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by normal-phase silica gel column chromatography to obtain compound 17C (0.40 g, 11.79%).

[0465] LC-MS (ESI): m / z = 434.9 [M+H] + .

[0466] Step 3: Compound 17C (212 mg, 0.49 mmol), intermediate 1 (260 mg, 0.73 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (41 mg, 0.049 mmol), and potassium phosphate (0.21 g, 0.98 mmol) were sequentially added to a mixed solvent of 1,4-dioxane (20 mL) and distilled water (4 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 2 hours. After the reaction was completed, ethyl acetate and saturated brine were added, the mixture was separated, washed, and the organic phase was concentrated to dryness under reduced pressure. The residue was rapidly purified by reverse-phase silica gel column chromatography to obtain compound 17 (45 mg, 17.37%).

[0467] LC-MS (ESI): m / z = 530.1 [M+H] + .

[0468] 1H NMR(400MHz, CDCl3)δ9.49(s,1H),8.70-8.53(m,1H),8.21-7.99(m,2H),7.59-7.45(m,1H),7.41-7.29(m,3H),7.24-7.12(m,1H),6 .73-6.53(m,1H),4.44-4.22(m,1H),3.0-2.92(m,1H),2.87-2.65(m,2H),2.41-2.21(m,2H),0.90-0.81(m,2H),0.70-0.53(m,2H).

[0469] Example 18:

[0470] Step 1: Dissolve 13A (3g, 23.3mmol), cyclopropylamine (2g, 35mmol), and DIEA (9ml) in 30ml of DMSO and react at 80°C for 4 hours. After the reaction is complete, dilute with water, extract three times with ethyl acetate, and combine the organic phases for column chromatography purification to obtain 18A (2.2g, 63%).

[0471] LC-MS (ESI): m / z = 150.1 [M+H] + .

[0472] Step 2: Diiodothiophene (1 g, 2.98 mmol), 18A (0.44 g, 2.98 mmol), cesium carbonate (1.46 g, 4.47 mmol), cuprous iodide (57 mg, 0.3 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (0.14 g, 0.6 mmol) were dissolved in 25 mL of 1,4-dioxane. After purging with nitrogen three times, the mixture was reacted overnight at 100°C. After the reaction was complete, 18B (70 mg, 7.5%) was obtained by direct rotary evaporation column chromatography.

[0473] LC-MS (ESI): m / z = 357.9 [M+H] +

[0474] Step 3: Dissolve 18B (70 mg, 0.2 mmol), intermediate 1 (91 mg, 0.26 mmol), potassium phosphate (76 mg, 0.36 mmol), Ruphos Pd G3 (17 mg, 0.020 mmol), and Xphos (19 mg, 0.040 mmol) in a mixed solvent of 1,4-dioxane (6 ml) and water (0.5 ml). After nitrogen purging three times, react at 95 degrees Celsius for 3 hours. After the reaction is complete, purify by column chromatography to obtain compound 18 (9 mg, 10%).

[0475] LC-MS (ESI): m / z = 453.1 [M+H] +

[0476] 1 H NMR (400MHz, DMSO) δ10.89(s,1H),8.47(d,2H),7.55-7.45(m,1H),7.39-7. 33(m,1H),7.32-7.27(m,1H),7.22-7.18(m,1H),6.92(d,1H),4.40-4.30(m, 1H),3.18-3.03(m,1H),2.89-2.71(m,1H),2.59-2.51(m,1H),2.40-2.28(m ,1H),2.19(s,3H),2.07-1.99(m,1H),1.16-1.07(m,2H),0.73-0.61(m,2H).

[0477] Example 19:

[0478] Step 1: 2-Amino-5-methylpyrazine (2 g, 18.33 mmol) was dissolved in dioxane (50 mL), and K3PO4 (11.67 g, 54.99 mmol), compound 19A (6.62 g, 22.00 mmol), and Xantphos Pd G3 (1.89 g, 1.83 mmol) were added at room temperature. Under nitrogen protection, the mixture was heated to 100 °C for 6 h. After the reaction was complete, the mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound 19B (2.1 g, yield: 40.67%).

[0479] LC-MS(ESI): m / z = 282.0 [M+H] + .

[0480] Step 2: Using 19B (1.0 g, 3.54 mmol) and cyclopropyltrifluoromethanesulfonate (0.67 g, 3.54 mmol) as starting materials, compound 19C (0.3 g, yield: 26.27%) was synthesized according to the method described in Step 2 of Example 13.

[0481] LC-MS(ESI): m / z = 322.0 [M+H] + .

[0482] Step 3: Using 19C (0.2g, 0.62mmol) and intermediate 1 (0.22g, 0.62mmol) as raw materials, compound 19 (30mg, yield: 10.39%) was synthesized according to the method in step 3 of Example 13.

[0483] LC-MS (ESI): m / z = 465.2 [M+H] + .

[0484] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.45(d,1H),7.97(s,1H),7.47-7.27(m,6H),4.39-4.35(m,1H),3.13-3.05(m,1 H),2.87-2.73(m,1H),2.60-2.52(m,1H),2.40-2.28(m,4H),2.12-2.00(m,1H),1.05-0.93(m,2H),0.67-0.58(m,2H).

[0485] Example 20:

[0486] Step 1: Compound 20A (10.12 g, 33.64 mmol) was dissolved in dioxane (30 mL), and K3PO4 (19.47 g, 91.74 mmol), 1-methyl-1H-1,2,4-triazol-3-amine (3.0 g, 30.58 mmol), and Xantphos Pd G3 (3.16 g, 3.06 mmol) were added at room temperature. Under nitrogen protection, the mixture was heated to 100 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the organic phase was concentrated under reduced pressure. The mixture was then slurried with ethyl acetate to give compound 20B (5.6 g, yield: 67.56%).

[0487] LC-MS(ESI): m / z = 271.0 [M+H] + .

[0488] Step 2: Using 20B (400 mg, 1.48 mmol) and cyclopropyltrifluoromethanesulfonate (422.1 mg, 2.22 mmol) as raw materials, compound 20C (130 mg, yield: 28.32%) was obtained by following the synthesis method in Step 2 of Example 13.

[0489] LC-MS(ESI): m / z = 311.1 [M+H] + .

[0490] Step 3: Using 20C (100 mg, 0.32 mmol) and intermediate 1 (111.8 mg, 0.32 mmol) as raw materials, compound 20 (10 mg, yield: 6.86%) was obtained by following the synthesis method in step 3 of Example 13.

[0491] LC-MS (ESI): m / z = 454.1 [M+H] + .

[0492] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.36(s,1H),7.42-7.34(m,2H),7.33-7.26(m,1H),7.25-7.12(m,3H),4.38-4.29(m,1H),3.84(s,3 H),2.99-2.90(m,1H),2.85-2.72(m,1H),2.59-2.52(m,1H),2.39-2.25(m,1H),2.10-1.97(m,1H),1.01-0.93(m,2H),0.61-0.53(m,2H).

[0493] Example 21:

[0494] Step 1: Using 2-amino-5-methylpyrazine (2 g, 18.33 mmol) and 20A (6.62 g, 22.00 mmol) as starting materials, compound 21B (3.4 g, yield: 65.76%) was synthesized according to the method in Step 1 of Example 19.

[0495] LC-MS(ESI): m / z = 282.0 [M+H] + .

[0496] Step 2: Using 21B (1.0 g, 3.54 mmol) and cyclopropyltrifluoromethanesulfonate (0.67 g, 3.54 mmol) as raw materials, compound 21C (0.35 g, yield: 30.65%) was obtained by following the synthesis method in Step 2 of Example 13.

[0497] LC-MS(ESI): m / z = 322.0 [M+H] + .

[0498] Step 3: Using 21C (0.2g, 0.62mmol) and intermediate 1 (0.22g, 0.62mmol) as raw materials, compound 21 (50mg, yield: 17.32%) was synthesized according to the method in step 3 of Example 13.

[0499] LC-MS (ESI): m / z = 465.2 [M+H] + .

[0500] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.52(s,1H),8.13(s,1H),7.49-7.09(m,6H),4.38-4.35(m,1H),3.13-3.04(m,1 H),2.86-2.73(m,1H),2.61-2.52(m,1H),2.40-2.27(m,4H),2.11-2.01(m,1H),1.06-0.92(m,2H),0.69-0.50(m,2H).

[0501] Example 22:

[0502] Step 1: Using 2-amino-5-methylpyrimidine (1.73 g, 9.97 mmol) and 21A (3.00 g, 9.97 mmol) as starting materials, compound 22A (2.4 g, yield: 85.33%) was synthesized according to the method in Step 1 of Example 19.

[0503] LC-MS(ESI): m / z=282.0; 284.0[M+H] + .

[0504] Step 2: Using 22A (1.0 g, 3.54 mmol) and cyclopropyltrifluoromethanesulfonate (0.67 g, 3.54 mmol) as raw materials, compound 22B (0.45 g, yield: 39.40%) was obtained by following the synthesis method in Step 2 of Example 13.

[0505] LC-MS(ESI): m / z=322.0; 324.0[M+H] + .

[0506] Step 3: Using 22B (0.40 g, 1.24 mmol) and intermediate 1 (0.52 g, 1.49 mmol) as raw materials, compound 22 (90 mg, yield: 15.59%) was obtained by following the synthesis method in step 3 of Example 13.

[0507] LC-MS (ESI): m / z = 465.1 [M+H] + .

[0508] 1H NMR(400MHz, CDCl3)δ8.43(s,2H),8.21(s,1H),7.39-7.30(m,3H),7.28-7.25(m,1H),7.20-7.10(m,2H),4.42-4.25 (m,1H),3.30-3.20(m,1H),2.86-2.66(m,2H),2.38-2.28(m,2H),2.25(s,3H),1.15-1.05(m,2H),0.73-0.63(m,2H).

[0509] Example 23:

[0510] Step 1: Dissolve 9D (300 mg, 0.86 mmol) in THF (15 mL), add DMF (36 mg, 0.49 mmol), then add thionyl chloride (510 mg, 4.3 mmol), heat to 55 °C and stir for 2 hours. After cooling and concentration, dissolve the crude product in DCM (15 mL), and slowly add it dropwise in dichloromethane (15 mL) of cyclopropylamine (0.14 g, 1.64 mmol) and triethylamine (250 mg, 2.46 mmol) under ice bath. After the addition is complete, continue stirring for 2 hours, dilute with water, extract twice with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to obtain the target compound 23A (180 mg, yield: 58.3%).

[0511] LC-MS (ESI): m / z = 377.0 [M+H] +

[0512] Step 2: Compound 23A (130 mg, 0.35 mmol) was dissolved in 1,4-dioxane (20 mL) and water (0.5 mL). Intermediate 1 (0.15 g, 0.42 mmol), potassium phosphate (0.22 g, 1.05 mmol), and Ruphos Pd G2 (27.00 mg, 0.035 mmol) were added sequentially. After nitrogen purging, the mixture was heated to 100 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 23 (45 mg, 27.6%).

[0513] LC-MS (ESI): m / z = 472.1 [M+H] +

[0514] 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),10.92(s,1H),8.48-8.46(m,1H),8.38-8.36(m,1H),7.58-7.56(m,1H),7.53-7.52(m,1H),7.46-7.39(m,2 H),7.37-7.36(m,1H),6.73(t,1H),4.40-4.36(m,1H),3.72(s,3H),2.8 5-2.76(m,1H),2.59-2.53(m,1H),2.41-2.30(m,1H),2.09-2.02(m,1H).

[0515] Example 24:

[0516] Step 1: Compounds 13B (1.5 g, 7.89 mmol) and 24B (1.5 g, 8.28 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and glacial acetic acid (10 mL). After the addition was complete, the mixture was heated to 100 °C and stirred for 16 hours. The reaction was monitored by TLC until the starting material was completely reacted. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 2). The organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 24C (2.2 g, yield: 82.92%).

[0517] LC-MS (ESI): m / z = 336.0 [M+H] + .

[0518] Step 2: Under nitrogen protection, compound 24C (350 mg, 1.04 mmol) was dissolved in DMF (8 mL), and sodium hydride (60%, 120 mg, 3.12 mmol) was added. After the addition was complete, the mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, cyclopropanesulfonyl chloride (220 mg, 1.56 mmol) was added. The reaction of the starting material was monitored by TLC until complete. Then, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 24D (180 mg, yield: 39.26%).

[0519] LC-MS (ESI): m / z = 440.0 [M+H] + .

[0520] Step 3: Compound 24D (180 mg, 0.41 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), followed by the sequential addition of intermediate 1 (220 mg, 0.61 mmol), potassium phosphate (260 mg, 1.23 mmol), Ruphos Pd G3 (34 mg, 0.041 mmol), and Xphos (39 mg, 0.082 mmol). After the addition was complete, nitrogen was introduced, and the mixture was heated to 95 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 24 (42 mg, yield: 17.62%).

[0521] LC-MS (ESI): m / z = 583.2 [M+H] + .

[0522] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.16(d,1H),7.59-7.36(m,6H),4.40-4.35(m,1H),3.81-3.76( m,1H),2.85-2.76(m,1H),2.58-2.52(m,1H),2.36-2.32(m,1H),2.08-2.04(m,1H),1.26-1.24(m,4H).

[0523] Example 25:

[0524] Step 1: 9D (150 mg, 0.43 mmol) was added to THF (15 mL), followed by DMF (31 mg, 0.43 mmol) and thionyl chloride (510 mg, 4.3 mmol). The mixture was heated to 55 °C and stirred for 2 hours. After cooling and concentration, the crude acyl chloride was dissolved in DCM (15 mL) for later use. Under ice bath conditions, the crude acyl chloride DCM solution was slowly added dropwise to a solution of 1-amino-1-cyclopropyl cyanide hydrochloride (77 mg, 0.65 mmol) and triethylamine (170 mg, 1.72 mmol) in dichloromethane (15 mL). After the addition was complete, stirring was continued for 2 hours. The solution was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 25A (140 mg, yield: 79%).

[0525] LC-MS(ESI): m / z = 412.0 [M+H] + .

[0526] Step 2: Compound 25A (140 mg, 0.34 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.5 mL). Intermediate 1 (240 mg, 0.68 mmol), potassium phosphate (220 mg, 1.02 mmol), and Ruphos Pd G3 (34 mg, 0.044 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 25 (50 mg, yield: 29%).

[0527] LC-MS (ESI): m / z = 507.1 [M+H] + .

[0528] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),9.83(s,1H),8.53-8.47(m,1H),8.46-8. 41(m,1H),7.59-7.54(m,1H),7.53-7.49(m,1H),7.47-7.38(m,2H),7.38-7.33( m,1H),6.78-6.71(m,1H),4.42-4.32(m,1H),2.87-2.74(m,1H),2.60-2.52(m,1 H),2.42-2.30(m,1H),2.10-2.00(m,1H),1.59-1.51(m,2H),1.35-1.27(m,2H).

[0529] Example 26:

[0530] Step 1: 9D (208 mg, 0.60 mmol) was added to THF (15 mL), followed by DMF (31 mg, 0.43 mmol) and thionyl chloride (510 mg, 4.3 mmol). The mixture was heated to 55 °C and stirred for 2 hours. After cooling and concentration, the crude acyl chloride was dissolved in DCM (15 mL) for later use. The crude acyl chloride DCM solution was slowly added dropwise to a solution of morpholine (78 mg, 0.90 mmol) and triethylamine (240 mg, 2.4 mmol) in dichloromethane (15 mL) under ice bath conditions. After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 26A (95 mg, yield: 38%).

[0531] LC-MS (ESI): m / z = 417.0 [M+H] + .

[0532] Step 2: Compound 26A (90 mg, 0.22 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.5 mL). Intermediate 1 (150 mg, 0.44 mmol), potassium phosphate (140 mg, 0.66 mmol), and Ruphos Pd G3 (17 mg, 0.022 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 26 (40 mg, yield: 36%).

[0533] LC-MS (ESI): m / z = 512.1 [M+H] + .

[0534] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.37-8.30(m,1H),7.65-7.59(m,1H),7.58-7.49(m,2H),7.46-7.36(m,2H),7.35-7.30(m,1H),6.59-6.5 2(m,1H),4.42-4.32(m,1H),3.67-3.50(m,6H),3.29-3.23(m,2H),2.86 -2.74(m,1H),2.60-2.52(m,1H),2.42-2.28(m,1H),2.10-2.00(m,1H).

[0535] Example 27:

[0536] Step 1: N-methyl-4-iodopyrazole (386 mg, 1.86 mmol) was dissolved in 25 mL of THF. Under a nitrogen atmosphere, iPrMgCl·LiCl solution (1.43 mL, 1.86 mmol, 1.3 M in THF) was added dropwise. The reaction was carried out at 0 °C for 0.5 h. Then, a 9 °C solution (410 mg, 1.24 mmol, in 5 mL THF) was slowly added, followed by a further reaction at room temperature for 2 h. After the reaction was complete by TLC and LCMS, the reaction solution was slowly poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was then separated by silica gel column chromatography to obtain compound 27A (136 mg, 26.5%).

