Small molecule TNF-α inhibitor and use thereof

Abstract

Disclosed are a small molecule TNF-α inhibitor and a use thereof. The present invention provides a compound represented by formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compounds of the present invention have good inhibitory activity against TNF-α-induced NF-κB activation, and have good pharmacodynamic and pharmacokinetic properties or safety, and can be used for preventing and / or treating diseases associated with TNF-α.

Description

Small molecule TNF-α inhibitors and their uses

[0001] This application claims priority to Chinese patent application 2024114924564, filed on October 24, 2024; Chinese patent application 2025109602832, filed on July 11, 2025; and Chinese patent application 2025114922192, filed on October 17, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical technology, specifically to a class of small molecule TNF-α inhibitors and their uses. Background Technology

[0003] TNF-α, or tumor necrosis factor-α, is a member of the TNF supergroup. TNF-α exists in two active forms: transmembrane mTNF-α and secreted sTNF-α. Membrane-anchored mTNF-α can be cleaved into sTNF-α by TNF-α convertase, thus becoming free in the intercellular space. TNF-α expression increases in many pathological conditions, including sepsis, malignant tumors, heart failure, and chronic inflammatory diseases.

[0004] TNF-α exerts various biological functions by binding to its corresponding receptor TNFR on the cell membrane. TNFR includes two receptors, TNFR1 and TNFR2. TNFR1 is widely expressed in all cells, while TNFR2 is mainly expressed in T cells and endothelial cells. TNFR1 can be activated by transmembrane mTNF-α and soluble sTNF-α, thereby regulating inflammatory responses and cell apoptosis or necrosis. At the onset of rheumatoid arthritis or other autoimmune diseases, sTNF-α secreted by myeloid cells can activate TNFR1, promoting inflammation and inducing disease. TNFR2 is mainly activated by mTNF-α, and the activated receptor can regulate immune cell function and organ repair through the NF-κB signaling pathway. Physiologically, TNF-α is a key component of normal immune responses, and TNF-α is regulated by activating the immune system. However, excessive secretion of TNF-α can trigger various immune diseases and cause damage to the body. Therefore, TNF-α is considered a key factor in the development of autoimmune diseases, and therapeutic drugs can alleviate these diseases by blocking the interaction between TNF-α and TNFR1 / 2.

[0005] Currently approved TNF-α inhibitors for treating inflammatory or autoimmune disorders are mainly macromolecular TNF-α inhibitors, such as: fully human antibodies adalimumab and golimumab, human-mouse chimeric antibody infliximab, PEG-modified Fab' fragments such as pecelizumab, and TNFR2 fusion protein etanercept. These TNF-α inhibitors have been used to treat autoimmune diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, ankylosing spondylitis, ulcerative colitis, and uveitis. Studies have found that these macromolecular biological drugs currently have immunogenicity and adverse reactions caused by macromolecular administration, such as vasculitis, serum sickness, infusion reactions, and allergic reactions (Leone et al., J. Clin. Med. (2023), 12, 1630; Bendtzen, Front Immunol. 2015 Apr 8:6:152).

[0006] Several small molecule inhibitors targeting TNF-α are currently under development. These inhibitors have demonstrated good disease-improving effects in animal models of rheumatoid arthritis (O'Connell et al., Nat Communi (2019) 10:5795; Xiao et al., J. Med. Chem. (2020) 63(23), 15050–15071; Dietrich et al., J. Med. Chem. (2021) 64, 417-429; Vugler et al., Front. Pharmacol. (2022) 13:1037983). Furthermore, small molecules have better tissue penetration than large molecule drugs and are expected to overcome the adverse reactions and limitations of large molecule antibodies. Currently, the most representative small molecule TNF-α inhibitor, SAR441566, is still in Phase II clinical trials. Therefore, there is a need to develop new, highly effective, and low-toxicity small molecule TNF-α inhibitors to meet clinical treatment needs. Summary of the Invention

[0007] This invention provides a small molecule TNF-α inhibitor of formula (IA), its stereoisomer, or a pharmaceutically acceptable salt thereof. The compounds of this invention exhibit good inhibitory activity against TNF-α-induced NF-κB activation and possess favorable pharmacodynamic, pharmacokinetic, or safety profiles, and can be used for the prevention and / or treatment of TNF-α-related diseases.

[0008] To address this, the present invention adopts the following technical solution:

[0009] On the one hand, this application provides a compound having the formula (IA), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0010] Wherein, ring A is selected from 4-10 membered heterocyclic alkyl groups, and the 4-10 membered heterocyclic alkyl group contains at least one nitrogen atom attached to a carbonyl group;

[0011] X 1 X 2 X 3 and X 4 Each is independently selected from N and CR 6 And specify X 1 X 2 X 3 and X 4 At most two values ​​in the set are N at the same time;

[0012] Q is selected from

[0013] Z 1 Z 2 and Z 3 Each is independently selected from N and CR 7 And stipulate Z 1 Z 2 and Z 3 At most two values ​​in the set are N at the same time;

[0014] R 1 Selected from -C 1-3 alkylene -OH, -C 1-3 Alkylene-CN, -C 3-6 Cycloalkyl-OH, -C 3-6 Cycloalkyl-CN,-NR 8 R 9 -OC 1-3 alkylene-OH and -OC 1-3 Alkylene-CN, -OC 3-6 Cycloalkyl-OH and -OC 3-6 Cycloalkyl-CN, wherein the C 1-3 Alkylene and C 3-6 Each cycloalkyl group is independently and optionally bound by one or more R a Replaced;

[0015] R 2 Each is independently selected from hydrogen, halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-6 Alkyl and N(C) 1-6 alkyl)2, wherein the C 1-6 Alkyl and C 1-6 Alkoxy groups are each independently and optionally separated by one or more R groups. b Replaced;

[0016] R 3 Each is independently selected from hydrogen and halogens;

[0017] R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by one, two, or three R groups. c Replaced;

[0018] R 5 Selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Haloalkoxy, -SC 1-6 Alkyl, -SC 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Haloalkenyl;

[0019] R 6 Selected from hydrogen, halogen, cyano and C 1-6 alkyl;

[0020] R 7 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. d Replaced;

[0021] R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. e Replaced;

[0022] m is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0023] n is an integer selected from 0, 1, 2, and 3;

[0024] R a R b R cR d and R e Each is independently selected from halogen, cyano, amino, hydroxyl, C 1-3 Alkyl, -C 1-3 alkylene-OH, C 1-3 Alkoxy, NHC 1-3 Alkyl and N(C) 1-3 Alkyl)2.