[0537] LC-MS (ESI): m / z = 413.9 [M+H] + .

[0538] Step 2: Compound 27A (136 mg, 0.33 mmol) was dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (0.5 mL), followed by intermediate 1 (172 mg, 0.49 mmol), potassium phosphate (210 mg, 0.99 mmol), and Xphos Pd G2 (26 mg, 0.033 mmol). After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 80 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to obtain compound 27B (86 mg, 51.2%).

[0539] LC-MS (ESI): m / z = 509.1 [M+H] + .

[0540] Step 3: 27B (86 mg, 0.17 mmol) was added to DCM (5 mL), followed by the addition of Des Martin oxidant (108 mg, 0.25 mmol). The mixture was stirred overnight at room temperature, then washed with saturated sodium sulfite solution. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and prepared by HPLC to obtain compound 27 (46 mg, yield: 53.6%).

[0541] LC-MS (ESI): m / z = 507.0 [M+H] +

[0542] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.45-8.41(m,1H),8.31(s,1H),7.88(s,1H),7.77-7.73(m,1H),7.58-7.53(m,2H),7.45-7.3 3(m,3H),6.60(t,,1H),4.40-4.35(m,1H),3.87(s,3H),2.89-2.73(m,1H),2.60-2.53(m,1H),2.44-2.25(m,1H),2.10-2.00(m,1H).

[0543] Example 28:

[0544] Step 1: Compound 17A (2.65 g, 17.31 mmol) was dissolved in N,N-dimethylformamide (100 mL), followed by the sequential addition of 2,4-dibromoselenophenol (5.00 g, 17.31 mmol), cuprous iodide (0.33 g, 1.73 mmol), potassium phosphate (5.51 g, 25.96 mmol), and 1,10-phenanthroline (0.31 g, 1.73 mmol). The mixture was purged with nitrogen three times, and the reaction was carried out overnight at 95 °C. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 28A (3.10 g, yield: 49.60%). LC-MS (ESI): m / z = 361.8 [M+H] + .

[0545] Step 2: Compound 28A (3.00 g, 8.31 mmol) was added to methanol (50 mL) solvent, followed by sodium hydroxide (1.00 g, 24.93 mmol) and distilled water (5 mL). The mixture was reacted overnight at room temperature. After the reaction was complete, dichloromethane (200 mL) and distilled water (200 mL) were added, and the pH was adjusted to 3-4 with 1 mol / L hydrochloric acid. After extraction twice with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by normal-phase silica gel column chromatography to obtain compound 28B (1.20 g, 41.63%).

[0546] LC-MS (ESI): m / z = 347.9 [M+H] + .

[0547] Step 3: Compound 28B (1.20 g, 3.46 mmol) was added to N,N-dimethylformamide (20 mL) solvent, followed by the sequential addition of bicyclo[1.1.1]pentane-1-amine hydrochloride (0.41 g, 3.46 mmol), N-methylimidazolium (0.43 g, 5.19 mmol), and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (1.16 g, 4.15 mmol). The reaction was carried out at room temperature for 5 hours. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was separated and washed. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by normal-phase silica gel column chromatography to obtain compound 28C (1.20 g, 84.20%). LC-MS (ESI): m / z = 412.9 [M+H] + .

[0548] Step 4: 28C (200 mg, 0.49 mmol), intermediate 1 (0.21 mg, 0.59 mmol), potassium phosphate (0.21 g, 0.98 mmol), and Ruphos-Pd-G 3 (41 mg, 0.05 mmol) were added to 1,4-dioxane (20 mL), followed by distilled water (2 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 hours. After the reaction was complete, ethyl acetate and saturated brine were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by reversed-phase silica gel column chromatography to obtain compound 28 (50 mg, 18.57%).

[0549] LC-MS (ESI): m / z = 556.1 [M+H] + .

[0550] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),9.67(s,1H),8.85-8.70(m,1H),8.45-8.35(m,1H),7.86-7.76(m,1H),7.67-7.53(m,2H),7. 47-7.30(m,2H),6.87-6.77(m,1H),4.43-4.33(m,1H),2.88-2.74(m,1H),2.61-2.51(m,2H),2.45-2.25(m,1H),2.20-2.00(m,7H).

[0551] Example 29:

[0552] Step 1: 9D (300 mg, 0.86 mmol) was added to THF (15 mL), followed by DMF (36 mg, 0.49 mmol) and thionyl chloride (1.02 g, 8.6 mmol). The mixture was heated to 60 °C and stirred for 2 hours. The crude product obtained by concentration was dissolved in DCM (15 mL) and slowly added dropwise under ice bath to a solution of 1-methylcyclopropylamine hydrochloride (185 mg, 1.72 mmol) and triethylamine (347 mg, 3.44 mmol) in dichloromethane (15 mL). After the addition was complete, the mixture was stirred for another 2 hours. The solution was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 29A (210 mg, yield: 63%).

[0553] LC-MS (ESI): m / z = 400.9 [M+H] + .

[0554] Step 2: Compound 29A (210 mg, 0.53 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (275 mg, 0.80 mmol), potassium phosphate (334 mg, 1.59 mmol), and Ruphos-Pd-G2 (41 mg, 0.05 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 29 (145 mg, 56%).

[0555] LC-MS (ESI): m / z = 496.2 [M+H] + .

[0556] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.54(s,1H),8.47-8.39(m,2H),7. 61-7.54(m,1H),7.51(d,1H),7.47-7.38(m,2H),7.36(d,1H),6.72(t,1H) ,4.42-4.30(m,1H),2.89-2.73(m,1H),2.63-2.52(m,1H),2.43-2.27(m,1 H),2.13-1.99(m,1H),1.38(s,3H),0.78-0.69(m,2H),0.68-0.54(m,2H).

[0557] Example 30:

[0558] Step 1: 9D (300 mg, 0.86 mmol) was added to THF (15 mL), followed by DMF (36 mg, 0.49 mmol) and thionyl chloride (1.02 g, 8.6 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and then slowly added dropwise under ice bath to a solution of 1-(fluoromethyl)cyclopropylamine hydrochloride (205 mg, 1.72 mmol) and triethylamine (347 mg, 3.44 mmol) in dichloromethane (15 mL). After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 30A (230 mg, yield: 64%).

[0559] LC-MS (ESI): m / z = 418.9 [M+H] + .

[0560] Step 2: Compound 30A (230 mg, 0.55 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (288 mg, 0.80 mmol), potassium phosphate (350 mg, 1.59 mmol), and Ruphos-Pd-G2 (43 mg, 0.05 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 30 (145 mg, 53%).

[0561] LC-MS (ESI): m / z = 514.1 [M+H] + .

[0562] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),9.67(s,1H),8.50-8.40(m,2H),7.63-7.32(m,5H),6.77-6.70(m,1H),4.53(s,1 H),4.44-4.33(m,2H),2.89-2.71(m,1H),2.65-2.52(m,1H),2.43-2.27(m,1H),2.13-1.98(m,1H),1.00-0.85(m,4H).

[0563] Example 31:

[0564] Step 1: 9D (200 mg, 0.57 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (676 mg, 5.7 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and then slowly added dropwise under ice bath to a solution of cis-3-fluorocyclobutylamine hydrochloride (143 mg, 1.14 mmol) and triethylamine (230 mg, 2.28 mmol) in dichloromethane (15 mL). After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 31A (160 mg, yield: 67%).

[0565] LC-MS (ESI): m / z = 419.0 [M+H] + .

[0566] Step 2: Compound 31A (160 mg, 0.38 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (164 mg, 0.57 mmol), potassium phosphate (198 mg, 1.14 mmol), and Ruphos-Pd-G2 (24 mg, 0.04 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 31 (70 mg, 36%).

[0567] LC-MS (ESI): m / z = 514.2 [M+H] + .

[0568] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.58-9.52(m,1H),8.50-8.35(m,2H),7.61 -7.55(m,1H),7.52-7.48(m,1H),7.47-7.38(m,2H),7.37-7.34(m,1H),6.76-6.6 9(m,1H),4.99-4.76(m,1H),4.42-4.33(m,1H),4.04-3.91(m,1H),2.91-2.74(m, 3H),2.63-2.51(m,1H),2.42-2.27(m,1H),2.26-2.11(m,2H),2.10-2.01(m,1H).

[0569] Example 32:

[0570] Step 1: 9D (200 mg, 0.57 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (676 mg, 5.7 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and then slowly added dropwise under ice bath to a solution of trans-3-fluorocyclobutylamine hydrochloride (143 mg, 1.14 mmol) and triethylamine (230 mg, 2.28 mmol) in dichloromethane (15 mL). After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 32A (200 mg, yield: 83%).

[0571] LC-MS (ESI): m / z = 419.0 [M+H] + .

[0572] Step 2: Compound 32A (200 mg, 0.48 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (204 mg, 0.72 mmol), potassium phosphate (305 mg, 1.44 mmol), and Ruphos-Pd-G2 (30 mg, 0.05 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 32 (65 mg, 27%).

[0573] LC-MS (ESI): m / z = 514.2 [M+H] + .

[0574] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.62-9.55(m,1H),8.50-8.35(m,2H),7.61-7.54(m,1H),7.52-7.48(m,1H),7.47-7.38(m,2H),7.37-7.3 4(m,1H),6.76-6.69(m,1H),5.36-5.15(m,1H),4.64-4.50(m,1H),4.42 -4.33(m,1H),2.91-2.74(m,1H),2.63-2.30(m,6H),2.11-2.00(m,1H).

[0575] Example 33:

[0576] Step 1: 9D (333 mg, 0.96 mmol) was added to THF (20 mL), followed by DMF (31 mg, 0.43 mmol) and thionyl chloride (510 mg, 4.3 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude acyl chloride was dissolved in DCM (15 mL) for later use. Under ice bath conditions, the crude acyl chloride DCM solution was slowly added dropwise to a solution of 3-oxacyclobutane (110 mg, 1.50 mmol) and triethylamine (390 mg, 3.84 mmol) in dichloromethane (20 mL). After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 33A (200 mg, yield: 52%).

[0577] LC-MS (ESI): m / z = 403.0 [M+H] + .

[0578] Step 2: Compound 33A (200 mg, 0.50 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Intermediate 1 (350 mg, 1.0 mmol), potassium phosphate (320 mg, 1.50 mmol), and Ruphos Pd G3 (39 mg, 0.050 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 33 (60 mg, yield: 24%).

[0579] LC-MS (ESI): m / z = 498.1 [M+H] + .

[0580] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.88(d,1H),8.51-8.45(m,1H),8.43-8.3 7(m,1H),7.60-7.55(m,1H),7.54-7.50(m,1H),7.47-7.39(m,2H),7.38-7.35(m ,1H),6.73(t,1H),5.04-4.94(m,1H),4.79(t,2H),4.52(t,2H),4.42-4.34(m,1 H),2.86-2.75(m,1H),2.60-2.52(m,1H),2.42-2.30(m,1H),2.10-2.01(m,1H).

[0581] Example 34:

[0582] Step 1: Compound 10A (10.00 g, 34.62 mmol), 2-hydroxy-3-pyridinecarboxaldehyde (4.26 g, 34.62 mmol), CuI (0.66 g, 3.46 mmol), 1,10-phenanthroline (1.25 g, 6.92 mmol), and potassium phosphate (11.02 g, 51.93 mmol) were sequentially added to N,N-dimethylformamide (100 mL). After nitrogen purging, the mixture was heated to 95 °C and reacted for 12 hours. After the reaction was complete, the mixture was filtered, and ethyl acetate and saturated brine were added to the filtrate. The mixture was separated, washed, and the resulting organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 34A (2.60 g, 22.69%). LC-MS (ESI): m / z = 331.9 [M+H]+.

[0583] Step 2: N-methyl-4-iodopyrazole (2.51 g, 12.08 mmol) was dissolved in tetrahydrofuran (50 mL). Under a nitrogen atmosphere, iPrMgCl·LiCl solution (9.30 mL, 12.08 mmol, 1.3 M in THF) was added dropwise. After reacting at 0 °C for 0.5 h, a tetrahydrofuran solution of 34A (2.00 g, 6.04 mmol) (20 mL) was slowly added. The mixture was then heated to room temperature and reacted for another 3 h. After the reaction was complete, the reaction solution was slowly poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was concentrated to dryness under reduced pressure. The residue was separated by normal-phase silica gel column chromatography to obtain compound 34B (1.10 g, 44.07%). LC-MS (ESI): m / z = 414.0 [M+H]+.

[0584] Step 3: 34B (1.10 g, 2.66 mmol) was added to dichloromethane (50 mL), followed by the addition of Dys-Martin oxidant (2.26 g, 5.32 mmol). The mixture was stirred overnight at room temperature, then washed with saturated sodium sulfite solution. The organic phase was washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was separated by normal-phase silica gel column chromatography to obtain compound 34C (0.80 g, 73.08%). LC-MS (ESI): m / z = 412.0 [M+H]+.

[0585] Step 4: Compound 34C (200 mg, 0.49 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the sequential addition of intermediate 1 (0.21 g, 0.59 mmol), potassium phosphate (0.31 g, 1.47 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (41 mg, 0.049 mmol). The mixture was purged with nitrogen three times, and the temperature was raised to 80 °C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 34 (56 mg, 20.78%). LC-MS (ESI): m / z = 555.0 [M+H]+.

[0586] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.75-8.65(m,1H),8.31(s,1H),7.88(s,1H),7.85-7.81(m,1H),7.78-7.74(m,1H),7.64-7.54(m,2H),7. 46-7.29(m,2H),6.72-6.65(m,1H),4.41-4.31(m,1H),3.87(s,3H),2.8 6-2.73(m,1H),2.58-2.52(m,1H),2.42-2.27(m,1H),2.11-1.98(m,1H).

[0587] Example 35:

[0588] Step 1: Using 19A (3g, 9.97mmol) and 1-methyl-1H-1,2,4-triazol-3-amine (0.98g, 9.97mmol) as starting materials, compound 35A (2.1g, yield: 77.69%) was synthesized according to the method in Step 1 of Example 20.

[0589] LC-MS(ESI): m / z = 271.0 [M+H] + .

[0590] Step 2: Using 35A (1.0 g, 3.69 mmol) and cyclopropyltrifluoromethanesulfonate (1.05 g, 5.54 mmol) as raw materials, compound 35B (180 mg, yield: 15.68%) was obtained by following the synthesis method in Step 2 of Example 20.

[0591] LC-MS(ESI): m / z = 311.1 [M+H] + .

[0592] Step 3: Using 35B (50 mg, 0.16 mmol) and intermediate 1 (55.9 mg, 0.16 mmol) as raw materials, compound 35 (20 mg, yield: 27.42%) was obtained by following the synthesis method in step 3 of Example 20.

[0593] LC-MS (ESI): m / z = 454.2 [M+H] + .

[0594] 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.08(s,1H),7.48-7.35(m,4H),7.29-7.21(m,2H),4.40-4.31(m,1H),3.72(s,3H),3.08- 2.98(m,1H),2.88-2.73(m,1H),2.59-2.52(m,1H),2.39-2.27(m,1H),2.13-1.97(m,1H),0.85-0.76(m,2H),0.65-0.53(m,2H).

[0595] Example 36:

[0596] Step 1: Using 36A (6.0 g, 18.82 mmol) as the starting material, compound 36B (3.8 g, yield: 67.30%) was synthesized according to the method in Step 1 of Example 19.

[0597] LC-MS(ESI): m / z = 300.0 [M+H] + .

[0598] Step 2: Using 36B (1.0 g, 3.33 mmol) as the starting material, compound 36C (0.21 g, yield: 18.53%) was obtained by following the synthesis method in Step 2 of Example 13.

[0599] LC-MS (ESI): m / z = 340.0 [M+H] + .

[0600] Step 3: Using 36C (0.2g, 0.59mmol) and intermediate 1 (0.25g, 0.71mmol) as raw materials, compound 36 (35mg, yield: 12.33%) was obtained by following the synthesis method in step 3 of Example 13.

[0601] LC-MS (ESI): m / z = 483.1 [M+H] + .

[0602] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.54(s,1H),8.01(s,1H),7.50-7.16(m,5H),4.39-4.35(m,1H),3.19-3.07(m, 1H),2.90-2.76(m,1H),2.61-2.52(m,1H),2.41-2.28(m,4H),2.11-2.00(m,1H),1.06-1.01(m,2H),0.67-0.61(m,2H)

[0603] Example 37:

[0604] Step 1: Using 37A (5.85 g, 18.33 mmol) as the starting material, compound 37B (4.1 g, yield: 74.55%) was synthesized according to the method in Step 1 of Example 19.

[0605] LC-MS(ESI): m / z = 300.0 [M+H] + .

[0606] Step 2: Using 37B (1.0 g, 3.33 mmol) as the starting material, compound 37C (0.15 g, yield: 13.23%) was obtained by following the synthesis method in Step 2 of Example 13.

[0607] LC-MS (ESI): m / z = 340.0 [M+H] + .

[0608] Step 3: Using 37C (0.2g, 0.59mmol) and intermediate 1 (0.25g, 0.71mmol) as raw materials, compound 37 (10mg, yield: 3.52%) was synthesized according to the method in step 3 of Example 13.

[0609] LC-MS (ESI): m / z = 483.1 [M+H] + .

[0610] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.54(s,1H),7.98(s,1H),7.48-7.24(m,5H),4.39-4.35(m,1H),3.13-3.07(m,1 H),2.87-2.74(m,1H),2.57-2.52(m,1H),2.41-2.23(m,4H),2.12-1.99(m,1H),1.03-0.98(m,2H),0.63-0.59(m,2H).

[0611] Example 38:

[0612] Step 1: 9D (200 mg, 0.57 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (0.679 g, 5.7 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and slowly added dropwise under ice bath to a solution of trans-3-methoxycyclobutane hydrochloride (120 mg, 1.14 mmol) and triethylamine (230 mg, 2.28 mmol) in dichloromethane (15 mL). After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 38A (190 mg, yield: 77%).

[0613] LC-MS(ESI): m / z = 431.0 [M+H] + 。

[0614] Step 2: Compound 38A (190 mg, 0.44 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (213 mg, 0.61 mmol), potassium phosphate (280 mg, 1.32 mmol), and Ruphos-Pd-G2 (33 mg, 0.04 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 38 (68 mg, 30%).

[0615] LC-MS (ESI): m / z = 526.1 [M+H] + 。

[0616] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.62-9.56(m,1H),8.47-8.37(m,2H ),7.60-7.54(m,1H),7.53-7.47(m,1H),7.47-7.39(m,2H),7.37-7.34(m,1 H),6.75-6.67(m,1H),4.53-4.33(m,2H),4.05-3.89(m,1H),3.15(s,3H),2 .87-2.74(m,1H),2.61-2.50(m,1H),2.43-2.16(m,5H),2.12-1.97(m,1H).

[0617] Example 39:

[0618] Step 1: 9D (200 mg, 0.57 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (0.679 g, 5.7 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and then slowly added dropwise under ice bath to a solution of (S)-2-methylazacyclobutane hydrochloride (122 mg, 1.14 mmol) and triethylamine (230 mg, 2.28 mmol) in dichloromethane (15 mL). After the addition was complete, the mixture was stirred for another 2 hours. The solution was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 39A (160 mg, yield: 70%).

[0619] LC-MS(ESI): m / z = 401.0 [M+H] + 。

[0620] Step 2: Compound 39A (160 mg, 0.40 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (210 mg, 0.60 mmol), potassium phosphate (254 mg, 1.20 mmol), and Ruphos-Pd-G2 (33 mg, 0.04 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to obtain compound 39 (130 mg, 66%).

[0621] LC-MS (ESI): m / z = 496.1 [M+H] + 。

[0622] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.39-8.33(m,1H),7.72-7.64(m,1H),7.58 -7.49(m,2H),7.46-7.36(m,2H),7.35-7.30(m,1H),6.58-6.51(m,1H),4.60-4.3 0(m,2H),4.41-3.38(m,2H),2.87-2.74(m,1H),2.61-2.50(m,1H),2.47-2.30(m, 2H),2.12-1.97(m,1H),1.85-1.74(m,1H),1.46-1.39(m,2H),1.11-1.04(m,1H).

[0623] Example 40:

[0624] Step 1: N-methyl-3-iodopyrazole (1.00 g, 4.80 mmol) was dissolved in THF (25 mL). Under a nitrogen atmosphere, iPrMgCl·LiCl solution (3.70 mL, 4.80 mmol, 1.3 M in THF) was added dropwise. The reaction was carried out at 0 °C for 0.5 h. Then, a 9 °C solution (1.06 g, 3.21 mmol, in 5 mL THF) was slowly added, followed by a further reaction at room temperature for 2 h. After the reaction was complete by TLC and LCMS, the reaction solution was slowly poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was then separated by silica gel column chromatography to obtain compound 40A (185 mg, 14.0%).

[0625] LC-MS (ESI): m / z = 413.9 [M+H] + .

[0626] Step 2: Compound 40A (185 mg, 0.45 mmol) was dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (0.5 mL). Intermediate 1 (234 mg, 0.67 mmol), potassium phosphate (285 mg, 1.34 mmol), and Xphos Pd G2 (35 mg, 0.045 mmol) were added. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 80 °C and reacted for 10 h. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 40B (140 mg, 61.5%).

[0627] LC-MS (ESI): m / z = 509.1 [M+H] + .

[0628] Step 3: Add 40B (140 mg, 0.28 mmol) to DCM (5 mL), then add Dys-Martin oxidant (178 mg, 0.41 mmol), stir overnight at room temperature, then wash with saturated sodium sulfite solution, collect the organic phase, wash with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate and prepare compound 40 (53 mg, 38.1%) by HPLC.

[0629] LC-MS (ESI): m / z = 507.0 [M+H] + .

[0630] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.42-8.38(m,1H),7.87-7.84(m,1H),7.78-7.74(m,1H),7.63-7.47(m,2H),7.44-7.32(m,3H),6.8 3-6.81(m,1H),6.59(t,1H),4.40-4.34(m,1H),3.90(s,3H),2.88-2.73(m,1H),2.56-5.52(m,1H),2.40-2.28(m,1H),2.09-2.01(m,1H).

[0631] Example 41:

[0632] Step 1: 3-Bromo-2-benzyloxypyridine (2 g, 7.58 mmol), N-cyclopropyl-4-pyrazoleboronic acid pinacol ester (2.06 g, 11.36 mmol), potassium phosphate (2.41 g, 22.64 mmol), and XPhos Pd G2 (595 mg, 0.76 mmol) were dissolved in a mixed solution of dioxane (20 mL) and water (1 mL). The mixture was heated to 80 °C and reacted for 2 h. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound 41B (860 mg, 38.9%).

[0633] LC-MS(ESI): m / z = 292.1 [M+H] + .

[0634] Step 2: Compound 41B (860 mg, 2.95 mmol) was dissolved in methanol (50 mL), and wet palladium on carbon (400 mg) was added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was directly filtered, and the filtrate was concentrated to dryness to obtain the target compound 41C (530 mg, 89.2%), which could be used directly in the next step without purification.

[0635] LC-MS(ESI): m / z = 202.1 [M+H] + .

[0636] Step 3: Compound 41C (530 mg, 2.63 mmol), 2,5-diiodothiophene (1.32 g, 3.95 mmol), cuprous iodide (100 mg, 0.53 mmol), 1,10-o-phenanthroline (208 mg, 1.05 mmol), and potassium phosphate (1.67 g, 7.90 mmol) were added to anhydrous DMF (20 mL), stirred overnight at 80 °C under a nitrogen atmosphere, filtered, diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified by silica gel column chromatography to obtain the target compound 41D (110 mg, 10.2%).

[0637] LC-MS (ESI): m / z = 410.1 [M+H] + .

[0638] Step 4: Compound 41D (110 mg, 0.27 mmol), intermediate 1 (141 mg, 0.40 mmol), potassium phosphate (171 mg, 0.81 mmol), and Xphos Pd G2 (21 mg, 0.027 mmol) were added to a mixed solution of dioxane (10 mL) and water (0.5 mL). Under nitrogen protection, the mixture was heated to 80 °C and stirred for 2 h. The reaction solution was filtered, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by HPLC to obtain the target compound 41 (51 mg, yield: 37.5%).

[0639] LC-MS (ESI): m / z = 505.1 [M+H] + .

[0640] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.45(s,1H),8.30-8.11(m,1H),8.05(s,1H) ,7.93-7.89(m,1H),7.59-7.51(m,2H),7.46-7.37(m,2H),7.35-7.32(m,1H),6.60- 6.54(t,1H),4.42-4.34(m,1H),3.83-3.75(m,1H),2.86-2.73(m,1H),2.62-2.53( m,1H),2.45-2.30(m,1H),2.12-2.00(m,1H),1.13-1.02(m,2H),1.01-0.90(m,2H).

[0641] Example 42:

[0642] Step 1: Compound 13B (1.00 g, 5.26 mmol) was added to N,N-dimethylformamide (20 mL) solvent, followed by sodium hydride (0.42 g, 10.52 mmol). The mixture was stirred at room temperature for 30 minutes, and then 2-chloro-5-cyclopropylpyrimidine (0.85 g, 5.52 mmol) was added. The mixture was heated to 80 °C and reacted for 2 hours. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was separated and washed. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was rapidly purified by normal-phase silica gel column chromatography to obtain the title compound 42A (1.10 g, 67.83%).

[0643] LC-MS(ESI): m / z=308.0; 310.0[M+H] + .

[0644] Step 2: Compound 42A (1.10 g, 3.57 mmol) was added to N,N-dimethylformamide (20 mL) solvent, followed by sodium hydride (0.17 g, 7.14 mmol). The mixture was stirred at room temperature for 30 minutes, and then cyclopropyl trifluoromethanesulfonate (1.02 g, 5.35 mmol) was added. The mixture was heated to 60 °C and reacted for 2 hours. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was separated and washed. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was rapidly purified by normal-phase silica gel column chromatography to obtain the title compound 42B (0.50 g, 40.23%).

[0645] LC-MS(ESI): m / z=348.0; 350.0[M+H] + .

[0646] Step 3: Compound 42B (200 mg, 0.57 mmol), intermediate 1 (0.24 g, 0.68 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (48 mg, 0.057 mmol), and potassium phosphate (0.36 g, 1.71 mmol) were sequentially added to 1,4-dioxane (20 mL) solvent. After purging with nitrogen three times, the mixture was heated to 80 °C and reacted for 12 hours. After the reaction was completed, ethyl acetate and saturated brine were added, the mixture was separated, washed, and the organic phase was concentrated to dryness under reduced pressure. The residue was rapidly purified by reversed-phase silica gel column chromatography to obtain compound 42 (77 mg, 27.31%).

[0647] LC-MS (ESI): m / z = 491.1 [M+H] + .

[0648] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.24(s,2H),7.46-7.36(m,4H),7.35 -7.25(m,2H),4.43-4.33(m,1H),3.20-3.12(m,1H),2.88-2.73(m,1H),2.60 -2.52(m,1H),2.41-2.27(m,1H),2.12-2.02(m,1H),1.88-1.72(m,1H),0.98-0.81(m,4H),0.74 -0.61(m,2H),0.54-0.45(m,2H).

[0649] Example 43:

[0650] Step 1: 9D (200 mg, 0.57 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (676 mg, 5.7 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and slowly added under ice bath to a solution of 3-methoxymethylazacyclobutane hydrochloride (110 mg, 0.83 mmol) and triethylamine (170 mg, 1.65 mmol) in dichloromethane (15 mL). After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 43A (200 mg, yield: 85%).

[0651] LC-MS(ESI): m / z = 431.0 [M+H] + .

[0652] Step 2: Compound 43A (150 mg, 0.35 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (160 mg, 0.45 mmol), potassium phosphate (220 mg, 1.05 mmol), and Ruphos Pd G2 (54 mg, 0.07 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 43 (23 mg, 12.5%).

[0653] LC-MS (ESI): m / z = 526.2 [M+H] + .

[0654] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.38-8.35(m,1H),7.76-7.73(m,1H),7.57 -7.55(m,1H),7.52-7.51(m,1H),7.45-7.38(m,2H),7.34-7.33(m,1H),6.56(t,1 H),4.40-4.36(m,1H),4.09-4.01(m,2H),3.77-3.68(m,2H),3.47(d,2H),3.26(s ,3H),2.85-2.76(m,2H),2.61-2.53(m,1H),2.40-2.30(m,1H),2.11-2.01(m,1H).

[0655] Example 44:

[0656] Step 1: 9D (191 mg, 0.55 mmol) was added to THF (15 mL), followed by DMF (31 mg, 0.43 mmol) and thionyl chloride (510 mg, 4.3 mmol). The mixture was heated to 55 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL). Then, the crude product was slowly added dropwise to a solution of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride (98 mg, 0.72 mmol) and triethylamine (170 mg, 1.65 mmol) in dichloromethane (15 mL) under ice bath conditions. After the addition was complete, the mixture was stirred for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 44A (160 mg, yield: 56%).

[0657] LC-MS (ESI): m / z = 431.1 [M+H] + .

[0658] Step 2: Compound 44A (150 mg, 0.35 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Intermediate 1 (240 mg, 0.70 mmol), potassium phosphate (220 mg, 1.05 mmol), and Ruphos PdG3 (27 mg, 0.035 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 44 (35 mg, yield: 19%).

[0659] LC-MS (ESI): m / z = 526.1 [M+H] + .

[0660] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.39-8.32(m,1H),7.74-7.63(m,1H), 7.58-7.49(m,2H),7.45-7.37(m,2H),7.36-7.31(m,1H),6.60-6.52(m,1H), 4.40-4.34(m,1H),4.08-4.00(m,1H),3.50-3.40(m,2H),2.85-2.75(m,1H), 2.60-2.52(m,1H),2.41-2.30(m,1H),2.25-2.15(m,2H),2.10-1.96(m,3H).

[0661] Example 45:

[0662] Step 1: 9D (191 mg, 0.55 mmol) was added to THF (15 mL), followed by DMF (31 mg, 0.43 mmol) and thionyl chloride (510 mg, 4.3 mmol). The mixture was heated to 55 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL). Then, under ice bath conditions, the crude product was slowly added dropwise to a solution of 4-aminotetrahydropyran (83 mg, 0.83 mmol) and triethylamine (170 mg, 1.65 mmol) in dichloromethane (15 mL). After the addition was complete, the mixture was stirred for another 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 45A (160 mg, yield: 68%).

[0663] LC-MS (ESI): m / z = 431.1 [M+H] + .

[0664] Step 2: Compound 45A (160 mg, 0.37 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Then, intermediate 1 (260 mg, 0.74 mmol), potassium phosphate (240 mg, 1.11 mmol), and Ruphos Pd G3 (29 mg, 0.037 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 45 (90 mg, yield: 46%).

[0665] LC-MS (ESI): m / z = 526.2 [M+H] + .

[0666] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.42(d,1H),8.47-8.40(m,2H),7.60-7.55(m,1H) ),7.52-7.48(m,1H),7.47-7.39(m,2H),7.38-7.34(m,1H),6.73(t,1H),4.42-4.33(m,1 H),4.07-3.96(m,1H),3.88-3.80(m,2H),3.48-3.39(m,2H),2.86-2.75(m,1H),2.60-2 .52(m,1H),2.42-2.30(m,1H),2.10-2.01(m,1H),1.90-1.81(m,2H),1.56-1.43(m,2H).

[0667] Example 46:

[0668] Step 1: Using 46A (13.52 mg, 71.15 mmol) and 2-chloro-5-cyclopropylpyrimidine (10 g, 64.68 mmol) as starting materials, compound 46B (16 g, yield: 80.27%) was synthesized according to the method in Step 1 of Example 13.

[0669] LC-MS (ESI): m / z = 308.0 [M+H] + .

[0670] Step 2: Using 46B (1g, 3.25mmol) and 4-bromo-4,4-difluoro-1-butene (0.51g, 3.25mmol) as starting materials, compound 46C (860mg, yield: 68.98%) was obtained by following the synthesis method in Step 2 of Example 13.

[0671] LC-MS (ESI): m / z = 384.0 [M+H] + .

[0672] Step 3: Using 46C (100 mg, 0.32 mmol) and intermediate 1 (111.8 mg, 0.32 mmol) as raw materials, compound 46 (240 mg, yield: 35.00%) was obtained by following the synthesis method in step 3 of Example 13.

[0673] LC-MS (ESI): m / z = 527.2 [M+H] + .

[0674] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.27(s,2H),7.52-7.38(m,2H),7.3 8-7.29(m,3H),7.27-7.22(m,1H),4.91-7.76(m,1H),4.66-4.57(m,2H),4. 39-4.31(m,1H),2.87-2.72(m,1H),2.61-2.52(m,1H),2.40-2.26(m,1H),2 .14-2.01(m,1H),1.88-1.73(m,1H),0.95-0.84(m,2H),0.74-0.64(m,2H).

[0675] Example 47:

[0676] Step 1: Compound 47A (2.00 g, 10.53 mmol) was dissolved in 1,4-dioxane (50 mL) solvent, and 2-bromo-5-cyclopropylpyrazine (2.10 g, 10.53 mmol), potassium phosphate (3.35 g, 15.79 mmol), and Xantphos Pd G3 (1.09 g, 1.05 mmol) were added. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 100 °C and reacted for 10 h. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then purified by normal-phase silica gel column chromatography to obtain compound 47B (1.10 g, 36.14%).