[0025] In some embodiments, the present invention provides compounds represented by formula (IA), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (IA) have the structural features of formula (I):

[0026] Wherein, ring A is selected from 4-10 membered heterocyclic alkyl groups, and the 4-10 membered heterocyclic alkyl group contains at least one nitrogen atom attached to a carbonyl group;

[0027] X 1 and X 2 Each is independently selected from N and CR 6 ;

[0028] Q is selected from

[0029] Z 1 Z 2 and Z 3 Each is independently selected from N and CR 7 And stipulate Z 1 Z 2 and Z 3 At most two values ​​in the set are N at the same time;

[0030] R 1 Selected from -C 1-3 alkylene -OH, -C 1-3 Alkylene-CN, -C 3-6 Cycloalkyl-OH, -C 3-6 Cycloalkyl-CN,-NR 8 R 9 -OC 1-3 alkylene-OH and -OC 1-3 Alkylene-CN, -OC 3-6 Cycloalkyl-OH and -OC 3-6 Cycloalkyl-CN, wherein the C 1-3 Alkylene and C 3-6 Each cycloalkyl group is independently and optionally bound by one or more R a Replaced;

[0031] R 2 Each is independently selected from hydrogen, halogen, cyano, amino, hydroxyl, C1-6 Alkyl, C 1-6 Alkoxy, NHC 1-6 Alkyl and N(C) 1-6 alkyl)2, wherein the C 1-6 Alkyl and C 1-6 Alkoxy groups are each independently and optionally separated by one or more R groups. b Replaced;

[0032] R 3 Each is independently selected from hydrogen and halogens;

[0033] R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by one, two, or three R groups. c Replaced;

[0034] R 5 Selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Haloalkoxy, -SC 1-6 Alkyl, -SC 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Haloalkenyl;

[0035] R 6 Selected from hydrogen, halogen, cyano and C 1-6 alkyl;

[0036] R 7 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. d Replaced;

[0037] R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. e Replaced;

[0038] m is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0039] n is an integer selected from 0, 1, 2, and 3;

[0040] R a R b R c R d and R e Each is independently selected from halogen, cyano, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, NHC 1-3 Alkyl and N(C) 1-3 Alkyl)2.

[0041] In some embodiments, the halogen may be fluorine, chlorine, bromine or iodine, preferably fluorine.

[0042] In some implementations, the C 1-3 The alkyl group can be methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0043] In some implementations, the C 1-3 The alkoxy group can be methoxy, ethoxy, n-propoxy, or isopropoxy, with methoxy being preferred.

[0044] In some implementations, the C 1-3 The alkylene group may be -CH2-, -CH2CH2- or -CH2CH2CH2-, preferably -CH2-.

[0045] In some implementations, the C 3-6 Cycloalkylene can be

[0046] In some implementations, the C 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0047] In some implementations, the C 1-6 Haloalkyl is a C that is substituted with one or more halogens. 1-6 Alkyl groups, preferably C substituted with one or more halogens. 1-3 Alkyl groups, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3.

[0048] In some implementations, the C 1-6The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy.

[0049] In some implementations, the C 1-6 Haloalkoxy groups are C atoms that are substituted with one or more halogens. 1-6 Alkoxy groups, preferably C groups substituted with one or more halogens. 1-3 Alkyl groups, such as -OCH2F, -OCH2Cl, -OCHF2, -OCHCl2, -OCCl3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3 or -OCF2CF3, more preferably -OCHF2.

[0050] In some implementations, the -SC 1-6 The alkyl group may be methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, or tert-butylthio, preferably methylthio.

[0051] In some implementations, the -SC 1-6 The haloalkyl group is -SC substituted with one or more halogens. 1-6 Alkyl groups, preferably -SC groups substituted with one or more halogens. 1-3 Alkyl groups, such as -SCH2F, -SCH2Cl, -SCHF2, -SCHCl2, -SCCl3, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3 or -SCF2CF3, more preferably -SCHF2.

[0052] In some implementations, the C 3-6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0053] In some embodiments, the heteroatom of the 3-6 membered heterocyclic alkyl group is selected from N, O or S, and the number of heteroatoms is 1 or 2; preferably, the heteroatom of the 3-6 membered heterocyclic alkyl group is O, and the number of heteroatoms is 1.

[0054] In some embodiments, the 3-6 membered heterocyclic alkyl group may be an oxocyclic butyl group, an azocyclic butyl group, or a tetrahydrofuranyl group.

[0055] In one implementation, the C 2-6 The alkenyl group can be C 2-4 Alkenyl, such as vinyl, propenyl or butenyl, preferably vinyl.

[0056] In some implementations, the C 2-6 The halogenated alkenyl group can be a C that is substituted with one or more halogens. 2-6Alkenyl groups, preferably haloethenes, for example:

[0057] In some embodiments, the heteroatom of the 4-10 member heterocyclic alkyl group is selected from N, O or S, and contains at least one nitrogen atom, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom of the 4-10 member heterocyclic alkyl group is N, and the number of heteroatoms is 1 or 2.

[0058] In some embodiments, the 4-10 member heterocyclic alkylene group may be a monocyclic heterocyclic alkylene group or a polycyclic monocyclic heterocyclic alkylene group, wherein the number of rings of the polycyclic group may be bicyclic or tricyclic, and the polycyclic group may be fused, spirocyclic, or bridged; preferably, the 4-10 member heterocyclic alkylene group may be a 4-7 member monocyclic heterocyclic alkylene group or a 7-10 member bicyclic heterocyclic alkylene group;

[0059] In some embodiments, the 4-10 membered heterocyclic alkylene group is a 4-6 membered monocyclic heterocyclic alkylene group, wherein the 4-6 membered monocyclic heterocyclic alkylene group contains at least one nitrogen atom attached to a carbonyl group;

[0060] Preferably, the 4-6 member monocyclic heterocyclic alkyl group can be...

[0061] In some embodiments, the 4-6 membered monocyclic heterocyclic alkylene group may be...

[0062] In some embodiments, ring A is a 6-9 membered bicyclic heterocyclic alkylene group, wherein the 6-9 membered bicyclic heterocyclic alkylene group contains at least one nitrogen atom bonded to a carbonyl group; preferably, the 6-9 membered bicyclic heterocyclic alkylene group may be...

[0063] In some embodiments, the 6-9 membered bicyclic heterocyclic alkylene group may be... In some implementation schemes, R 1 -C 1-3 alkylene-OH, wherein the C 1-3 Alkylene is optionally surrounded by one or more R a Replaced; in other implementations, R 1 -C 1-3 alkylene-CN, wherein the C 1-3 Alkylene is optionally surrounded by one or more R a Replaced; in other implementations, R 1 -C 3-6 cycloalkyl-OH, wherein the C 3-6 The cyclohexene alkyl group is optionally surrounded by one or more Ra Replaced; in other implementations, R 1 -C 3-6 Cycloalkyl-CN, wherein the C 3-6 The cyclohexene alkyl group is optionally surrounded by one or more R a Replaced; in other implementations, R 1 For -NR 8 R 9 In other implementations, R 1 -OC 1-3 alkylene-OH, wherein the C 1- 3 alkylene groups are optionally surrounded by one or more R a Replaced; in other implementations, R 1 -OC 1-3 alkylene-CN, wherein the C 1- 3 alkylene groups are optionally surrounded by one or more R a Replaced; in other implementations, R 1 -OC 3-6 cycloalkyl-OH, wherein the C 3-6 The cyclohexene alkyl group is optionally surrounded by one or more R a Replaced; in other implementations, R 1 -OC 3-6 Cycloalkyl-CN, wherein the C 3-6 The cyclohexene alkyl group is optionally surrounded by one or more R a What it replaced.

[0064] In some implementation schemes, R 1 Selected from -C 1-3 alkylene -OH, -C 1-3 Alkylene-CN, -C 3-6 Cycloalkyl-OH, -C 3-6 Cycloalkyl-CN and -NR 8 R 9 Wherein C 1-3 Alkylene and C 3-6 Each cycloalkyl group is independently and optionally bound by one or more R a What it replaced.