[0677] LC-MS(ESI): m / z=308.0; 310.0[M+H] + .

[0678] Step 2: Using 47B (1.00 g, 3.25 mmol) as the starting material, compound 47C (0.25 g, yield: 22.12%) was obtained by following the synthesis method in Step 2 of Example 42.

[0679] LC-MS(ESI): m / z=348.0; 350.1[M+H] + .

[0680] Step 3: Using 47C (200 mg, 0.57 mmol) and intermediate 1 (0.24 g, 0.68 mmol) as raw materials, compound 47C (0.25 g, yield: 22.12%) was obtained by following the synthesis method in step 3 of Example 42.

[0681] LC-MS (ESI): m / z = 491.2 [M+H] + .

[0682] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.51-8.45(m,1H),8.24-8.18(m,1H),7.46-7.15(m,6H),4.41-4.28(m,1H),3.11-3.03(m,1H),2.88-2.7 3(m,1H),2.61-2.52(m,1H),2.40-2.25(m,1H),2.16-2.00(m,2H),1.10 -1.02(m,2H),1.00-0.92(m,2H),0.91-0.84(m,2H),0.65-0.56(m,2H).

[0683] Example 48:

[0684] Step 1: Compound 22A (1.00 g, 3.54 mmol) was added to N,N-dimethylformamide (50 mL) solvent, followed by sodium hydride (0.25 g, 10.62 mmol). The reaction was carried out at room temperature for 30 minutes, followed by the addition of 3-bromo-3,3-difluoropropene (1.11 g, 7.08 mmol), and the reaction was carried out overnight at room temperature. After the reaction was complete, ethyl acetate and saturated brine were added, the mixture was separated, washed, and the organic phase was concentrated to dryness under reduced pressure. The residue was rapidly purified by normal-phase silica gel column chromatography to obtain compound 48A (0.52 g, yield: 40.96%).

[0685] LC-MS(ESI): m / z=357.8; 359.8[M+H] + .

[0686] 1H NMR (400MHz, DMSO) δ8.29(s,2H),7.73-7.63(m,1H),7.44-7.36(m,1H),7.17-7.09(m,1H),4.87-4.71(m,1H),4.64-4.51(m,2H),2.13(s,3H).

[0687] Step 2: Using 48A (200 mg, 0.56 mmol) and intermediate 1 (0.23 g, 0.67 mmol) as raw materials, compound 48 (90 mg, yield: 32.18%) was obtained by following the synthesis method in step 3 of Example 42.

[0688] LC-MS (ESI): m / z = 501.2 [M+H] + .

[0689] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.33(s,2H),7.48-7.30(m,5H),7.28-7.23(m,1H),4.91-4.76(m,1H),4.70-4.6 0(m,2H),4.40-4.30(m,1H),2.89-2.73(m,1H),2.60-2.50(m,1H),2.42-2.26(m,1H),2.14(s,3H),2.10-2.02(m,1H).

[0690] Example 49:

[0691] Step 1: Using 46A (2g, 6.49mmol) and cyclopropyltrifluoromethanesulfonate (1.85g, 9.73mmol) as starting materials, compound 49A (660mg, yield: 29.20%) was obtained by following the synthesis method in Step 2 of Example 13.

[0692] LC-MS (ESI): m / z = 348.1 [M+H] + .

[0693] Step 2: Using 49A (500 mg, 1.44 mmol) and intermediate 1 (503.4 mg, 1.44 mmol) as raw materials, compound 49 (168 mg, yield: 23.83%) was obtained by following the synthesis method in step 3 of Example 13.

[0694] LC-MS (ESI): m / z = 491.2 [M+H] + .

[0695] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.29(s,2H),7.45-7.29(m,5H),7.27-7.22(m,1H),4.40-4.30(m,1H),3.18-3.09(m,1H),2.87-2.74( m,1H),2.59-2.51(m,1H),2.39-2.27(m,1H),2.10-2.01(m,1H),1.87- 1.76(m,1H),1.01-0.86(m,4H),0.73-0.66(m,2H),0.56-0.45(m,2H).

[0696] Example 50:

[0697] Step 1: 9D (200 mg, 0.57 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (676 mg, 5.7 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and slowly added to a solution of 3-(methoxysulfonyl)azacyclobutane (110 mg, 0.83 mmol) and triethylamine (170 mg, 1.65 mmol) in dichloromethane (15 mL) under ice bath conditions. After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 50A (200 mg, yield: 85%).

[0698] LC-MS (ESI): m / z = 465.0 [M+H] + .

[0699] Step 2: Compound 50A (150 mg, 0.35 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Intermediate 1 (160 mg, 0.45 mmol), potassium phosphate (220 mg, 1.05 mmol), and Ruphos PdG2 (54 mg, 0.07 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 50 (15 mg, 16%).

[0700] LC-MS (ESI): m / z = 560.1 [M+H] + .

[0701] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.43-8.41(m,1H),7.87-7.85(m,1H),7.58-7.55(m,1H),7.53-7.52(m,1H),7.45-7.39(m,2H),7.3 5-7.34(m,1H),6.60(t,1H),4.44-4.17(m,6H),3.02(s,3H),2.87-2.76(m,1H),2.59-2.55(m,1H),2.40-2.30(m,1H),2.10-2.01(m,1H).

[0702] Example 51:

[0703] Step 1: 9D (100 mg, 0.29 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (338 mg, 2.9 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and slowly added to a solution of N-methylpiperazine (57 mg, 0.57 mmol) and triethylamine (115 mg, 1.14 mmol) in dichloromethane (15 mL) under ice bath conditions. After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 51A (80 mg, yield: 66%).

[0704] LC-MS (ESI): m / z = 430.0 [M+H] + .

[0705] Step 2: Compound 51A (80 mg, 0.19 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.5 mL). Then, intermediate 1 (80 mg, 0.29 mmol), potassium phosphate (99 mg, 0.53 mmol), and Ruphos Pd G2 (12 mg, 0.02 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 51 (10 mg, 10.2%).

[0706] LC-MS (ESI): m / z = 525.1 [M+H] + .

[0707] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.34-8.31(m,1H),7.60-7.52(m,3H),7.45-7.38(m,2H),7.34-7.33(m,1H),6.55(t,1H),4.40-4.3 6(m,1H),3.63-3.56(m,2H),3.26-3.24(m,2H),2.85-2.76(m,1H),2.59-2.53(m,1H),2.40-2.24(m,5H),2.19(s,3H),2.09-2.01(m,1H).

[0708] Example 52:

[0709] Step 1: 9D (100 mg, 0.29 mmol) was added to THF (15 mL), followed by DMF (0.05 mL) and thionyl chloride (338 mg, 2.9 mmol). The mixture was heated to 60 °C and stirred for 2 hours. After cooling and concentration, the crude product was dissolved in DCM (15 mL) and slowly added to a solution of 1-methyl-1H-pyrazole-4-amine (55 mg, 0.57 mmol) and triethylamine (115 mg, 1.14 mmol) in dichloromethane (15 mL) under ice bath conditions. After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 52A (80 mg, yield: 66%).

[0710] LC-MS (ESI): m / z = 427.0 [M+H] + .

[0711] Step 2: Compound 52A (80 mg, 0.19 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.5 mL). Then, intermediate 1 (80 mg, 0.29 mmol), potassium phosphate (99 mg, 0.53 mmol), and Ruphos-Pd-G2 (12 mg, 0.02 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was subjected to reverse-phase medium-pressure reaction to prepare compound 52 (6 mg, 6.1%).

[0712] LC-MS (ESI): m / z = 522.1 [M+H] + .

[0713] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),10.92(s,1H),8.51-8.48(m,2H),8.09(s,1H),7.66(s,1H),7.60-7.57(m,1H),7.54(d,1H),7.47-7.40( m,2H),7.38(d,1H),6.79(t,1H),4.41-4.36(m,1H),3.82(s,3H),2.86 -2.77(m,1H),2.60-2.53(m,1H),2.42-2.31(m,1H),2.09-1.98(m,1H).

[0714] Example 53:

[0715] Step 1: Compound 53A (4.00 g, 18.10 mmol), 2,5-dibromothiophene (6.56 g, 27.1 mmol), cuprous iodide (340 mg, 1.81 mmol), 1,10-o-phenanthroline (710 mg, 3.62 mmol), and potassium phosphate (11.52 g, 54.3 mmol) were added to anhydrous DMF (100 mL). The mixture was stirred and reacted at 100 °C for 2 h under a nitrogen atmosphere. After filtration, the mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 53B (320 mg, 4.6%).

[0716] LC-MS (ESI): m / z = 381.9 [M+H] + .

[0717] Step 2: Compound 53B (250 mg, 0.65 mmol), 3-cyclopropyl-1H pyrazole (106 mg, 0.98 mmol), potassium phosphate (417 mg, 1.96 mmol), and Xantphos PdG2 (58 mg, 0.065 mmol) were added to dioxane (10 mL), and the mixture was heated to 90 °C and stirred for 16 h under nitrogen protection. The reaction solution was filtered, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 53C (84 mg, 35.7%).

[0718] LC-MS(ESI): m / z = 362.0 [M+H] + .

[0719] Step 3: Compound 53C (84 mg, 0.23 mmol), intermediate 1 (121 mg, 0.35 mmol), potassium phosphate (148 mg, 0.69 mmol), and Xphos Pd G2 (18 mg, 0.023 mmol) were added to a mixed solution of dioxane (10 mL) and water (0.5 mL). Under nitrogen protection, the mixture was heated to 80 °C and stirred for 2 h. The reaction solution was filtered, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by HPLC to obtain the target compound 53 (5 mg, 4.3%).

[0720] LC-MS (ESI): m / z = 505.1 [M+H] + .

[0721] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.49(s,1H),8.41-8.37(m,1H),7.75(s,1H) ,7.60-7.49(m,2H),7.46-7.37(m,2H),7.34-7.31(m,1H),7.12-7.08(m,1H),6.94- 6.90(m,1H),4.40-4.34(m,1H),2.85-2.75(m,1H),2.62-2.54(m,1H),2.42-2.28( m,1H),2.10-2.02(m,1H),1.85-1.70(m,1H),0.97-0.87(m,2H),0.69-0.57(m,2H).

[0722] Example 54:

[0723] Step 1: 9A (1 g, 7.99 mmol) was added to DMF (50 mL) solvent, along with 2,5-dibromo-3-fluorothiophene (2.08 g, 7.99 mmol), cuprous iodide (0.30 g, 1.60 mmol), potassium carbonate (2.21 g, 15.98 mmol), and 1,10-phenanthroline (0.29 g, 1.60 mmol). Under nitrogen purging protection, the mixture was heated to 85 °C and reacted overnight. After cooling, the mixture was filtered, and the filtrate was diluted with water. The mixture was extracted three times with EA, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was then purified by silica gel column chromatography to obtain compound 55A (0.31 g, yield: 13%) and compound 54A (0.47 g, yield: 19%).

[0724] Compound 55A: LC-MS (ESI): m / z = 303.9 [M+H] + And 305.9 [M+H] + .

[0725] 1 H NMR (400MHz, DMSO-d6) δ7.72-7.67(m,1H),7.54-7.50(m,1H),7.46(s,1H),6.43(t,1H),5.18(t,1H),4.33(d,2H)

[0726] Compound 54A: LC-MS (ESI): m / z = 303.9 [M+H] + And 305.9 [M+H] + .

[0727] 1H NMR (400MHz, DMSO-d6) δ8.25(d,1H),7.63(s,1H),7.57-7.53(m,1H),6.60(t,1H),5.36-5.15(m,1H),4.40(s,2H).

[0728] Step 2: Add 54A (0.47 g, 1.55 mmol) to DCM (30 mL), add Dys-Martin oxidant (0.99 g, 2.33 mmol), stir overnight at room temperature, wash with saturated sodium sulfite solution, collect the organic phase, wash with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to obtain target compound 54B (0.46 g, yield: 98%).

[0729] LC-MS (ESI): m / z = 301.9 [M+H] + And 303.9 [M+H] + .

[0730] Step 3: 54B (0.24 g, 0.69 mmol) was added to a mixed solvent of tert-butanol (20 mL) and water (5 mL), followed by the addition of 2-methyl-2-butene (0.39 g, 5.52 mmol), sodium dihydrogen phosphate (0.66 g, 5.52 mmol), and sodium chlorite (0.31 g, 3.45 mmol). The mixture was stirred overnight at room temperature. The reaction of the starting material was monitored by TLC until complete. 2 M hydrochloric acid was added to adjust the pH to 2-3. The mixture was filtered, the filter cake was washed with water, and dried to obtain the target compound 54C (0.15 g, yield: 60%).

[0731] LC-MS (ESI): m / z = 317.9 [M+H] + And 319.9 [M+H] + .

[0732] Step 4: Add 54C (140 mg, 0.43 mmol) to THF (15 mL), add DMF (32 mg, 0.44 mmol), and then add thionyl chloride (520 mg, 4.4 mmol). Heat to 65 °C and stir for 2 hours. After cooling and concentration, dissolve the crude product in DCM (15 mL) and slowly add it dropwise to a solution of cyclopropylamine (50 mg, 0.88 mmol) and triethylamine (130 mg, 1.32 mmol) in dichloromethane (15 mL) under ice bath conditions. After the addition is complete, continue stirring for 2 hours. Dilute with water, extract twice with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify and separate the target compound 54D (100 mg, yield: 64%) by silica gel column chromatography.

[0733] LC-MS (ESI): m / z = 357.0 [M+H]+ And 359.0 [M+H] + .

[0734] 1 H NMR(400MHz,DMSO-d6)δ9.13-9.06(m,1H),8.55-8.50(m,1H),8.40-8.35(m,1H),7 .67(s,1H),6.78(t,1H),2.91-2.83(m,1H),0.79-0.72(m,2H),0.58-0.52(m,2H).

[0735] Step 5: Compound 54D (100 mg, 0.28 mmol) was dissolved in 1,4-dioxane (15 mL) and water (0.7 mL). Intermediate 1 (200 mg, 0.56 mmol), potassium phosphate (180 mg, 0.84 mmol), and Ruphos Pd G3 (22 mg, 0.028 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 54 (30 mg, yield: 21%).

[0736] LC-MS (ESI): m / z = 500.1 [M+H] + .

[0737] 1 H NMR (400MHz, DMSO-d6)) δ10.93(s,1H),9.20(d,1H),8.56-8.51(m,1H),8.42-8.38(m,1H),7.68(s,1H),7.51-7.43(m,3H),6.81-6.75(m, 1H),4.40-4.33(m,1H),2.92-2.74(m,2H),2.60-2.52(m,1H),2.42-2 .30(m,1H),2.10-2.01(m,1H),0.78-0.71(m,2H),0.58-0.52(m,2H).

[0738] Example 55:

[0739] Step 1: Add 55A (0.31 g, 1.02 mmol) to DCM (30 mL), add Dys-Martin oxidant (0.65 g, 1.53 mmol), stir overnight at room temperature, wash with saturated sodium sulfite solution, collect the organic phase, wash with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to obtain target compound 55B (0.21 g, yield: 68%).

[0740] LC-MS (ESI): m / z = 301.9 [M+H] + And 303.9 [M+H] + .

[0741] Step 2: 55B (0.21 g, 0.60 mmol) was added to a mixed solvent of tert-butanol (20 mL) and water (5 mL), followed by the addition of 2-methyl-2-butene (0.34 g, 4.80 mmol), sodium dihydrogen phosphate (0.58 g, 4.80 mmol), and sodium chlorite (0.27 g, 3.00 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until the starting material was completely reacted. 2 M hydrochloric acid was added to adjust the pH to 2-3. The mixture was filtered, the filter cake was washed with water, and dried to obtain the target compound 55C (0.19 g, yield: 87%).

[0742] LC-MS (ESI): m / z = 317.9 [M+H] + And 319.9 [M+H] + .

[0743] Step 3: Add 55C (190 mg, 0.60 mmol) to THF (20 mL), then add DMF (44 mg, 0.60 mmol) and thionyl chloride (710 mg, 6.0 mmol) sequentially. Heat to 65 °C and stir for 2 hours. After cooling and concentration, dissolve the crude product in DCM (15 mL) and slowly add it dropwise to a solution of cyclopropylamine (69 mg, 1.20 mmol) and triethylamine (180 mg, 1.80 mmol) in dichloromethane (15 mL) under ice bath conditions. After the addition is complete, continue stirring for 2 hours. Dilute with water, extract twice with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain the target compound 55D (150 mg, yield: 70%).

[0744] LC-MS (ESI): m / z = 357.0 [M+H] + And 359.0 [M+H] + .

[0745] 1 H NMR(400MHz,DMSO-d6)δ9.30-9.14(m,1H),8.48-8.34(m,1H),8.16-8.03(m,1H),7 .50(s,1H),6.66(t,1H),2.92-2.80(m,1H),0.79-0.69(m,2H),0.56-0.46(m,2H).

[0746] Step 4: Compound 55D (150 mg, 0.42 mmol) was dissolved in 1,4-dioxane (15 mL) and water (0.7 mL). Intermediate 1 (290 mg, 0.84 mmol), potassium phosphate (270 mg, 1.26 mmol), and Ruphos Pd G3 (33 mg, 0.042 mmol) were added sequentially. After the addition was complete, nitrogen gas was introduced, and the mixture was heated to 95 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse-phase medium-pressure reaction to prepare compound 55 (40 mg, yield: 19%).

[0747] LC-MS (ESI): m / z = 500.1 [M+H] + .

[0748] H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.28(d,1H),8.47-8.41(m,1H),8.20-8.15(m,1H),7.62-7.56(m,1H),7.51(s,1H),7.49-7.44(m,2H),6. 68(t,1H),4.43-4.35(m,1H),2.91-2.75(m,2H),2.60-2.52(m,1H),2.4 1-2.29(m,1H),2.09-2.00(m,1H),0.76-0.70(m,2H),0.56-0.50(m,2H).

[0749] Example 56:

[0750] Step 1: Compound 28B (0.80 g, 2.31 mmol) was added to N,N-dimethylformamide (20 mL) solvent, followed by the sequential addition of morpholine (0.30 g, 3.46 mmol), N-methylimidazolium (0.97 g, 3.46 mmol), and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (0.47 g, 5.78 mmol). The reaction was carried out at room temperature for 2 hours. After the reaction was complete, ethyl acetate and saturated brine were added, and the mixture was separated and washed. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by normal-phase silica gel column chromatography to obtain compound 56A (0.45 g, 46.91%). LC-MS (ESI): m / z = 416.9 [M+H] + .

[0751] Step 2: 56A (100 mg, 0.24 mmol), intermediate 1 (100 mg, 0.29 mmol), potassium phosphate (76 mg, 0.36 mmol), and Ruphos-Pd-G 3 (20 mg, 0.02 mmol) were added to 1,4-dioxane (20 mL), purged three times with nitrogen, and reacted at 85 °C for 12 hours. After completion, ethyl acetate and saturated brine were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by reversed-phase silica gel column chromatography to obtain compound 56 (70 mg, 52.12%). LC-MS (ESI): m / z = 560.1 [M+H] + .

[0752] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.66-8.58(m,1H),7.83-7.78(m,1H),7.69-7.51(m,3H),7.46-7.29(m,2H),6.70-6.60(m,1H), 4.43-4.33(m,1H),3.72-3.49(m,6H),3.29-3.18(m,2H),2.89-2.74(m,1H),2.61-2.51(m,1H),2.43-2.27(m,1H),2.12-1.99(m,1H).

[0753] Example 57:

[0754] Step 1: Compound 46B (2.00 g, 6.49 mmol) was added to N,N-dimethylformamide (20 mL), sodium hydride (0.78 g, 19.47 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, 1-bromo-cyclopropaneformonitrile (1.89 g, 12.98 mmol) was added, and the mixture was reacted at 110 °C for 4 hours. After the reaction was completed, ethyl acetate and saturated brine were added, the mixture was separated, washed, and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography and SFC to obtain compounds 57A-P1 (216 mg, 8.92%) and 57A-P2 (212 mg, 8.75%).

[0755] SFC analysis method: Instrument: CAS-05-ANA-SFC-D; Column: AD column; Mobile phase: A: CO2, B: 0.05% MNH3 in ethanol; Elution flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm; Cycle time: 3.0 min; Sample preparation: Sample concentration 20 mg / mL, acetonitrile solution injection: 5 μL.

[0756] Compound 57A-P1: 216 mg, (SFC retention time: 1.587 min), LC-MS (ESI): m / z = 373.0; 375.0 [M+H] + .

[0757] Compound 57A-P2: 212 mg, (SFC retention time: 1.928 min), LC-MS (ESI): m / z = 373.0; 375.0 [M+H] + .

[0758] Step 2: 57A-P1 (50 mg, 0.13 mmol), intermediate 1 (55 mg, 0.16 mmol), potassium phosphate (83 mg, 0.39 mmol), and Ruphos-Pd-G3 (11 mg, 0.013 mmol) were added to 1,4-dioxane (10 mL), purged three times with nitrogen, and reacted at 85 °C for 12 hours. After completion, ethyl acetate and saturated brine were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by reversed-phase silica gel column chromatography to obtain compound 57-1 (35 mg, 50.63%). LC-MS (ESI): m / z = 516.2 [M+H] + .

[0759] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.35(s,2H),7.48-7.28(m,5H),7.2 7-7.19(m,1H),4.40-4.30(m,1H),3.80-3.73(m,1H),2.87-2.74(m,1H),2. 60-2.52(m,1H),2.40-2.26(m,1H),2.11-1.99(m,2H),1.89-1.79(m,1H),1 .72-1.62(m,1H),1.16-1.06(m,1H),0.97-0.89(m,2H),0.76-0.69(m,2H).

[0760] 57A-P2 (50 mg, 0.13 mmol), intermediate 1 (55 mg, 0.16 mmol), potassium phosphate (83 mg, 0.39 mmol), and Ruphos-Pd-G3 (11 mg, 0.013 mmol) were added to 1,4-dioxane (10 mL), purged three times with nitrogen, and reacted at 85 °C for 12 hours. After completion, ethyl acetate and saturated brine were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by reversed-phase silica gel column chromatography to give compound 57-2 (16 mg, 23.15%). LC-MS (ESI): m / z = 516.2 [M+H]+ .

[0761] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.35(s,2H),7.47-7.28(m,5H),7.27 -7.21(m,1H),4.37-4.34(m,1H),3.80-3.71(m,1H),2.88-2.74(m,1H),2.6 0-2.50(mz,1H),2.42-2.26(m,1H),2.12-1.97(m,2H),1.90-1.80(m,1H),1 .71-1.63(m,1H),1.17-1.07(m,1H),0.98-0.89(m,2H),0.77-0.68(m,2H).

[0762] Example 58:

[0763] Step 1: Compound 58A (10.0 g, 70.16 mmol) was added to a reaction flask, dissolved in DCM, cooled to 0°C, and DAST (18.2 ml, 140.32 mmol) was slowly added. The mixture was then allowed to react at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the solution was slowly poured into a saturated sodium bicarbonate solution. The organic phase was separated, dried, concentrated, and purified by silica gel column chromatography to obtain compound 58B (9.6 g, yield: 83.19%).

[0764] LC-MS (ESI): m / z = 165.1 [M+H] + .

[0765] Step 2: Compounds 58B (9.6 g, 58.34 mmol) and 13B (11.12 g, 58.34 mmol) were added to a reaction flask, dissolved in 1,4-dioxane (150 ml), and p-toluenesulfonic acid (10.05 g, 58.34 mmol) was added. The reaction was carried out at 100 °C for 16 hours. After the reaction was completed by TLC monitoring, most of the solvent was removed by concentration under reduced pressure. Then, saturated sodium bicarbonate solution was slowly added, and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, concentrated, and purified by silica gel column chromatography to obtain compound 58C (7.7 g, yield: 41.49%).

[0766] LC-MS (ESI): m / z = 318.0 [M+H] + .

[0767] Step 3: Compound 58C (3.5 g, 11.00 mmol) was added to a reaction flask, dissolved in DMF, and NaH (1.32 g, 33.00 mmol) was added at 60 °C. The reaction was maintained at this temperature for 30 min. Then, cyclopropyl trifluoromethanesulfonate (10.46 g, 55.00 mmol) was added, and the reaction was maintained at this temperature for 3 h. After the reaction was completed by TLC monitoring, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was separated, dried, concentrated, and purified by silica gel column chromatography to obtain compound 58D (500 mg, yield: 12.69%).

[0768] LC-MS (ESI): m / z = 358.0 [M+H] + .

[0769] Step 4: Compound 58D (500 mg, 1.40 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Intermediate 1 (588 mg, 1.68 mmol), potassium phosphate (890 mg, 4.20 mmol), and Ruphos Pd G3 (117 mg, 0.14 mmol) were added sequentially. The mixture was purged with nitrogen three times and reacted at 90 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by reverse-phase column chromatography to obtain compound 58 (60 mg, yield: 8.56%).

[0770] LC-MS (ESI): m / z = 501.2 [M+H] + .

[0771] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.66(s,2H),7.49-7.36(m,5H),7.34-7.29(m,1H),7.18-6.87(m,1H),4.41-4.34(m,1H),3. 29-3.24(m,1H),2.86-2.72(m,1H),2.59-2.52(m,1H),2.41-2.28(m,1H),2.11-2.02(m,1H),0.95-0.89(m,2H),0.57-0.52(m,2H).

[0772] Example 59:

[0773] Step 1: Using compound 9D (210 mg, 0.60 mmol) and (S)-2-methylmorpholine (91 mg, 0.90 mmol) as starting materials, the target compound 59A (190 mg, 73%) was obtained by following the synthesis method in Step 1 of Example 26.

[0774] LC-MS(ESI): m / z = 431.0 [M+H] + .

[0775] Step 2: Using compound 59A (190 mg, 0.44 mmol) as a starting material, compound 59 (51 mg, 22%) was synthesized according to the second step of Example 26.

[0776] LC-MS (ESI): m / z = 526.1 [M+H] + .

[0777] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.36-8.32(m,1H),7.64-7.50(m,3H) ),7.46-7.36(m,2H),7.35-7.31(m,1H),6.56(t,1H),4.49-4.21(m,2H),3. 91-3.69(m,1H),3.57-3.35(m,3H),3.29-3.09(m,1H),2.96-2.76(m,2H),2 .64-2.53(m,1H),2.42-2.29(m,1H),2.10-2.00(m,1H),1.17-0.98(m,3H).

[0778] Example 60:

[0779] Step 1: Using compound 9D (210 mg, 0.60 mmol) and (S)-3-methylmorpholine (91 mg, 0.90 mmol) as starting materials, the target compound 60A (190 mg, 73%) was obtained by following the synthesis method in Step 1 of Example 26.

[0780] LC-MS(ESI): m / z = 431.0 [M+H] + .

[0781] Step 2: Using compound 60A (190 mg, 0.44 mmol) as the starting material, compound 60 (55 mg, 24%) was synthesized according to the second step of Example 26.

[0782] LC-MS (ESI): m / z = 526.1 [M+H] + .

[0783] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.35-8.30(m,1H),7.62-7.50(m,3H),7.47-7.37(m,2H),7.35-7.32(m,1H),6.55(t,1H),4.61-4.06( m,2H),3.94-3.33(m,5H),3.20-3.02(m,1H),2.89-2.72(m,1H),2.59- 2.51(m,1H),2.42-2.23(m,1H),2.13-1.86(m,1H),1.30-1.18(m,3H).

[0784] Example 61:

[0785] Step 1: Using compound 9D (200 mg, 0.57 mmol) and (R)-2-methylmorpholine (83 mg, 0.83 mmol) as starting materials, the target compound 61A (150 mg, 63.7%) was obtained by the synthesis method in Step 1 of Example 26.

[0786] LC-MS(ESI): m / z = 431.0 [M+H] + .

[0787] Step 2: Using compound 61A (100 mg, 0.23 mmol) as the starting material, compound 61 (60 mg, 49.1%) was synthesized according to the second step of Example 26.

[0788] LC-MS (ESI): m / z = 526.1 [M+H] + .

[0789] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.36-8.33(m,1H),7.63-7.60(m,1H),7.56-7.51(m,2H),7.45-7. 37(m,2H),7.34-7.33(m,1H),6.56(t,1H),4.40-4.25(m,2H),3.89-3.71(m,1H),3.53-3.44(m,3H),3.30 -3.09(m,1H),2.89-2.75(m,2H),2.57-2.53(m,1H),2.42-2.29(m,1H),2.08-2.00(m,1H),1.15-0.99(m,3H).

[0790] Example 62:

[0791] Step 1: Using compound 9D (200 mg, 0.57 mmol) and (R)-3-methylmorpholine (83 mg, 0.83 mmol) as starting materials, the target compound 62A (190 mg, 73%) was obtained by the synthesis method in Step 1 of Example 26.

[0792] LC-MS(ESI): m / z = 431.0 [M+H] + .

[0793] Step 2: Using compound 62A (120 mg, 0.28 mmol) as the starting material, compound 62 (55 mg, 37.5%) was synthesized according to the second step of Example 26.

[0794] LC-MS (ESI): m / z = 526.1 [M+H] + .

[0795] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.34 -8.32(m,1H),7.61-7.52(m,3H),7.44-7.38(m,2H),7.34 -7.33(m,1H),6.56(t,1H),4.52-4.13(m,2H),3.90-3.50(m,5H),3.18 -3.05(m,1H),2.85-2.76(m,1H),2.59-2.52(m,1H),2.41-2.30(m,1H),2.08-1.02(m,1H),1.27-1.20(m,3H).

[0796] Example 63:

[0797] Step 1: Using compound 28B (0.40 g, 1.15 mmol) and (R)-1,2-dimethylpiperazine (0.20 g, 1.72 mmol) as starting materials, compound 63A (0.35 g, 68.51%) was synthesized according to the method described in Step 1 of Example 56. LC-MS (ESI): m / z = 444.1 [M+H] + .

[0798] Step 2: Using compound 63A (0.35 g, 0.79 mmol) and intermediate 1 (0.33 g, 0.95 mmol) as starting materials, compound 63 (60 mg, 12.97%) was synthesized according to the method described in Step 2 of Example 56. LC-MS (ESI): m / z = 587.1 [M+H] + .

[0799] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.64-8.58(m,1H),7.84-7.76(m,1H),7. 64-7.52(m,3H),7.45-7.31(m,2H),6.67-6.60(m,1H),4.43-4.33(m,1H),4.304 .10(m,1H),3.27-3.23(m,1H),3.20-2.90(m,1H),2.87-2.72(m,2H),2.70-2.5 2(m,2H),2.42-2.28(m,1H),2.18(s,3H),2.15-1.95(m,3H),1.10-0.80(m,3H).

[0800] Example 64:

[0801] Step 1: Using 24C (1.0 g, 2.98 mmol) as the starting material, compound 64A (0.2 g, yield: 17.87%) was obtained by following the synthesis method in step 2 of Example 13.

[0802] LC-MS (ESI): m / z = 376.0 [M+H] + .

[0803] Step 2: Using 64A (0.2g, 0.53mmol) and intermediate 1 (0.22g, 0.62mmol) as raw materials, compound 64 (50mg, yield: 18.12%) was synthesized according to the method in step 3 of Example 13.

[0804] LC-MS (ESI): m / z = 519.1 [M+H] + .

[0805] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.85(s,2H),7.53-7.28(m,6H),4.39-4.35(m,1H),3.35-3.32(m,1H),2. 86-2.73(m,1H),2.59-2.53(m,1H),2.41-2.28(m,1H),2.11-2.03(m,1H),1.01-0.86(m,2H),0.63-0.52(m,2H).

[0806] Example 65:

[0807] Step 1: Using compound 9D (210 mg, 0.60 mmol) and ((S)-2-methyl-N-methylpiperazine (103 mg, 0.90 mmol) as starting materials, the target compound 65A (105 mg, 39%) was obtained by following the first step synthesis method in Example 51.

[0808] LC-MS (ESI): m / z = 444.0 [M+H] + .

[0809] Step 2: Using compound 65A (105 mg, 0.24 mmol) as the starting material, compound 65 (83 mg, 65%) was synthesized according to the second step of Example 51.

[0810] LC-MS (ESI): m / z = 539.2 [M+H] + .

[0811] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.43-8.34(m,1H),7.71-7.65(m,1H) ,7.57-7.52(m,2H),7.47-7.39(m,2H),7.36-7.32(m,1H),6.60(t,1H),4.6 1-4.33(m,2H),3.80.-3.50(m,2H),3.30-3.12(m,3H),2.97-2.71(m,5H),2 .61-2.52(m,1H),2.45-2.19(m,1H),2.12-1.93(m,1H),1.40-1.09(m,3H).

[0812] Example 66:

[0813] Step 1: Using compound 9D (210 mg, 0.60 mmol) and (R)-3-methyl-N-methylpiperazine (103 mg, 0.90 mmol) as starting materials, the target compound 66A (110 mg, 41%) was obtained by following the synthesis method in Step 1 of Example 51.

[0814] LC-MS (ESI): m / z = 444.0 [M+H] + .

[0815] Step 2: Using compound 66A (110 mg, 0.25 mmol) as the starting material, compound 66 (23 mg, 17%) was synthesized according to the second step of Example 51.

[0816] LC-MS (ESI): m / z = 539.2 [M+H] +.