[0065] In some implementation schemes, R 1 Selected from -C 1-3 alkylene -OH and -C 1-3 alkylene-CN, wherein the C 1-3 Alkylene is optionally surrounded by one or more R a What it replaced.

[0066] In some implementation schemes, R 1 Selected from Preferably, R 1 for

[0067] In some implementation schemes, R 1 Selected from Preferably, R 1 Selected from

[0068] In some implementation schemes, R 1 Selected from In some embodiments, ring A is selected from 4-6 membered monocyclic heterocyclic alkylene groups and 6-9 membered bicyclic heterocyclic alkylene groups, wherein the bicyclic alkylene group can be a fused ring, a spiro ring, or a bridged ring, and the 4-6 membered monocyclic heterocyclic alkylene group and the 6-9 membered bicyclic heterocyclic alkylene group contain at least one nitrogen atom attached to a carbonyl group.

[0069] In some embodiments, ring A is a 4-6 membered monocyclic heterocyclic alkyl group, wherein the 4-6 membered monocyclic heterocyclic alkyl group contains at least one nitrogen atom attached to a carbonyl group; in other embodiments, ring A is a 6-9 membered bicyclic heterocyclic alkyl group, wherein the 6-9 membered bicyclic heterocyclic alkyl group contains at least one nitrogen atom attached to a carbonyl group.

[0070] In some implementations, ring A is selected from... The above One nitrogen terminus is attached to a carbonyl group.

[0071] In some implementations, ring A is selected from... The above One nitrogen terminus is attached to a carbonyl group.

[0072] In some implementations, ring A is selected from... in One nitrogen terminus is attached to a carbonyl group; preferably, ring A is...

[0073] In some implementations, ring A is selected from... in One nitrogen terminus is attached to a carbonyl group; preferably, ring A is...

[0074] In some implementations, ring A is selected from... in One nitrogen terminus is attached to a carbonyl group. In some embodiments, R 2 Each is independently selected from hydrogen, halogen, hydroxyl, and C. 1-3 alkyl;

[0075] In some implementation schemes, R 2 Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, and methyl, preferably, R 2 Each is independently selected from hydrogen, methyl, and hydroxyl.

[0076] In some implementation schemes, R 2 Each is independently selected from hydrogen and methyl. In some embodiments, m is selected from integers 0, 1, and 2.

[0077] In some implementations, m is 0; in others, m is 1; and in still others, m is 2.

[0078] In some implementation schemes, X 1 X 2 X 3 and X 4 Two of them are N, and the other two are CR. 6 In some implementation schemes, X 1 and X 2 Let N, X 3 and X 4 For CR 6 In some implementation schemes, X 1 and X 2 Let N, X 3 and X 4 For CH; in other implementations, X 1 and X 4 Let N, X 2 and X 3 For CR 6 In other implementation schemes, X 1 and X 4 Let N, X 2 and X 3 For CH.

[0079] In some implementation schemes, X 1 and X 2 For N; in other implementations, X 1 and X 2 Each independently for CR 6In other implementation schemes, X 1 Let N, X 2 For CR 6 In other implementation schemes, X 1 For CR 6 X 2 Let N be the number of elements in the array.

[0080] In some implementation schemes, X 1 and X 2 Each is independently selected from N or CH; preferably, X 1 and X 2 Let N be the number of elements in the array.

[0081] In some implementation schemes, R 6 For hydrogen; in other embodiments, R 6 For halogen; in other embodiments, R 6 It is a cyano group.

[0082] In some implementation schemes, R 6 Selected from hydrogen and fluorine.

[0083] In some implementation schemes, structural units Selected from Preferably, structural unit for

[0084] In some implementation schemes, structural units Selected from Preferably, structural unit for

[0085] In some implementation schemes, R 3 For hydrogen; in other embodiments, R 3 Each is an independent halogen.

[0086] In some implementation schemes, R 3 Each is independently selected from hydrogen, fluorine, chlorine, bromine, and iodine.

[0087] In some implementation schemes, R 3 Each is independently selected from hydrogen and fluorine; preferably, R 3 It is hydrogen.

[0088] In some implementations, n is selected from 0 and 1.

[0089] In some implementations, n is 0; in others, n is 1.

[0090] In some implementation schemes, R4 C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R c Replaced; in other implementations, R 4 For H; in other implementations, R 4 C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally surrounded by one or more R c Replaced; in other implementations, R 4 C 3-6 Heterocyclic alkyl, the C 3-6 Heterocyclic alkyl groups are optionally surrounded by one or more R c Replaced, the C 3-6 Heterocyclic alkyl groups contain one heteroatom selected from N, O, or S.

[0091] In some implementation schemes, R 4 Selected from H, C 1-3 alkyl,

[0092] In some implementation schemes, R 4 C 1-3 Alkyl; preferably, R 4 It is a methyl group.

[0093] In some implementations, Q is In other implementations, Q is In other implementations, Q is In other implementations, Q is

[0094] In some implementation schemes, Z 1 Z 2 and Z 3 Each independently for CR 7 In other implementation schemes, Z 1 For N, Z 2 and Z 3 Each independently for CR 7 In other implementation schemes, Z 2 For N, Z 1 and Z 3 Each independently for CR 7 In other implementation schemes, Z 3 For N, Z 1 and Z 2 Each independently for CR 7 In other implementation schemes, Z 1 For CR 7 Z2 and Z 3 For N; in other implementations, Z 2 For CR 7 Z 1 and Z 3 For N; in other implementations, Z 3 For CR 7 Z 1 and Z 2 Let N be the number of elements in the array.

[0095] In some implementation schemes, Z 1 Z 2 and Z 3 For CH.

[0096] In some implementation schemes, R 5 It is cyano; in other embodiments, R 5 C 1-6 Alkyl; in other embodiments, R 5 C 1-6 alkoxy; in other embodiments, R 5 C 3-6 cycloalkyl; in other embodiments, R 5 C 1-6 Haloalkoxy; in other embodiments, R 5 -SC 1-6 Alkyl; in other embodiments, R 5 -SC 1-6 Halogenated alkyl; in other embodiments, R 5 C 2-6 Alkenyl; in other embodiments, R 5 C 2-6 Haloalkenyl groups.

[0097] In some implementation schemes, R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups, preferably C 1-3 Halogenated alkoxy groups.

[0098] In some implementation schemes, R 5 Selected from Preferably, R 5 for

[0099] In some implementation schemes, R 7 For hydrogen; in other embodiments, R 7 For halogen; in other embodiments, R 7 It is cyano; in other embodiments, R7 C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one, two, or three R's. d Replaced; in other implementations, R 7 C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally surrounded by one, two, or three R groups. d Replaced; in other implementations, R 7 C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three R's. d What it replaced.

[0100] In some implementation schemes, R 7 Each is independently selected from hydrogen, fluorine, chlorine, bromine, and iodine; preferably, R 7 Each is hydrogen independently.

[0101] In some implementation schemes, R 8 and R 9 Each is independently selected from hydrogen and C. 1-3 alkyl.