[0817] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.43-8.35(m,1H),7.70-7.64(m,1H),7.57-7 .52(m,2H),7.47-7.38(m,2H),7.38-7.32(m,1H),6.61(t,1H),4.98-4.49(m,1H),4. 42-4.32(m,1H),4.15-3.57(m,1H),3.54-3.42(m,2H),3.21-2.90(m,3H),2.89-2.72 (m,4H),2.62-2.50(m,1H),2.44-2.29(m,1H),2.10-2.00(m,1H),1.38-1.22(m,3H).

[0818] Example 67:

[0819] Step 1: Using compound 9D (210 mg, 0.60 mmol) and (R)-1,2-dimethylpiperazine (103 mg, 0.90 mmol) as starting materials, the target compound 67A (90 mg, 38%) was obtained by following the first step synthesis method in Example 26.

[0820] LC-MS (ESI): m / z = 444.0 [M+H] + .

[0821] Step 2: Using compound 67A (90 mg, 0.20 mmol) as the starting material, compound 67 (51 mg, 40%) was synthesized according to the second step of Example 26.

[0822] LC-MS (ESI): m / z = 539.2 [M+H] + .

[0823] 1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.43-8.34(m,1H),7.71-7.65(m,1H) ),7.57-7.52(m,2H),7.47-7.39(m,2H),7.36-7.32(m,1H),6.60(t,1H),4. 61-4.33(m,2H),3.80-3.50(m,2H),3.30-3.12(m,3H),2.97-2.71(m,5H),2 .61-2.52(m,1H),2.45-2.19(m,1H),2.12-1.93(m,1H),1.40-1.09(m,3H).

[0824] Example 68:

[0825] Step 1: Using compound 9D (210 mg, 0.60 mmol) and 3-S-1,3-dimethylpiperazine (103 mg, 0.90 mmol) as starting materials, the target compound 68A (90 mg, 38%) was obtained by following the first step synthesis method in Example 26.

[0826] LC-MS (ESI): m / z = 444.0 [M+H] + .

[0827] Step 2: Using compound 68A (90 mg, 0.20 mmol) as the starting material, compound 68 (49 mg, 37%) was synthesized according to the second step of Example 26.

[0828] LC-MS (ESI): m / z = 539.2 [M+H] + .

[0829] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.43-8.35(m,1H),7.70-7.64(m,1H),7.57-7 .52(m,2H),7.47-7.38(m,2H),7.38-7.32(m,1H),6.61(t,1H),4.98-4.49(m,1H),4. 42-4.32(m,1H),4.15-3.57(m,1H),3.54-3.42(m,2H),3.21-2.90(m,3H),2.89-2.72 (m,4H),2.62-2.50(m,1H),2.44-2.29(m,1H),2.10-2.00(m,1H),1.38-1.22(m,3H).

[0830] Example 69:

[0831] Step 1: Using compound 9D (200 mg, 0.60 mmol) and 2-oxa-6-aza-spiro[3,3]heptane (90 mg, 0.90 mmol) as raw materials, the target compound 69A (30 mg, 13%) was obtained by following the first step synthesis method in Example 51.

[0832] LC-MS (ESI): m / z = 429.0 [M+H] + .

[0833] Step 2: Using compound 69A (30 mg, 0.08 mmol) as the starting material, compound 69 (15 mg, 40%) was synthesized according to the second step of Example 51.

[0834] LC-MS (ESI): m / z = 524.1 [M+H] + .

[0835] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.40-8.36(m,1H),7.77-7.73(m,1H),7.59-7.50(m,2H),7.47-7.31(m,3H),6.57(t,1H),4. 72-4.63(m,4H),4.42-4.35(m,1H),4.24-4.16(m,4H),2.88-2.75(m,1H),2.61-2.53(m,1H),2.43-2.30(m,1H),2.11-2.01(m,1H).

[0836] Example 70:

[0837] Step 1: Using compound 9D (200 mg, 0.60 mmol) and 4,4-difluoropiperidine (109 mg, 0.90 mmol) as starting materials, the target compound 70A (30 mg, 13%) was obtained by following the first step synthesis method in Example 51.

[0838] LC-MS (ESI): m / z = 451.0 [M+H] + .

[0839] Step 2: Using compound 70A (30 mg, 0.08 mmol) as the starting material, compound 70 (15 mg, 40%) was synthesized according to the second step of Example 51.

[0840] LC-MS (ESI): m / z = 546.1 [M+H] + .

[0841] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.38-8.33(m,1H),7.70-7.64(m,1H),7.58-7.51(m,2H),7.46-7.31(m,3H),6.58(t,1H),4. 42-4.32(m,1H),3.77-3.67(m,2H),3.43-3.37(m,2H),2.87-2.74(m,1H),2.61-2.52(m,1H),2.43-2.29(m,1H),2.12-1.94(m,5H).

[0842] Example 71:

[0843] Step 1: Using compound 9D (200 mg, 0.57 mmol) and hexahydropyridine (72.8 mg, 0.86 mmol) as starting materials, the target compound 71A (150 mg, 66%) was obtained by the synthesis method in Step 1 of Example 26.

[0844] LC-MS (ESI): m / z = 415.0 [M+H] + .

[0845] Step 2: Using compound 71A (100 mg, 0.24 mmol) as the starting material, compound 71 (70 mg, 56.9%) was synthesized according to the second step of Example 26.

[0846] LC-MS (ESI): m / z = 510.2 [M+H] + .

[0847] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.33-8.31(m,1H),7.57-7.52(m,3H),7.44-7.37(m,2H),7.34-7.33(m,1H),6.54(t,1H),4.40-4.35(m ,1H),3.59.-3.52(m,2H),3.22-3.20(m,2H),2.85-2.76(m,1H),2.59- 2.52(m,1H),2.41-2.30(m,1H),2.09-2.02(m,1H),1.63-1.43(m,6H).

[0848] Example 72:

[0849] Step 1: Using compound 9D (200 mg, 0.57 mmol) and (1S,2S)-2-fluorocyclopropane-1-amine hydrochloride (111 mg, 0.86 mmol) as starting materials, the target compound 72A (110 mg, 55%) was synthesized according to the first step of Example 26.

[0850] LC-MS (ESI): m / z = 405.0 [M+H] + .

[0851] Step 2: Using compound 72A (110 mg, 0.27 mmol) as the starting material, compound 72 (50 mg, 36%) was synthesized according to the second step of Example 26.

[0852] LC-MS (ESI): m / z = 500.2 [M+H] + .

[0853] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),9.29-9.24(m,1H),8.47-8.41(m,2H),7.57 -7.55(m,1H),7.51(d,1H),7.45-7.39(m,2H),7.35(d,1H),6.73(t,1H),4.93-4. 75(m,1H),4.40-4.35(m,1H),3.27-3.19(m,1H),2.85-2.76(m,1H),2.59-2.53(m ,1H),2.41-2.30(m,1H),2.09-2.02(m,1H),1.45-1.34(m,1H),1.13-1.05(m,1H).

[0854] Example 73:

[0855] Step 1: Using compound 9D (200 mg, 0.57 mmol) and (1R,2S)-2-fluorocyclopropane-1-amine hydrochloride (111 mg, 0.86 mmol) as starting materials, the target compound 73A (130 mg, 65%) was synthesized according to the first step of Example 26.

[0856] LC-MS (ESI): m / z = 405.0 [M+H] + .

[0857] Step 2: Using compound 73A (100 mg, 0.25 mmol) as the starting material, compound 73 (38 mg, 31%) was synthesized according to the second step of Example 26.

[0858] LC-MS (ESI): m / z = 500.2 [M+H] + .

[0859] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.59-9.55(m,1H),8.47-8.45(m,2 H),7.58-7.56(m,1H),7.51(d,1H),7.45-7.39(m,2H),7.36(d,1H),6.74 (t,1H),4.96-4.76(m,1H),4.40-4.35(m,1H),3.03-2.97(m,1H),2.89-2 .73(m,1H),2.59-2.53(m,1H),2.41-2.30(m,1H),2.09-2.01(m,1H),1.24 -1.12(m, 1H), 1.00-0.90(m, 1H).

[0860] Example 74:

[0861] Step 1: Using compound 9D (200 mg, 0.57 mmol) and 2,2-difluorocyclopropylamine hydrochloride (111 mg, 0.86 mmol) as starting materials, the target compound 74A (120 mg, 52%) was obtained by the synthesis method in Step 1 of Example 26.

[0862] LC-MS(ESI): m / z = 423.0 [M+H] + .

[0863] Step 2: Using compound 74A (100 mg, 0.24 mmol) as the starting material, compound 74 (408 mg, 33%) was synthesized according to the second step of Example 26.

[0864] LC-MS (ESI): m / z = 518.2 [M+H] + .

[0865] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.65-9.60(m,1H),8.50-8.44(m,2H),7.58-7.56(m,1H),7.52(d,1H),7.46-7.39(m,2H),7.36(d,1 H),6.75(t,1H),4.40-4.36(m,1H),3.63-3.55(m,1H),2.85-2.763(m,1H),2.59-2.53(m,1H),2.41-2.30(m,1H),2.09-1.94(m,2H),1.76 -1.67(m,1H).

[0866] Example 75:

[0867] Step 1: Using compound 9D (200 mg, 0.60 mmol) and 6-azaspirocyclic[2.5]octane (103 mg, 0.90 mmol) as starting materials, the target compound 75A (200 mg, 80%) was obtained by following the first step synthesis method in Example 26.

[0868] LC-MS (ESI): m / z = 441.0 [M+H] + .

[0869] Step 2: Using compound 75A (200 mg, 0.45 mmol) as the starting material, compound 75 (110 mg, 35%) was synthesized according to the second step of Example 26.

[0870] LC-MS (ESI): m / z = 536.1 [M+H] + .

[0871] Example 76:

[0872] Step 1: Using compound 9D (200 mg, 0.60 mmol) and bridged morpholine (103 mg, 0.90 mmol) as starting materials, the target compound 76A (200 mg, 80%) was obtained by following the first step synthesis method in Example 26.

[0873] LC-MS (ESI): m / z = 429.0 [M+H] + .

[0874] Step 2: Using compound 76A (200 mg, 0.47 mmol) as the starting material, compound 76 (100 mg, 37%) was synthesized according to the second step of Example 26.

[0875] LC-MS (ESI): m / z = 524.1 [M+H]+ .

[0876] Example 77:

[0877] Step 1: Compound 77A (1 g, 6.17 mmol, synthetic method referred to SITRYX THERAPEUTICS-WO2023 / 247958,2023,A1), compound 77B (2.12 g, 9.26 mmol), potassium phosphate (3.9 g, 18.5 mmol) and ruphos Pd G2 (478 mg, 0.62 mmol) were added to a mixed solution of dioxane (50 mL) and water (2 mL). Under nitrogen protection, the mixture was heated to 90 °C and stirred for 2 h. The reaction solution was filtered, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by HPLC to obtain the target compound 77C (600 mg, 36%).

[0878] LC-MS (ESI): m / z = 267.2 [M+H] + .

[0879] Step 2: Compound 77C (600 mg, 2.25 mmol) was dissolved in methanol (20 mL), and wet palladium on carbon (200 mg, 10%) was added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was directly filtered, and the filtrate was concentrated to dryness to obtain the target compound 77D (400 mg, crude product), which could be used directly in the next step without purification.

[0880] LC-MS (ESI): m / z = 177.1 [M+H] + .

[0881] Step 3: Compound 77D (300 mg, 1.70 mmol), 2,5-dibromothiophene (412 mg, 1.70 mmol), cuprous iodide (100 mg, 0.5 mmol), 1,10-o-phenanthroline (104 mg, 0.55 mmol), and potassium phosphate (0.80 g, 3.7 mmol) were added to anhydrous DMF (20 mL), stirred overnight at 80 °C under a nitrogen atmosphere, filtered, diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified by silica gel column chromatography to obtain the target compound 77E (100 mg, 17%).

[0882] LC-MS (ESI): m / z = 337.0 [M+H] + .

[0883] Step 4: Using compound 77E (700 mg, 0.21 mmol) as the starting material, compound 77 (11 mg, 11%) was synthesized according to the second step of Example 26.

[0884] LC-MS (ESI): m / z = 480.1 [M+H] + .

[0885] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.44-8.41(m,1H),8.16-8.13(m,1H),7.58-7.54(m,2H),7.46-7.38(m,2H),7.36-7.35(m ,1H),7.00(s,1H),6.63(t,1H),4.41-4.36(m,1H),2.85-2.77(m,1H),2.59-2.52(m,1H),2.41-2.31(m,4H),2.10-2.02(m,1H).

[0886] Example 78:

[0887] Step 1: Compound 78A (10.0 g, 87.67 mmol), sodium dichlorofluoroacetate (26.91 g, 175.34 mmol), and potassium carbonate (24.24 g, 175.34 mmol) were added to a reaction flask, dissolved in DMF, and reacted at 120 °C for 30 min. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 78B (11.6 g, yield: 80.66%).

[0888] LC-MS (ESI): m / z = 165.0 [M+H] + .

[0889] Step 2: Compound 78B (11.6 g, 70.70 mmol) was added to a reaction flask, dissolved in methanol, and Pd / C (5.8 g, 10%) was added. The reaction was carried out under a hydrogen atmosphere for 2 hours. After the reaction was completed by TLC monitoring, the mixture was filtered, the filtrate was collected, and concentrated under reduced pressure to obtain compound 78C (7.4 g, yield: 78.06%).

[0890] LC-MS (ESI): m / z = 135.0 [M+H] + .

[0891] Step 3: Compound 78C (1.40 g, 10.44 mmol), 19A (3.14 g, 10.44 mmol), Xantphos Pd G3 (0.98 g, 1.04 mmol) and cesium carbonate (10.20 g, 31.32 mmol) were added to a reaction flask, dissolved in 1,4-dioxane, purged with nitrogen three times, and reacted at 110 °C for 16 hours. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 78D (0.76 g, yield: 23.75%).

[0892] LC-MS (ESI): m / z = 307.0 [M+H] + .

[0893] Step 4: Compound 78D (760 mg, 2.47 mmol) was added to a reaction flask, dissolved in DMF, and NaH (297 mg, 7.41 mmol) was added at 60 °C. The reaction was maintained at this temperature for 30 min. Then, cyclopropyl trifluoromethanesulfonate (2.35 g, 12.35 mmol) was added, and the reaction was maintained at this temperature for 3 h. After the reaction was completed by TLC monitoring, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, the organic phase was separated, dried and concentrated, and purified by silica gel column chromatography to obtain compound 78E (250 mg, yield: 29.17%).

[0894] LC-MS (ESI): m / z = 347.0 [M+H] + .

[0895] Step 5: Compound 78E (250 mg, 0.72 mmol) was dissolved in 1,4-dioxane (20 mL) and water (1 mL). Intermediate 1 (301 mg, 0.86 mmol), potassium phosphate (459 mg, 2.16 mmol), and Ruphos Pd G3 (60 mg, 0.07 mmol) were added sequentially. The mixture was purged with nitrogen three times and reacted at 90 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by reverse-phase column chromatography to obtain compound 78 (18 mg, yield: 5.10%).

[0896] LC-MS (ESI): m / z = 490.2 [M+H] + .

[0897] 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.71(s,1H),7.94-7.62(m,1H),7.51-7.46(m,1H),7.45-7.36(m,3H),7.36-7.25(m,2H),4.40-4.33( m,1H),3.16-3.09(m,1H),2.85-2.74(m,1H),2.59-2.52(m,1H),2.40- 2.27(m,1H),2.10-2.02(m,1H),0.89-0.83(m,2H),0.65-0.59(m,2H).

[0898] Example 79:

[0899] Step 1: Compound 9D (210 mg, 0.60 mmol) and 7-oxa-4-azaspiro[2.5]octane (102 mg, 0.90 mmol) were synthesized according to the first step of Example 26 to obtain target compound 79A (120 mg, 45%).

[0900] LC-MS(ESI): m / z = 443.0 [M+H] + .

[0901] Step 2: Compound 79 (51 mg, 22%) was synthesized by synthesizing compound 79A (120 mg, 0.27 mmol) according to the second step of Example 26.

[0902] LC-MS (ESI): m / z = 538.2 [M+H] + .

[0903] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.36-8.30(m,1H),7.69-7.46(m,3H),7.47-7.28(m,3H),6.55(t,1H),4.42-4.33( m,1H),4.01-3.36(m,6H),2.89-2.75(m,1H),2.60-2.50(m,1H),2.45-2.28(m,1H),2.16-2.00(m,1H),1.40-0.54(m,4H).

[0904] Example 80:

[0905] Step 1: Using compound 9D (200 mg, 0.57 mmol) and 4-oxa-7-azaspiro[2.5]octane hydrochloride (128 mg, 0.86 mmol) as starting materials, the target compound 80A (130 mg, 51%) was synthesized according to the first step of Example 26.

[0906] LC-MS(ESI): m / z = 443.0 [M+H] + .

[0907] Step 2: Using compound 80A (100 mg, 0.23 mmol) as the starting material, compound 80 (20 mg, 16%) was synthesized according to the second step of Example 26.

[0908] LC-MS (ESI): m / z = 538.2 [M+H] + .

[0909] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.35-8.33(m,1H),7.64-7.52(m,3H),7.44-7.38(m,2H),7.34-7.32(m,1H),6.58-6.52(m,1H),4.40-4.3 5(m,1H),3.68-3.59(m,4H),3.36-3.27(m,2H),2.85-2.76(m,1H),2.59 -2.53(m,1H),2.41-2.31(m,1H),2.10-2.01(m,1H),0.74-0.52(m,4H).

[0910] Example 81:

[0911] Step 1: Using compound 9D (200 mg, 0.57 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (117 mg, 0.86 mmol) as starting materials, the target compound 81A (120 mg, 48.6%) was obtained by the synthesis method in Step 1 of Example 26.

[0912] LC-MS (ESI): m / z = 429.0 [M+H] + .

[0913] Step 2: Using compound 81A (120 mg, 0.34 mmol) as the starting material, compound 81 (20 mg, 13.6%) was synthesized according to the second step of Example 26.

[0914] LC-MS (ESI): m / z = 524.2 [M+H]+ .

[0915] H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.36-8.34(m,1H),7.69-7.65(m,1H),7.56 -7.52(m,2H),7.44-7.38(m,2H),7.34-7.33(m,1H),6.58-6.54(m,1H),4.84-4.2 6(m,3H),3.85-3.62(m,2H),3.44-3.34(m,1H),3.27-3.18(m,1H),2.84-2.76(m, 1H),2.58-2.53(m,1H),2.41-2.29(m,1H),2.09-2.00(m,1H),1.83-1.75(m,2H).

[0916] Example 82:

[0917] Step 1: Using compound 9D (200 mg, 0.57 mmol) and 3,3-difluoropyrrolidine hydrochloride (123 mg, 0.86 mmol) as starting materials, the target compound 82A (200 mg, 51%) was obtained by the synthesis method in Step 1 of Example 26.

[0918] LC-MS (ESI): m / z = 437.0 [M+H] + .

[0919] Step 2: Using compound 82A (200 mg, 0.46 mmol) and intermediate 1 (241 mg, 0.69 mmol) as raw materials, compound 82 (50 mg, 20%) was synthesized according to the second step of Example 26.

[0920] LC-MS (ESI): m / z = 532.1 [M+H] + .

[0921] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.41-8.37(m,1H),7.73-7.68(m,1H),7 .57-7.51(m,2H),7.45-7.37(m,2H),7.36-7.32(m,1H),6.62-6.55(m,1H),4.4 1-4.33(m,1H),3.91-3.77(m,2H),3.68(t,1H),3.58(t,1H),2.86-2.75(m,1H ),2.60-2.51(m,1H),2.49-2.40(m,2H),2.39-2.30(m,1H),2.10-2.01(m,1H).

[0922] Example 83:

[0923] Step 1: Using compound 9D (200 mg, 0.57 mmol) and 1-difluoromethylcyclopropane-1-amine hydrochloride (123 mg, 0.86 mmol) as starting materials, the target compound 83A (180 mg, 72%) was obtained by the synthesis method in Step 1 of Example 26.

[0924] LC-MS (ESI): m / z = 437.0 [M+H] + .

[0925] Step 2: Using compound 83A (180 mg, 0.41 mmol) and intermediate 1 (216 mg, 0.62 mmol) as raw materials, compound 83 (100 mg, 46%) was synthesized according to the second step of Example 26.

[0926] LC-MS (ESI): m / z = 532.1 [M+H] + .

[0927] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.78(s,1H),8.51-8.41(m,2H),7.60-7 .55(m,1H),7.53-7.49(m,1H),7.47-7.39(m,2H),7.38-7.34(m,1H),6.75(t,1 H),6.19-5.91(m,1H),4.42-4.34(m,1H),2.87-2.75(m,1H),2.61-2.52(m,1H ),2.43-2.29(m,1H),2.10-2.01(m,1H),1.16-1.09(m,2H),1.08-0.97(m,2H).

[0928] Example 84:

[0929] Step 1: Using compound 9D (300 mg, 0.86 mmol) and 1-trifluoromethylcyclopropylamine hydrochloride (215 mg, 1.72 mmol) as starting materials, the target compound 84A (300 mg, yield: 77%) was obtained by following the synthesis method in Step 1 of Example 26.

[0930] LC-MS (ESI): m / z = 455.0 [M+H] + .

[0931] Step 2: Using intermediate 1 (230 mg, 0.66 mmol) and compound 84A (300 mg, 0.66 mmol) as starting materials, compound 84 (160 mg, yield: 44%) was synthesized according to the method in step 2 of Example 26.

[0932] LC-MS (ESI): m / z = 550.2 [M+H] + .

[0933] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.94(s,1H),8.51-8.42(m,2H),7.59-7.55(m,1H), 7.53-7.49(m,1H),7.47-7.39(m,2H),7.38-7.35(m,1H),6.77-6.73(m,1H),4.42-4.34(m 1H),2.88-2.74(m,1H),2.60-2.53(m,1H),2.42-2.29(m,1H),2.11-1.95(m,1H),1.37-1.31(m,2H),1.25-1.19(m,2H).

[0934] Example 85:

[0935] Step 1: Using compound 9D (300 mg, 0.86 mmol) and thiomorpholine-1,1-dioxide hydrochloride (232 mg, 1.72 mmol) as starting materials, the target compound 85A (320 mg, yield: 77%) was obtained by following the synthesis method in Step 1 of Example 26.

[0936] LC-MS (ESI): m / z = 465.0 [M+H] + .

[0937] Step 2: Using intermediate 1 (241 mg, 0.69 mmol) and compound 85A (320 mg, 0.69 mmol) as starting materials, compound 85 (115 mg, yield: 30%) was synthesized according to the method in step 2 of Example 26.

[0938] LC-MS (ESI): m / z = 560.0 [M+H] + .

[0939] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.40-8.35(m,1H),7.76-7.71(m,1H), 7.59-7.51(m,2H),7.48-7.37(m,2H),7.36-7.32(m,1H),6.63-6.57(m,1H), 4.42-4.33(m,1H),4.07-3.97(m,2H),3.75-3.65(m,2H),3.25-3.17(m,4H), 2.87-2.72(m,1H),2.60-2.51(m,1H),2.41-2.27(m,1H),2.09-2.00(m,1H).

[0940] Example 86:

[0941] Step 1: Using compound 9D (300 mg, 0.86 mmol) and (R)-3-(trifluoromethyl)morpholine hydrochloride (330 mg, 1.72 mmol) as starting materials, the target compound 86A (300 mg, yield: 72%) was obtained by following the synthesis method in Step 1 of Example 26.

[0942] LC-MS (ESI): m / z = 485.0 [M+H] + .

[0943] Step 2: Using intermediate 1 (215 mg, 0.62 mmol) and compound 86A (300 mg, 0.62 mmol) as starting materials, compound 86 (190 mg, yield: 53%) was synthesized according to the method in step 2 of Example 26.

[0944] LC-MS (ESI): m / z = 580.2 [M+H] + .

[0945] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.40-8.35(m,1H),7.72-7.60(m,1H),7.59-7.50(m,2H),7.48-7.37(m,2H),7.36-7.32(m,1H),6.62-6.5 5(m,1H),5.17-5.02(m,1H),4.41-4.02(m,3H),3.85-3.32(m,4H),2.85 -2.75(m,1H),2.62-2.51(m,1H),2.41-2.28(m,1H),2.10-2.00(m,1H).

[0946] Example 87:

[0947] Step 1: Using compound 9D (300 mg, 0.86 mmol) and (S)-3-(trifluoromethyl)morpholine hydrochloride (329 mg, 1.72 mmol) as starting materials, the target compound 87A (320 mg, yield: 77%) was obtained by following the synthesis method in Step 1 of Example 26.

[0948] LC-MS (ESI): m / z = 485.0 [M+H] + .

[0949] Step 2: Using intermediate 1 (230 mg, 0.66 mmol) and compound 87A (320 mg, 0.66 mmol) as starting materials, compound 87 (178 mg, yield: 47%) was synthesized according to the method in step 2 of Example 26.

[0950] LC-MS (ESI): m / z = 580.2 [M+H] + .

[0951] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.40-8.35(m,1H),7.72-7.60(m,1H),7.59-7.51(m,2H),7.45-7.37(m,2H),7.36-7.30(m,1H),6.62-6.6 0(m,1H),5.17-5.06(m,1H),4.43-3.92(m,3H),3.85-3.35(m,4H),2.87 -2.74(m,1H),2.62-2.51(m,1H),2.42-2.27(m,1H),2.10-2.00(m,1H).

[0952] Example 88:

[0953] Step 1: 41A (2.1 g, 7.95 mmol), N-methyl-4-pyrazolephenol (1.56 g, 15.9 mmol), potassium tert-butoxide (2.67 g, 23.85 mmol), CuI (605 mg, 3.18 mmol), and 2,2,6,6-tetramethyl-3,5-heptadecane (598 mg, 3.18 mmol) were dissolved in N-methylpyrrolidone. The mixture was heated to 110 °C and reacted for 16 h. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound 88A (250 mg, 11%).

[0954] LC-MS (ESI): m / z = 282.1 [M+H] + .

[0955] Step 2: Compound 88A (250 mg, 0.89 mmol) was dissolved in methanol (10 mL), and wet palladium on carbon (10%, 100 mg) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was monitored by LCMS until the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain the target compound 88B (140 mg, 83%), which could be used directly in the next step without purification.

[0956] LC-MS (ESI): m / z = 192.1 [M+H] + .

[0957] Step 3: Compound 88B (140 mg, 0.73 mmol), 2,5-dibromothiophene (266 mg, 1.10 mmol), cuprous iodide (28 mg, 0.15 mmol), 1,10-o-phenanthroline (58 mg, 0.29 mmol), and potassium phosphate (466 mg, 2.20 mmol) were added to anhydrous DMF (20 mL), stirred overnight at 80 °C under a nitrogen atmosphere, filtered, diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified by silica gel column chromatography to obtain the target compound 88C (95 mg, 37%).

[0958] LC-MS(ESI):m / z=352.0&354.0[M+H] + .

[0959] Step 4: Compound 88C (95 mg, 0.27 mmol), intermediate 1 (141 mg, 0.39 mmol), potassium phosphate (171 mg, 0.81 mmol), and Xphos Pd G2 (21 mg, 0.027 mmol) were added to a mixed solution of dioxane (10 mL) and water (0.5 mL). Under nitrogen protection, the mixture was heated to 80 °C and stirred for 2 h. The reaction solution was filtered, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by HPLC to obtain the target compound 88 (9 mg, 7%).

[0960] LC-MS (ESI): m / z = 495.1 [M+H] + .

[0961] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.97(d,1H),7.76(s,1H),7.56(d,1H),7.58-7.54(m,1H),7.46-7.37(m,3H),7.34-7.32(m,1H), 7.00(d,1H),6.39(t,1H),4.41-4.34(m,1H),3.81(s,3H),2.86-2.75(m,1H),2.60-2.50(m,1H),2.43-2.28(m,1H),2.10-2.02(m,1H).

[0962] Example 89:

[0963] Step 1: Using compound 9D (200 mg, 0.60 mmol) and 4,4-dimethyl-1,4-azasilane (103 mg, 0.90 mmol) as starting materials, the target compound 89A (210 mg, 82%) was obtained by following the synthesis method in Step 1 of Example 26.

[0964] LC-MS (ESI): m / z = 459.0 [M+H] + .

[0965] Step 2: Using compound 89A (210 mg, 0.45 mmol) and intermediate 1 (200 mg, 0.50 mmol) as raw materials, compound 89 (106 mg, 35%) was synthesized according to the second step of Example 26.

[0966] LC-MS (ESI): m / z = 554.1 [M+H] + .

[0967] 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.23-8.15(m,1H),7.50-7.39(m,3H),7.35-7.20(m,3H),6.44(t,1H),4.32-4.22(m,1H),3.84-3.4 4(m,2H),3.37-3.28(m,2H),2.80-2.62(m,1H),2.46-2.38(m,1H),2.32-2.17(m,1H),2.00-1.90(m,1H),0.75-0.51(m,4H),0.01(s,6H).

[0968] Biological test evaluation

[0969] The present application is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present application.

[0970] I. Determination of VAV1 protein degradation

[0971] Western Blot experiment: Jurkat cells in logarithmic growth phase were seeded into 12-well plates at a certain cell density, 0.5 mL per well, and incubated overnight at 37°C with 5% CO2.

[0972] The cells were observed under a microscope the following day to confirm their state. Compound preparations were performed by weighing specific amounts of the series of compounds or controls from this patent. A high-concentration stock solution was first prepared using DMSO. A serial dilution method was then used to prepare compound solutions with concentrations of 1000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, and 0 nM, with a final DMSO concentration of 0.1%. The solution was thoroughly mixed by shaking, and 0.5 mL of the solution was added to each well. After incubation for 24 hours, the cells were digested and collected in 1.5 mL EP tubes. The cells were centrifuged at 1000 rpm for 3 minutes, the supernatant was discarded, and the cell pellet was collected. The cells were resuspended once with an appropriate amount of PBS, centrifuged at 1000 rpm for 3 minutes, the supernatant was discarded, and the cell pellet was collected. An appropriate amount of RIPA lysis buffer containing PMSF was added, and the cells were lysed on crushed ice for 10-20 minutes. The cells were centrifuged at 12000 rpm for 15 minutes, the supernatant was collected, and the total protein concentration of the sample was determined using a BCA total protein quantification kit.

[0973] Using the 1x sample buffer and 5X Mix solution from the Simple Western blotting kit, homogenize the protein concentration of all test samples. Add the sample, primary antibody, secondary antibody, chromogenic buffer, and elution buffer sequentially according to the accompanying test plate loading instructions. Set the detection program and perform the analysis.

[0974] The test data were analyzed using the Simple Western blotting software "Compass for SW".

[0975] Experimental Results: The degradation rates of VAV1 at 10 nM for some specific compounds are shown in Table 1. For the VAV1 degradation rate at 10 nM, A indicates a degradation rate > 50% at 10 nM, B indicates a degradation rate < 10% at 10 nM ≤ 50%, and C indicates a degradation rate ≤ 10% at 10 nM; for DC... 50 A represents DC 50 ≤10nM, B means 10nM < DC 50 ≤100nM, C represents DC 50 >100nM; For Dmax, A means Dmax>90%, B means 60%<Dmax≤90%, and C means Dmax≤60%.

[0976] Table 1

[0977] Note: N / A indicates not tested.

[0978] Conclusion: The compounds of this application, such as those in the examples, exhibit excellent degradation performance in the in vitro Jurkat cell system.

[0979] II. Mouse Pharmacokinetic Test

[0980] 1. Experimental animals: Male C57 mice, 20-25g, 6 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0981] 2. Experimental Design: On the day of the experiment, C57 mice were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0982] Table 2. Dosage Information

[0983] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 95% (20% SBE-β-CD)

[0984] (DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl ether-β-cyclodextrin)

[0985] Blood samples of 0.03 mL were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. Brain tissue samples were also collected from the gavage group at 0.25, 2, and 24 h. The brain tissue was rinsed with cold physiological saline to remove residual blood, dried, and homogenized. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0986] To calculate the unbound brain-plasma ratio (Kp, uu), the binding rate of the analyte in mouse plasma and brain homogenate was determined using the rapid equilibrium dialysis (RED) method. The analyte stock solution was prepared with DMSO, and the working solution was diluted with 50% methanol. Plasma and brain homogenate samples of 1 μg / mL were prepared using blank mouse plasma and brain homogenate, respectively, and placed in an equilibrium dialysis apparatus. Dialysis was performed at 37°C with phosphate-buffered saline (PBS) for 6 hours. After incubation, the contents of each plasma / brain homogenate and buffer compartment were removed and mixed with an equal volume of blank control buffer or plasma / brain homogenate to maintain matrix similarity. All samples were subjected to protein precipitation, centrifuged, and the supernatant was analyzed by LC-MS / MS. The concentration of the analyte in the sample was semi-quantitatively determined using the ratio of the analyte peak area to the internal standard peak area (Area Ratio). The unbound brain-plasma ratio (Kp, uu) was calculated using the following formula.

[0987] (1) Unbound plasma protein fraction (% Unbound) ,Plasma = Buffer-side concentration / Plasma-side concentration * 100%

[0988] (2) Unbound fraction of brain homogenate (% Unbound) ,Brain = Buffer concentration / Brain homogenate concentration * 100%

[0989] (3) Unbound brain plasma ratio (Kp,uu) = %Unbound ,Brain *AUC brain / %Unbound ,Plasma *AUC plasma

[0990] Table 3.1 Pharmacokinetic parameters of the tested compounds in mouse plasma

[0991] Note: - indicates not applicable; NA indicates not tested.