[0102] In some implementation schemes, R a R b R c R d and R e Each is independently selected from halogens; in another embodiment, R a R b R c R d and R e Each is independently selected from cyano groups; in another embodiment, R a R b R c R d and R e Each is independently selected from amino groups; in another embodiment, R a R b R c R d and R e Each is independently selected from hydroxyl groups; in another embodiment, R a R b R c R d and R e Each was independently selected from C 1-3 Alkyl; in another embodiment, R a R b Rc R d and R e Each was independently selected from C 1-3 alkoxy; in another embodiment, R a R b R c R d and R e Each was independently selected from NHC 1-3 Alkyl; in another embodiment, R a R b R c R d and R e Each is independently selected from N(C) 1-3 alkyl)2; in another embodiment, R a R b R c R d and R e Each independently is -C 1-3 Alkylene-OH.

[0103] In some implementation schemes, R a R b R c R d and R e Each is independently selected from halogens, hydroxyl groups, and C. 1-3 alkyl.

[0104] In some implementation schemes, R a R b R c R d and R e Each is independently selected from halogens, hydroxyl groups, -CH2OH, and C. 1-3 alkyl.

[0105] In some implementation schemes, R a R b R c R d and R e Each is independently selected from fluorine, chlorine, hydroxyl, and methyl. In some embodiments, R a Selected from hydroxyl and methyl.

[0106] In some implementation schemes, R a Selected from -CH2OH and methyl. In some embodiments, the structural unit... Selected from Preferably, structural unit Selected from More preferably, structural unit for

[0107] In some implementation schemes, structural units Selected from Preferably, structural unit for

[0108] In some implementation schemes, structural units Selected from Preferably, structural unit Selected from More preferably, structural unit Selected from

[0109] In some implementation schemes, structural units Selected from

[0110] In some implementation schemes, structural units Selected from Preferably, structural unit Selected from

[0111] In some implementation schemes, structural units Selected from Preferably, structural unit for

[0112] In some embodiments, the present invention provides compounds represented by formula (IA), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (IA) have the structural features of formula (IIA):

[0113] Among them, R 1 Ring A, X 1 X 2 X 3 X 4 R 2 R 3 R 4 R 5 Q, Z 1 Z 2 Z 3m and n are as defined above.

[0114] In some embodiments, the present invention provides compounds represented by formula (IA), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (IA) have the structural features of formula (IIIA):

[0115] in,

[0116] R 1 Selected from Preferably, R 1 for

[0117] Ring A is a 4-6 membered monocyclic heterocyclic alkylene group or a 6-9 membered bicyclic heterocyclic alkylene group, wherein the bicyclic ring is a fused ring, a spirocyclic ring, or a bridged ring, and the 4-6 membered monocyclic heterocyclic alkylene group or the 6-9 membered bicyclic heterocyclic alkylene group contains at least one nitrogen atom attached to a carbonyl group; preferably, ring A is selected from... in One nitrogen terminus is attached to a carbonyl group;

[0118] R 2 Each is independently selected from hydrogen and methyl;

[0119] m is an integer selected from 0, 1, and 2;

[0120] X 1 and X 2 Let N, X 3 and X 4 For CH; or, X 1 and X 4 Let N, X 2 and X 3 For CH;

[0121] Q is selected from More preferably, Q is

[0122] R 4 C 1-3 Alkyl; preferably, R 4 It is methyl;

[0123] R 5 Selected from C 1-3 Halogenated alkoxy groups and -SC 1-3 Halogenated alkyl; preferably, R 5 Selected from More preferably, R 5 for

[0124] Preferred structural unit Selected from Preferably, structural unit Selected from

[0125] In some embodiments, the present invention provides a compound represented by formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (IA) has the structural features of formula (II):

[0126] Among them, R 1 Ring A, X 1 X 2 R 2 R 3 R 4 R 5 Q, Z 1 Z 2 Z 3 m and n are as defined above.

[0127] In some embodiments, the present invention provides a compound represented by formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (IA) has the structural features of formula (III):

[0128] Among them, R 1 Ring A, R 2 R 4 R 5 X 2 m and Q are as defined above.

[0129] In some embodiments, the present invention provides a compound represented by formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (IA) has the structural features of formula (IV):

[0130] Among them, R 1 Ring A, R 2 R 4 R 5 X 2 m and Q are as defined above.

[0131] Preferably,

[0132] R 1 Selected from More preferably, R 1 for

[0133] Ring A is a 4-6 membered monocyclic heterocyclic alkylene group or a 6-9 membered bicyclic heterocyclic alkylene group, wherein the bicyclic ring is a fused ring, a spirocyclic ring, or a bridged ring, and the 4-6 membered monocyclic heterocyclic alkylene group or the 6-9 membered bicyclic heterocyclic alkylene group contains at least one nitrogen atom attached to a carbonyl group; preferably, ring A is selected from... in One nitrogen terminus is attached to a carbonyl group; more preferably, ring A is...

[0134] R 2 Each is independently selected from hydrogen, methyl, and hydroxyl;

[0135] m is selected from 0 and 1;

[0136] X 2 For N or CH; more preferably, X 2 Let N be the number of people in the group.

[0137] Q is selected from More preferably, Q is

[0138] R 4 Selected from H, C 1-3 Alkyl or 3-6 membered heterocyclic alkyl; more preferably, R 4 C 1-3 Alkyl; more preferably, R 4 It is methyl;

[0139] R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups; more preferably, R 5 Selected from More preferably, R 5 for

[0140] Preferred structural unit Selected from More preferably, structural unit Selected from

[0141] In some embodiments, the present invention provides compounds represented by formula (IA), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (IA) have the structural features of formula (V):

[0142] Among them, R 1 R 4 R 5 Q is as defined above.

[0143] Preferably,

[0144] R 1 Selected from More preferably, R 1 for

[0145] Q is selected from More preferably, Q is

[0146] R 4 Selected from H, C 1-3 Alkyl or 3-6 membered heterocyclic alkyl; more preferably, R 4 C 1-3 Alkyl; more preferably, R 4 It is methyl;

[0147] R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups; more preferably, R 5 Selected from More preferably, R 5 for

[0148] In some embodiments, the compound represented by formula (IA) is any of the following compounds:

[0149] In some embodiments, the compound represented by formula (IA) is any of the following compounds:

[0150] In another aspect, the present invention provides a method for preparing a compound of formula (IA) according to any one of the first aspects of this application, the method comprising the following steps:

[0151] (1) Compound (IA) and compound (IB) undergo a coupling reaction under the catalysis of a transition metal to obtain compound (IA);

[0152] Among them, LG 1 Represents boric acid or borate esters, such as boric acid or pinacol borate ester; LG 2 Represents a leaving group, such as chlorine, bromine, or iodine, and LG1 and LG 2 The structures represented can be interchanged; in equations (IA), (IB), and (IA), rings A and X... 1 X 2 X 4 X 4 R 1 R 2 R 3 R 4 R 5 Q, Z 1 Z 2 Z 3 The definitions of m and n are as described above.

[0153] In some embodiments, the compound of formula (IA) is a compound of formula (I-A1), and the compound of formula (IA) is a compound of formula (I);

[0154] Among them, LG 1 Ring A, X 1 X 2 R 1 R 2 R 3 R 4 R 5 Q, Z 1 Z 2 Z 3 The definitions of m and n are as described above.