[0992] When compounds marked with "*" were used in the gavage test, brain tissue samples were collected from mice in the gavage group at 0.25, 2, and 24 hours. Therefore, blood samples were collected from 9 animals (3 animals / group) at 0.083, 0.25, 0.5, 1, 2, 4, 7, and 24 hours. As a result, the SD value could not be calculated from the PK parameters.

[0993] Table 3.2 Pharmacokinetic parameters of the tested compounds in mouse brains

[0994] Note: Plasma *AUC 0-t The calculation was performed at three blood collection time points: 15 min, 2 h, and 24 h.

[0995] Conclusion: The compounds of this application, such as the compounds in the examples, have favorable pharmacokinetic characteristics in mice.

[0996] III. Rat Pharmacokinetic Tests

[0997] 1. Experimental animals: Male SD rats, approximately 220g, 6-8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0998] 2. Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water. They were fed 4 hours after drug administration.

[0999] Table 4. Dosage Information

[1000] Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Gavage administration solvent: 10% DMSO + 90% (20% SBE-β-CD)

[1001] Blood samples of 0.15 ml were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[1002] Table 5. Pharmacokinetic parameters of the tested compounds in rat plasma.

[1003] Conclusion: The compounds of this application, such as the compounds in the examples, have favorable pharmacokinetic characteristics in rats.

[1004] IV. Pharmacokinetics of Beagle Dogs

[1005] 1. Experimental animals: Male beagle dogs, weighing approximately 8-11 kg, 6 dogs per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

[1006] 2. Experimental Method: On the day of the experiment, beagles were randomly grouped according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[1007] Blood samples of 1 mL were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[1008] Conclusion: The compounds of this application, such as the compounds in the examples, have favorable pharmacokinetic characteristics in beagle dogs.

[1009] V. Pharmacokinetic Tests in Monkeys

[1010] 1. Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[1011] 2. Experimental Methods: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14–18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[1012] Blood samples of 1.0 mL were collected from venous sites in the extremities before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Bloo...

Claims

1. A compound represented by general formula (I) or (IA), its stereoisomer, or a pharmaceutically acceptable salt thereof: L1 and L2 are each independently selected from the key and -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1 )C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl group is optionally further reinforced by 1-4 R groups. L replace; R L1 Selected from H, D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, -C(O)-C 3-6 cycloalkyl, -S(O)2-C 3-6 cycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, or cycloalkyl group is optionally further substituted with 1 to 4 groups selected from D, halogen, =O, CN, OH, and NH2; R L Selected from H, D, halogens, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic groups are optionally further substituted by 1-4 groups selected from D, halogen, =O, CN, OH and NH2; Or two R atoms located on the same carbon atom L Together with the carbon atom it is attached to, they form C 3-8 Cycloalkyl groups, 4-8 heterocyclic groups, wherein the cycloalkyl groups or heterocyclic groups are optionally further composed of 1-4 groups selected from D, halogens, =O, CN, OH, NH2, C. 1-2 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The group substituted by the halogenated alkoxy group; The ring C is selected from non-existent, phenyl, C 3-15 cycloalkyl groups, 4-15 membered heterocyclic groups; Ring D is selected from non-existent, phenyl, C 3-10 Cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl; Each R C and R D Each is independently selected from H, D, halogens, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, -OC 3-10 Cycloalkyl, -O- (4-8 membered heterocyclic), -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-8 membered heterocyclic groups), -S(O)2-NHC 3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -SC 3-6 Cycloalkyl, -S-(4-8 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)NHOH, -C(O)NHCN, -C(O)NHOC 1-4 Alkyl group, -C(S)NHC 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)NH (4-8 membered heterocyclic group), -C(O)- (4-8 membered heterocyclic group), -N=S(O)(C 1-3 Alkyl)2, -C 1-4 Alkyl-(4-8 membered heterocyclic group), -C 1-4 Alkyl-(3-8 membered cycloalkyl), -C(O)NR L1 -C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further reinforced by 1-4 R groups. X replace; Or any two R C R D Together with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further surrounded by 1-4 R groups. X replace; R B Selected from H, or, when L1 is not a bond or C1 is not a benzene ring, R B With R C Together with the atoms it is attached to, it forms a phenyl group, C 5-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups; R X Each is independently selected from D, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group, -C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl groups are optionally further selected from 1 to 4 groups selected from D, halogen, =O, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Substituted with cycloalkyl groups; n is an integer selected from 0 to 5; m is selected from integers between 0 and 5; The condition is Selected from At that time, L1 is not a key.

2. The compounds of general formulas (I) and (IA) according to claim 1, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein, General formula (I) is further shown in general formulas (II), (II-1), (III), (III-1), (IV), (IV-1), (V), (VI-1), (III-A), (IV-A), (VA), (VB), (VII), (VII-1), (IV-A-1): L 1-1 Selected from -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-8 cycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-C(O)N(R L1 )C(O)-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, cycloalkyl, optionally further comprises 1-4 R- L replace; L1 is selected from the key, -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-3 alkynyl-, -N(R) L1 )C(O)-、-OC 1-4 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L replace; L2 is selected from the key, -C 1-4 Alkyl-, -N(R) L1 )-、-N(R L1 )C(O)-, wherein the alkyl group is optionally further divided by 1-4 R L replace; R C1 Selected from C 1-6 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic groups), -N=S(O)(C 1-3 Alkyl)2, R E The alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace; R E Selected from 4-8 membered heterocyclic groups, wherein the heterocyclic group contains at least one P atom and optionally is further surrounded by 1-4 R atoms. X replace; Or any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-4 groups selected from D, halogen, =O, CN, C. 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Substituted with cycloalkyl or 4-8 membered heterocyclic groups; Ring D is selected from C 3-10 Cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl; Ring C1 is selected from C 3-10 Cycloalkyl, 5-6-membered heteroaryl, 4-10-membered heterocycloalkyl, 9-10-membered heteroaryl; Ring C A Selected from five-membered heteroaryl, 4-8-membered monocyclic heterocyclic alkyl, C 3-8 Monocyclic cycloalkyl, C 6-8 Bridged cycloalkyl groups, cuboalkyl groups; n3 is 2, and both R C2 Together with the carbon atoms it is attached to, they form 7-8 membered heterocycles, C 7-8 Cycloalkyl, wherein the heterocyclic or cycloalkyl group is optionally further substituted with 1-4 Rx; X1 and X2 are each independently selected from C and N. When both X1 and X2 are C, L1 is not a bond. n4 is 2, and both R C3 Together with the carbon atom it is attached to, it forms a phenyl group, C 3-8 Cycloalkyl, 4-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally further substituted by 1-4 Rx; Cyclone C2 is selected from 8-10 fused heterocyclic groups, 8-10 bicyclic heterocyclic groups, and C 10-15 Tricyclic cycloalkyl groups, 10-15 membered tricyclic heterocyclic groups; R D1 Selected from =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-8 membered heterocyclic groups), -SC 1-6 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-8 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-8 membered heterocyclic group), wherein the alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace; Each R C Each is independently selected from H, D, =O, =S, =NH, halogens, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further surrounded by 1-4 R groups. X replace; Each R D Each is independently selected from H, D, halogens, CN, =O, =S, =NH, CN, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 3-8 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Halogenated alkyl groups, -SF5, -P(O)(CH3)2, -S(O)-C 3-6 Cycloalkyl, -S(O)- (4-6 membered heterocyclic groups), -SC 3-6 Cycloalkyl, -S-(4-6 membered heterocyclic group), -S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 cycloalkyl, -C(O)NHC 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -C 1-2 Alkyl-(4-6 membered heterocyclic group), -NR L1 -(5-6 heteroaryl groups), -C(O)NHOH, -C(O)NHOC 1-4 Alkyl groups, -C(O)NHCN, -C(S)NHC 3-6 cycloalkyl, -C 1-4 Alkyl-NR L1 -C 3-6 cycloalkyl, -NR L1 -C 3-6 cycloalkyl, -NR L1 -(4-8 membered heterocyclic group), -S(O)2-NHC 3-6 Cycloalkyl, -S(O)2NH- (4-8 membered heterocyclic group), -C(O)NH (4-8 membered heterocyclic group), -C(O)- (7-8 membered binary heterocyclic group), -C(O)NR L1 -C 1-4 Alkyl groups, wherein the alkyl, alkenyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, or heteroaryl groups are optionally further surrounded by 1-4 R groups. X replace; R X Each group is independently selected from D, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamine group, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl groups are optionally further selected from 1 to 4 groups selected from D, halogen, =O, CN, OH, NH2, C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Substituted with cycloalkyl groups; R L1-1 Selected from D and C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, -C(O)-C 3-6 cycloalkyl, -S(O)2-C 3-6 cycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, alkenyl, or alkynyl groups are optionally further substituted with 1 to 4 groups selected from D, halogen, =O, CN, OH, and NH2; n1 is an integer selected from 1 to 2; n2 is an integer selected from 0 to 2; m1 is selected from integers between 0 and 1; The conditions are: (1) Not for *The site is the connection point between ring C1 and the right ring D; (2) When ring C2 is selected from 9-10 member heterocyclic groups, ring C2 contains at least one S atom or m1 is not 0; (3) When Selected from At that time, L2 is not -CH2- or -CH2CH2-; (4) The compound is not 3. The compounds of general formulas (II), (II-1), (III), (III-1), (IV), (IV-1), (V), (VI-1), (III-A), (IV-A), (VA), (VB), (VII), (IV-A-1), their stereoisomers, or pharmaceutically acceptable salts thereof according to claim 2, wherein, L 1-1 Selected from -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-,-C(O)N(R) L1 )-、-N(R L1 C(O)-, -O-, -N(R) L1 )-、-S-、-S(O)2N(R L1 )-、-N(R L1 S(O)2-, C 3-6 cycloalkyl, -N(R) L1 )C(O)N(R L1 )-、-N(R L1 )C(O)O-、-OC(O)N(R L1 )-、-OC 1-4 Alkyl-, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally further surrounded by 1-3 R groups. L Replacement; preferred L 1-1 Selected from -C(O)NH-, -O-, -NH-, -N(CH3)-, -CH2-, -CH(CH3)-, -S-, -NHC(O)-, -S(O)2NH-, -NHS(O)2-, -CH=CH-, -C≡C-, -C≡C-CH2-, -cyclopropyl-, -cyclobutyl-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, -O-CH2-, -CH2C(O)-, -C(O)CH2-; L1 is selected from the key, -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -N(R) L1 )C(O)-、-OC 1-3 Alkyl-, wherein the alkyl group is optionally further oxidized by 1-4 R- L Substitution; preferably L1 is selected from the bond, -O-CH2-; L2 is selected from the key, -C 1-3 Alkyl-, -N(R) L1 )-、-N(R L1 )C(O)-, wherein the alkyl group is optionally further divided by 1-4 R L Substitution; preferably L2 is selected from bond, -C(O)-, -NHC(O)-, -CH2C(O)-, -N(cyclopropyl)-, -N(CH2CF3)-, -C≡C-, -CH(CH3)-; R L1 Selected from H, D, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, -C(O)-C 3-4 cycloalkyl, -S(O)2-C 3-4 cycloalkyl, -C 1-3 Alkyl-C 3-4 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally further substituted with 1-3 groups selected from D, halogen, =O, CN, OH, and NH2; preferably R. L1 Selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, vinyl, propynyl, cyclopropyl; R L Selected from H, D, halogens, =O, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, or heterocyclic group is optionally further substituted by 1-3 groups selected from D, halogen, =O, CN, OH, and NH2; preferably R L Selected from H, D, F, Cl, =O, methyl, ethyl, trifluoromethyl, trifluoroethyl, vinyl, ethynyl, methoxy, cyclopropyl; R C Each is independently selected from D, F, Cl, =O, =S, =NH, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl. Ring D is selected from C 3-10 Cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl; preferably ring D is selected from... Preferred ring D is selected from R D Each is independently selected from D, F, Cl, =O, =S, =NH, CN, methyl, ethyl, vinyl, ethynyl, methoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, -OCD3, -ethynyl-cyclopropyl, -vinyl-cyclopropyl, -O-cyclobutyl, -C(O)NH-cyclopropyl, -C(O)NH-cyclobutyl, -C(O)NHCN, -C(O)NHOCH3, -C(S)NH-cyclopropyl, -C(S)NH-cyclobutyl, -O-cyclopropyl, difluoromethyl -C(O)N(CH3)CH2CHF2; R C1 Selected from C 1-4 Halogenated alkoxy groups, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocyclic groups), -SC 1-4 Haloalkyl, -SF5, -P(O)(C 1-3 Alkyl)2、-S(O)2-C 3-6 Cycloalkyl, -S(O)2- (4-6 membered heterocyclic group), -C(O)-C 3-6 Cycloalkyl, -C(O)- (4-6 membered heterocyclic groups), -N=S(O)(C 1-2 Alkyl)2, R E The alkyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally further reinforced with 1-2 R groups. X Replacement; preferred R C1 Selected from -OCF3, -OCHF2, -OCH2F, -O-cyclopropyl, -O-cyclobutyl, -SCF3, -SCHF2, -SCH2F, -SF5, -P(O)(CH3)2, -S(O)2-cyclopropyl, -S(O)2-cyclobutyl, -N=S(O)(CH3)2, R E Selected from 4-6 membered heterocyclic groups, wherein the heterocyclic group contains at least one P atom and optionally is further surrounded by 1-2 R atoms. X replace; Or any two R C R C1 R D Together with the atoms it is attached to, it forms a phenyl group, C 3-6 Cycloalkyl, 5-8-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected by 1-3 groups selected from D, F, Cl, =O, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Substituted with cycloalkyl or 4-6 membered heterocyclic groups; Ring C1 is selected from C 3-6 Monocycloalkyl, C 6-10 cycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Spirocycloalkyl, five-membered heteroaryl, six-membered heteroaryl, 4-8-membered monocyclic heterocycloalkyl, 6-10-membered fused heterocycloalkyl, 5-10-membered bridged heterocycloalkyl, 5-10-membered spirocycloalkyl; preferably, ring C1 is selected from... Ring C A Selected from five-membered heteroaryl, 4-8-membered monocyclic heterocyclic alkyl, C 3-8 Monocyclic cycloalkyl, C 6-8 Bridged cycloalkyl, cuboalkyl; preferably cycloC A Selected from The C2 ring is selected from benzo[5] heteroaryl, benzo[6] heteroaryl, benzo[5] heterocycloalkyl, benzo[6] heterocycloalkyl, 8-10 bicyclic heterocyclic, C 10-15 Tricyclic cycloalkyl, 10-15 membered tricyclic heterocyclic alkyl, 10-15 membered tricyclic heteroaryl; preferably, ring C2 is selected from... R X Each is independently selected from D, F, Cl, hydroxyl, cyano, amino, =O, =S, =CH2, =CF2, =CHF, =CHCH3, =CFCH3, =C(CH3)2, =C 4-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-2 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-2 Deuterated alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -C 1-4 Alkyl-(5-6-membered heteroaryl), -S(O)2-C 1-3 Alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further substituted by 1-4 groups selected from D, halogen, =O, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, or cyclopropyl. R L1-1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -S(O)2-C 3-4 Cycloalkyl, wherein the alkenyl or ynyl group is optionally further substituted with 1-4 groups selected from D or halogens; n is an integer selected from 0 to 2; m is an integer between 0 and 3.

4. The compounds of general formulas (II), (III), (IV), (IV-1), (V), (VI-1), (III-A), (III-1), (IV-A), (VA), (VB), (VII), (IV-A-1) according to claim 2, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Selected from Selected from *The site is the connection point with the right loop D; or Selected from or Selected from Selected from *The site is the connection point with the right loop D; Selected from *The site is the connection point with the right loop D; or Selected from Selected from Selected from Selected from Rx is selected from D, F, Cl, hydroxyl, cyano, methyl, ethyl, CH2CH2F, CH2CF3, CF3, CH2F, CHF2, cyclopropyl, vinyl, ethynyl, methoxy, -CH2-OCH3, =O, =S, =CH2, =CF2. -S(O)2-CH3; R L1-1 Selected from allyl, propargyl, cyclopropyl, -CH2-CH=C(F)2, -S(O)2-cyclopropyl, CN-substituted cyclopropyl.

5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Selected from one of the structures in Table 1 and Table 2.

6. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

7. The pharmaceutical composition according to claim 6, comprising 1-1500 mg of the compound of any one of claims 1-5, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

8. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5, or the pharmaceutical composition according to claim 6 or 7, in the preparation of a medicament for treating / preventing VAV1-mediated diseases.

9. The use according to claim 8, wherein the VAV1-mediated disease is selected from autoimmune diseases, preferably rheumatoid arthritis, multiple sclerosis, and inflammatory gastroenteritis.

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-5, its stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7 or 8, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is selected from autoimmune diseases, preferably rheumatoid arthritis, multiple sclerosis, and inflammatory gastroenteritis.

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