[0155] In some embodiments, the transition metal is, for example, palladium, or, for example, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (XPhos Pd G3).

[0156] If they are not commercially available, the starting materials of formula (1-A) or (1-B) can be prepared by methods similar to those described in the accompanying specific examples or by standard methods well known in the art.

[0157] In another aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. In a specific embodiment, the compound represented by formula (IA) is provided in a therapeutically effective amount. In a specific embodiment, the compound represented by formula (IA) is provided in a preventatively effective amount.

[0158] In another aspect, the present invention provides a compound represented by formula (IA), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition of the present invention in the preparation of a TNF-α inhibitor.

[0159] In another aspect, the present invention provides the use of a compound represented by formula (IA), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of TNF-α-related diseases.

[0160] In some implementations, the TNF-α-related diseases are: pain, nociceptive disorders, tumors, immune diseases (e.g., autoimmune diseases), inflammatory diseases, neurodegenerative diseases, metabolic diseases, or cardiovascular diseases.

[0161] In some implementations, the TNF-α-related diseases are: rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, uveitis, multiple sclerosis, Behçet's disease, hidradenitis suppurativa, vasculitis, neurogenic tuberous disease, Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis.

[0162] In another aspect, the present invention provides a compound represented by the present invention formula (IA), its stereoisomers, its pharmaceutically acceptable salts, or the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and / or treatment of disease.

[0163] The diseases mentioned are pain, nociceptive disorders, tumors, immune diseases (such as autoimmune diseases), inflammatory diseases, neurodegenerative diseases, metabolic diseases, or cardiovascular diseases.

[0164] In one embodiment, the disease is rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, uveitis, multiple sclerosis, Behcet's disease, hidradenitis suppurativa, vasculitis, neurogenic tuberous disease, Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis.

[0165] The terms used to describe this invention as appearing in this application specification and claims are defined as follows. For any specific term, if the meaning defined in this application differs from the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail; if not defined in this application, it shall have the meaning commonly understood by those skilled in the art.

[0166] In this application, the names of compounds correspond to their structural formulas. When the names of compounds and their structural formulas are inconsistent, the structural formula shall prevail, or the names shall be inferred based on the specific circumstances of the invention and the knowledge of those skilled in the art.

[0167] In this paper, the numerical ranges defined in the substituents, such as 1-6, 1-3, and 3-6, indicate integers within that range, such as 1-6 being 1, 2, 3, 4, 5, or 6.

[0168] The term "hydrogen" refers to -H.

[0169] The term "cyano" refers to -CN.

[0170] The term "amino" refers to -NH2.

[0171] The term "hydroxyl group" refers to -OH.

[0172] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0173] The term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group. For example, "C 1-6 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example, "C 1-3 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl. The alkyl group in this application is preferably C10. 1-3 alkyl.

[0174] "Cycloalkyl" refers to a compound composed of a specified ring of carbon atoms (e.g., C14, C24, C34, C44, C54, C6 ... 3-6 A saturated cyclic hydrocarbon group composed of ) . For example, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 cyclic carbon atoms. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0175] "Alkoxy" refers to the group -OR, where R is an alkyl group as described above. The alkoxy group of this invention is, for example, C... 1-6 Alkoxy, C 1-3 Alkoxy groups. Specifically, the alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0176] The term "alkylene" refers to a divalent alkyl group, where one hydrogen atom in an alkyl group is substituted, and the definition of an alkyl group is as described above, for example, C10. 1-3 Alkylenes. Specific alkylenes include, but are not limited to: -CH2-, -CH2CH2- or -CH2CH2CH2-, preferably -CH2-.

[0177] The term "cycloalkylene" refers to a divalent cycloalkyl group, where the definition of cycloalkyl is as described above, for example, C10. 3-6 Alkylenes. Specific cycloalkylenes include, but are not limited to:

[0178] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens. The number of halogens substituted can be 1, 2, 3, 4, or 5. The halogenated alkyl group in this application is preferably C10. 1-3 Halogenated alkyl groups, including but not limited to: -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3.

[0179] "Haloalkoxy" refers to the above-mentioned "alkoxy group" being replaced by one or more halogens. The number of halogens substituted can be 1, 2, 3, 4, or 5. The haloalkoxy group in this application is preferably C. 1-3 The haloalkoxy group, specifically including but not limited to: -OCH2F, -OCH2Cl, -OCHF2, -OCHCl2, -OCCl3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3 or -OCF2CF3, preferably -OCHF2.

[0180] "Heterocyclic alkyl" refers to a saturated monovalent cyclic group consisting of a specified number of ring atoms (e.g., 3-6, 4-10, 4-7, 7-10), a specified number of heteroatoms (e.g., 1), a specified heteroatom type (N, O, or S), and either monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more ring-bridged rings, fused rings, or spirocyclic systems), connected to the rest of the molecule by a carbon atom or heteroatom. The "heterocyclic alkyl" described in this invention can be a 3-6 membered heterocyclic alkyl, a 4-10 membered heterocyclic alkyl, a 4-7 membered monocyclic heterocyclic alkyl, or a 7-10 membered bicyclic heterocyclic alkyl. Examples of 3-6 membered heterocyclic alkyl groups in this invention include, but are not limited to, azirrobutyl, oxobutyl, and tetrahydrofuranyl.

[0181] The term "heterocyclic alkylene" refers to a divalent heterocyclic alkylene group, where the definition of heterocyclic alkylene is as described above, such as 4-10-membered heterocyclic alkylene, 4-7-membered monocyclic heterocyclic alkylene, or 7-10-membered bicyclic heterocyclic alkylene. Specific heterocyclic alkylene groups include, but are not limited to, those mentioned above. wait.

[0182] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of the present invention as defined above, and the salt possesses the desired pharmacological activity. Such salts include acid addition salts that form with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which can be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0183] The term "optionally" means that the event or condition subsequently described may, but is not required, occur, and the description includes both the possibility that said event or condition occurs and the possibility that said event or condition does not occur. For example, the term "optionally substituted by one or more substituents" means that it may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on a particular atom are substituted by a substituent.

[0184] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0185] The term "therapeutic effective dose" refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0186] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0187] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0188] The term "prevention" refers to reducing the risk of developing a disease.

[0189] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0190] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application may be realized and obtained by means of the methods described in the description.

[0191] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0192] The reagents and raw materials used in this invention are all commercially available.

[0193] The positive and progressive effects of this invention are as follows: Compared with the prior art, this invention has one or more of the following beneficial effects:

[0194] The compounds provided by this invention exhibit good inhibitory activity against TNF-α-induced NF-κB activation and can be used as TNF-α inhibitors for the prevention and / or treatment of TNF-α-related diseases. Furthermore, experiments have shown that the compounds of this invention also possess superior pharmacokinetic properties, lower risk of CYP-450 enzyme inhibition, lower risk of hERG inhibition, and good solubility or in vitro metabolic stability compared to structurally similar positive reference compounds. Detailed Implementation

[0195] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0196] 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. NMR measurements were performed using a Bruker Avance Neo 400 MHz NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d₆) or deuterated chloroform (CDCl₃) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0197] LCMS measurements were performed using SHIMADZU LCMS-2020.

[0198] Reversed-phase preparative liquid chromatography was performed using a Shimadzu LC20AP column and detected using a Kromasil Eternity XT (4250*80mm*10um) column.

[0199] Liquid chromatography was performed using an Agilent-1260 chromatographic column with a Chiralpak AD-3 50×4.6mm column.

[0200] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products, or can be synthesized using or in accordance with methods known in the art, or can be purchased from reagent companies such as Aladdin, Bidex Pharmaceuticals, and WuXi AppTec.

[0201] Synthesis of intermediate A1:

[0202] Synthesis route:

[0203] Synthesis of intermediate A1-3: Compound A1-1 (37.5 g, 187 mmol) was dissolved in acetonitrile (800 mL), and a solution of potassium hydroxide (209 g, 3.73 mol) dissolved in water (800 mL) was slowly added at 0°C. Then, compound A1-2 (79.7 g, 298 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0°C for half an hour. The reaction solution was then stirred at 0°C for 1 hour and at 25°C for 0.5 hours. The reaction solution was diluted with 500 mL of water and extracted three times with 300 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. After column purification, compound A1-3 was obtained as a pale yellow oily liquid, 30 g, yield 64%. 1 H NMR (400MHz, CDCl3) δ10.28 (s, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.36-7.32 (m, 1H), 7.19-7.17 (m, 1H), 6.73-6.34 (m, 1H).

[0204] Synthesis of intermediate A1-5: Compounds A1-3 (30 g, 120 mmol) and A1-4 (15.9 g, 131 mmol) were dissolved in anhydrous tetrahydrofuran (600 mL). Anhydrous potassium phosphate (76.1 g, 359 mmol) and dipotassium hydrogen phosphate (62.5 g, 359 mmol) were added at room temperature. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filter cake was washed three times with 100 mL of dichloromethane. The filtrates were combined, evaporated to dryness, and purified by column chromatography to give compound A1-5 as a pale yellow oil, 41 g, yield 97%. 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.58(d,J=8.0Hz,1H),7.36-7.30(m,1H),7.23(s,1H),6.76-6.38(m,1H),1.30(s,9H).

[0205] Synthesis of intermediate A1-7: Zinc powder (36 g, 551 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and cuprous chloride (6.54 g, 66.1 mmol) was added at room temperature. The reaction mixture was stirred at 70°C for half an hour. After the reaction mixture cooled to 50°C, compound A1-6 (23 g, 138 mmol, 15.2 mL) was slowly added to the reaction mixture at 50°C, and the reaction mixture was stirred at 50°C for another half hour. The reaction mixture was then cooled to 0°C, and a solution of compound 5 (19.5 g, 55.1 mol) dissolved in tetrahydrofuran (50 mL) was slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction solution was filtered, and the residue was washed three times with 100 mL of ethyl acetate. The combined organic phases were diluted with 500 mL of water and extracted three times with 100 mL of ethyl acetate. The combined filtrates were washed with saturated brine, and the organic phase was dried with anhydrous sodium sulfate and evaporated to dryness. The solution was purified by column chromatography and then purified by reverse phase separation (formic acid) to obtain compound A1-7 as a pale yellow oily liquid, 20.4 g, with a yield of 84%. 1 H NMR (400MHz, CDCl3) δ7.44 (d, J = 9.2Hz, 1H), 7.17-7.13 (m, 1H), 7.08 (brs, 1H), 6.79-6.41 (m, 1H), 5.62-5.56 (m, 1H),4.39-4.22(m,1H),4.13-4.06(m,2H),3.36-3.12(m,1H),3.10-2.91(m,1H),1.21-1.17(m,3H),1.13(s,9H).

[0206] Synthesis of intermediate A1-8: Compound A1-7 (30 g, 67.8 mmol) was dissolved in dichloromethane (50 mL), and a dioxane solution of hydrochloric acid (2 M, 200 mL) was added at room temperature. The reaction mixture was stirred at 25°C for 1 hour. After evaporating the reaction solution to dryness, 25.4 g of crude hydrochloride compound A1-8 was obtained as a pale yellow oily liquid. 1 H NMR(400MHz, DMSO-d6)δ8.72(brs,3H),7.57(d,J=7.2Hz,1H),7.45-7.15(m,3H),5.18-5 .16(m,1H),4.06-4.00(m,2H),3.25-3.18(m,1H),3.13-3.04(m,1H),1.13-1.09(m,3H).

[0207] Synthesis of intermediate A1-10: Compound A1-8 (25.4 g, 67.8 mmol) was dissolved in acetonitrile (100 mL), and N,N-diisopropylethylamine (26.3 g, 203 mmol, 35.4 mL) and compound A1-9 (13.1 g, 74.6 mmol) were added at room temperature. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction solution cooled to room temperature, it was filtered, the filtrate was evaporated to dryness, and purified by column chromatography to obtain compound A1-10 as a yellow oily liquid, 27 g, yield 81%.

[0208] Liquid chromatography data: Instrument: Agilent-1260; Column: Chiralpak AD-3 50×4.6mm; Mobile phase: Phase A was carbon dioxide, Phase B was ethanol (0.05% diethanolamine), gradient elution was used, with B ranging from 5% to 40% in A; Flow rate: 3 mL / min; Elution time: 0.887 min. 1 H NMR (400MHz, CDCl3) δ8.97-8.88(m,1H),8.08(d,J=8.8Hz,1H),7.47-7.45(m,1H),7.21-7.14(m,2H),7.08(s,1H),6 .84-6.44(m,2H),5.85-5.79(m,1H),4.18-4.11(m,2H),3.30-3.17(m,1H),2.94-2.90(m,1H),1.22(t,J=7.2Hz,3H). LC-MS(ESI)m / z:493.0[M] + .

[0209] Synthesis of intermediate A1-11: Compound A1-10 (33 g, 66.8 mmol) was dissolved in tetrahydrofuran (400 mL), and a 1 M toluene solution (1 M, 200 mL) of diisobutylaluminum hydride was slowly added dropwise at -78 °C. The reaction mixture was then stirred at -78 °C for 2 h, at 0 °C for 1 h, and at 25 °C for 1 h. The reaction mixture was then slowly added to 500 mL of saturated ammonium chloride under a nitrogen atmosphere at 0 °C with stirring and quenching; the reaction mixture was then stirred at 25 °C for half an hour. The reaction mixture was diluted with 500 mL of ethyl acetate, filtered, and then extracted three times with 200 mL of ethyl acetate. The combined filtrates were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. After purification by column chromatography, compound A1-11 was obtained as a yellow oily liquid, 28.6 g, yield 95%. 1H NMR (400MHz, CDCl3) δ9.01-8.78(m,1H),8.09(d,J=8.8Hz,1H),7.51-7.37(m,1H),7.20-7.10(m,2H),7.04- 6.93(m,1H),6.80-6.35(m,2H),5.59-5.47(m,1H),3.86-3.75(m,2H),2.48-2.32(m,1H),2.28-2.17(m,1H).

[0210] Synthesis of intermediate A1-12: Compound A1-11 (28.6 g, 63 mmol) was dissolved in ethyl acetate (400 mL), and 2-iodobenzoic acid (43.4 g, 155 mmol) was added at room temperature. The reaction mixture was stirred at 70 °C for 12 hours. After the reaction solution cooled to room temperature, it was filtered, and the filter cake was washed three times with 50 mL of dichloromethane. The filtrates were combined, evaporated to dryness, and purified by column chromatography to obtain compound A1-12 as a yellow oily liquid, 28.1 g, yield 99%. 1 H NMR (400MHz, CDCl3) δ9.81 (s, 1H), 8.90-8.75 (m, 1H), 8.08 (d, J = 9.2Hz, 1H), 7.47-7.45 (m, 1H), 7.22- 7.14(m,2H),7.10(s,1H),6.87-6.47(m,2H),5.95-5.89(m,1H),3.52-3.46(m,1H),3.15-2.94(m,1H).

[0211] Synthesis of intermediate A1-13: Compound A1-12 (28.1 g, 62.5 mmol), triethylamine (632 mg, 6.25 mmol, 0.87 mL), and zinc diiodide (1.99 g, 6.25 mmol) were dissolved in dichloromethane (300 mL), and trimethylcyanosilane (12.4 g, 125 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was slowly added to 300 mL of saturated sodium bicarbonate aqueous solution while stirring and quenching. The mixture was extracted three times with 200 mL of dichloromethane, and the combined organic phases were washed with saturated brine. The mixture was then dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain compound A1-13 as a reddish-brown oil, 32 g, yield 93%. 1H NMR (400MHz, CDCl3) δ9.10-8.66(m,1H),8.11(d,J=8.8Hz,1H),7.48-7.46(m,1H),7.23-7.13(m,2H),7.13- 6.96(m,1H),6.85-6.45(m,2H),5.69-5.56(m,1H),4.71-4.51(m,1H),2.77-2.29(m,2H),0.23-0.16(m,9H).

[0212] Synthesis of intermediate A1-14: Compound A1-13 (32 g, 58.3 mmol) was dissolved in anhydrous ethanol (300 mL), and anhydrous tin dichloride (55.3 g, 292 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction solution cooled to room temperature, it was evaporated to dryness, and then diluted with 1000 mL of saturated sodium bicarbonate aqueous solution and 1000 mL of ethyl acetate while stirring. The mixture was filtered, extracted three times with 500 mL of ethyl acetate, and the combined organic phases were washed with saturated brine. The solution was then dried over anhydrous sodium sulfate and evaporated to dryness to give 24 g of crude compound A1-14 as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ7.73-7.58(m,2H),7.52-7.41(m,2H),7.22-7.11(m,2H),7.01-6 .51(m,2H),6.10-6.00(m,1H),5.43-5.22(m,1H),3.27-3.08(m,1H),2.95-2.66(m,1H).

[0213] Synthesis of intermediate A1-15: Compound A1-14 (20 g, 46.6 mmol) was dissolved in tetrahydrofuran (400 mL), and 1,8-diazabicyclo[5.4.0]undecane-7-ene (14.2 g, 93.1 mmol, 14 mL) and diphenyl azidophosphate (19.2 g, 69.8 mmol) were reacted at 0°C with stirring at 25°C for 1 h, followed by stirring at 50°C for 12 h. The reaction mixture was used directly in the next step to give compound A1-15, 21.1 g, as a brown mixture.

[0214] Synthesis of intermediate A1-16: Compound A1-15 (21.1 g, 46.4 mmol) was dissolved in tetrahydrofuran (400 mL) and water (80 mL), and triphenylphosphine (18.3 g, 69.6 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was evaporated to dryness, then diluted with 300 mL of water and 200 mL of ethyl acetate, and extracted three times with 150 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to give compound A1-16 as a gray solid, 16 g, yield 80%. 1 H NMR(400MHz,DMSO-d6)δ7.70-7.41(m,3H),7.22-7.10(m,3H),7.05-6.45(m,2H),6.3 9-6.02(m,1H),4.75-4.47(m,1H),3.13-3.01(m,1H),2.85-2.55(m,1H),2.54(s,1H).

[0215] Synthesis of intermediate A1-17: Compound A1-16 (11 g, 25.7 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (7.79 g, 77.0 mmol) and BOC anhydride (di-tert-butyl dicarbonate) (8.4 g, 38.5 mmol, 8.8 mL) were added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction solution was diluted with 100 mL of water, extracted three times with 150 mL of dichloromethane, and the filtrates were combined and washed with saturated brine. The mixture was then dried over anhydrous sodium sulfate, evaporated to dryness, purified by column chromatography, and then purified by reverse-phase preparative separation (neutral) to give compound A1-17 as a white solid, 6 g, yield 44%. 1 H NMR(400MHz,DMSO-d6)δ7.71-7.59(m,2H),7.53-7.40(m,2H),7.26-7.06(m,2H),6.80-6.45(m,1H),6.3 6-6.09(m,1H),5.58-5.15(m,1H),3.30-3.10(m,1H),2.96-2.62(m,1H),2.54(s,1H),1.51-1.34(m,9H).

[0216] Synthesis of intermediate A1-18: Compound A1-17 (4 g, 7.56 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (415 mg, 0.57 mmol) and potassium acetate (1.11 g, 11.4 mmol) were dissolved in dioxane (40 mL) and water (5 mL) and placed in a 100 mL autoclave. The autoclave was first purged with nitrogen several times, then with carbon monoxide several times, and finally stirred at carbon monoxide (1 MPa) pressure and 110 °C for 12 hours. After the reaction solution cooled to room temperature, it was diluted with 50 mL of water and 50 mL of ethyl acetate, filtered, and the pH of the filtrate was adjusted to 6 with 1 mol of dilute hydrochloric acid aqueous solution. The filtrate was extracted three times with 30 mL of ethyl acetate, and the combined organic phases were washed with saturated brine. Then, anhydrous sodium sulfate was added and the solution was dried and evaporated to dryness. Then, 50 mL of petroleum ether and 10 mL of ethyl acetate were added and the solution was stirred. The mixture was filtered, and the filtrate was evaporated to dryness. The solution was then dissolved in dichloromethane and purified by TLC. The crude products were combined and purified by reverse phase separation (formic acid), and then purified by reverse phase separation (neutral) to obtain compound A1-18 as a pale yellow solid, 3 g, with a yield of 80%. 1 H NMR(400MHz,DMSO-d6)δ7.62-7.51(m,3H),7.24-7.02(m,3H),6.88-6.31(m,2H),6.19-6 .00(m,1H),5.48-5.24(m,1H),2.97-2.77(m,1H),2.73-2.58(m,1H),1.49-1.38(m,9H). LC-MS(ESI)m / z:494.2[M+H] + .

[0217] Synthesis of intermediate A1-19: Compound A1-18 (3 g, 6.07 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride solution (2 M, 30 mL) was added at room temperature. The reaction mixture was stirred at 25°C for 1 hour. After evaporating the reaction solution to dryness, 3.3 g of crude hydrochloride compound A1-19 was obtained as a pale yellow solid. LC-MS (ESI) m / z: 394.1 [M+H] + .

[0218] Synthesis of intermediate A1-20: Compound A1-19 (1.1 g, 2.56 mmol) and triethylamine (1.03 g, 10.2 mmol, 1.42 mL) were dissolved in N,N-dimethylformamide (10 mL), and n-butylphosphine anhydride (50% ethyl acetate solution) (2.03 g, 2.81 mmol, 50% purity) was added at room temperature. The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was diluted with 50 mL of water, extracted three times with 50 mL of ethyl acetate, and the combined filtrates were washed with saturated brine. The mixture was then dried over anhydrous sodium sulfate, evaporated to dryness, and purified by reverse phase separation (neutral) to give compound A1-20 as a white solid, 300 mg, yield 31%. 1 H NMR(400MHz, CDCl3)δ8.42(d,J=8.0Hz,1H),7.64-7.62(m,1H),7.53-7.51(m,1H),7.47-7.42(m,2H),7.41-7.37(m,1H) ,7.20-7.18(m,1H),7.04-6.65(m,1H),6.29-6.27(m,1H),4.93(t,J=6.8Hz,1H),3.47-3.41(m,1H),2.86-2.82(m,1H). LC-MS(ESI)m / z:376.1[M+H] + .

[0219] Synthesis of intermediate A1: Compound A1-20 (600 mg, 1.6 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydrogen (128 mg, 3.19 mmol, 60% purity) was added at 0°C. The reaction mixture was stirred at 0°C under a nitrogen atmosphere for half an hour. Then, iodomethane (680 mg, 4.79 mmol, 0.30 mL) was added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with 50 mL of water, extracted three times with 30 mL of ethyl acetate, and the combined filtrates were washed with saturated brine. The mixture was then dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude intermediate A1 as a pale yellow solid, 600 mg, yield 96%. 1 H NMR(400MHz,DMSO-d6)δ8.31-8.24(m,1H),7.79-7.59(m,2H),7.53-7.47(m,2H),7.44-7.41(m,1H),7.22-7 .20(m,1H),6.23(d,J=7.2Hz,1H),5.22(d,J=7.2Hz,1H),3.52-3.45(m,1H),3.33(s,3H),2.82-2.79(m,1H). LC-MS(ESI)m / z:390.0[M+H] + .

[0220] Synthesis of intermediate A2:

[0221] Synthesis route:

[0222] Synthesis of intermediate A2: Compound A1 (120 mg, 308 μmol), bis-pinacol borate (156.4 mg, 616 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (52.2 mg, 61.6 μmol), and potassium acetate (60.4 mg, 616 μmol) were placed in a 50 mL flask, and methoxy-cyclopentane (8 mL) was added. The mixture was stirred at 90 °C for 12 hours under nitrogen protection. The reaction mixture was filtered, and the filter cake was washed with dichloromethane and discarded. The filtrate and washings were evaporated to dryness. The crude compound A2, 140 mg, was obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 3). MS-ESI calculated value [M+H] + 482.2, measured value 482.2.

[0223] Example 1: Synthesis of Compound 1

[0224] Synthesis route:

[0225] Synthesis of intermediates 1-3: Compound 1-1 (1.9 g, 9.49 mmol) and compound 1-2 (1.84 g, 9.49 mmol) were placed in a 100 mL flask, and triethylamine (2.88 g, 28.5 mmol) and ethanol (30 mL) were added sequentially. The mixture was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give compound 1-3 as a colorless oil, 3.38 g, yield 99%. 1 H NMR(400MHz, CDCl3)δ8.27(s,2H),4.53-4.46(m,1H),4.45-4.37(m,1H),4.36-4.24(m,1H), 3.99-3.78(m,1H),3.24-3.09(m,2H),3.07-2.94(m,1H),1.47(s,9H),1.12(d,J=6.4Hz,3H).

[0226] Synthesis of intermediates 1-4: Compound 1-3 (3 g, 8.40 mmol) was placed in a 100 mL flask, and 50 mL of 2 M dioxane hydrochloride solution was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was evaporated to dryness to give compound 1-4 as a white solid, 2.45 g, yield 99%. 1H NMR(400MHz,DMSO-d6)δ9.85-9.52(m,2H),8.56-8.51(m,2H),4.61-4.45(m,2H) ,3.42-3.21(m,3H),3.19-3.09(m,1H),3.04-2.91(m,1H),1.29(d,J=6.4Hz,3H). LC-MS(ESI)m / z:257.1[M+H] + .

[0227] Synthesis of intermediates 1-6: Compounds 1-4 (1.95 g, 6.64 mmol), 1-5 (1.01 g, 13.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.55 g, 13.3 mmol), and 1-hydroxybenzotriazole (1.79 g, 13.3 mmol) were placed in a 100 mL flask. N,N-diisopropylethylamine (2.58 g, 19.9 mmol) and dichloromethane (50 mL) were added sequentially, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated to dryness, and purified by reverse phase separation (formic acid) to give compounds 1-6 as a yellow oil, 1.4 g, yield 67%. 1 H NMR(400MHz,DMSO-d6)δ8.58-8.36(m,2H),4.93-4.50(m,2H),4.45-4.24(m,2H),4.18-4 .01(m,2H),3.72-3.50(m,1H),3.39-3.11(m,2H),3.04-2.81(m,1H),1.13-0.97(m,3H). LC-MS(ESI)m / z:315.0[M+H] + .

[0228] Synthesis of intermediates 1-7: Compounds 1-6 (800 mg, 2.54 mmol), bis-pinacolborate (967 mg, 3.81 mmol), potassium acetate (498 mg, 5.08 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (186 mg, 0.25 mmol) were placed in a 100 mL flask, and dioxane (20 mL) was added. The mixture was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 10 / 1) and then slurried with ethyl acetate (3 mL) to give compound 1-7 as a white solid, 380 mg, yield 41%. 1H NMR (400MHz, CDCl3) δ8.62-8.57(m,2H),4.94-4.64(m,2.5H),4.52-4.27(m,0.5H),4.26-4.05(m,2H),3.84- 3.74(m,0.5H),3.70-3.61(m,1H),3.41-3.27(m,1H),3.25-2.95(m,2.5H),1.32(s,12H),1.23-1.15(m,3H). LC-MS(ESI)m / z:363.2[M+H] + .

[0229] Synthesis of Compound 1: Compounds 1-7 (92.9 mg, 257 μmol), compound A1 (50 mg, 128 μmol), potassium carbonate (53.2 mg, 385 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (10.9 mg, 12.8 μmol) were placed in a 50 mL flask. Dioxane (5 mL) and water (0.5 mL) were added. The mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction solution was diluted with water (80 mL) and extracted three times with ethyl acetate (80 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Compound 1 was purified by preparative separation (ammonia) to obtain 33.21 mg of white solid, yield 21.9%. 1 H NMR (400MHz, CDCl3) δ8.60-8.53(m,2H),8.52-8.46(m,1H),7.85-7.71(m,1H),7.61-7.54( m,1H),7.47-7.38(m,1H),7.38-7.28(m,2H),7.05-6.58(m,1H),6.27(d,J=7.2Hz,1H),4.97 (d,J=7.2Hz,1H),4.90-4.79(m,1H),4.77-4.44(m,2H),4.40-4.10(m,2H),3.82-3.66(m,1H ),3.52(s,3H),3.49-3.32(m,2H),3.31-2.95(m,3H),2.91-2.85(m,1H),1.36-1.20(m,3H). LC-MS(ESI)m / z:590.3[M+H] + .

[0230] Example 2: Synthesis of Compound 2

[0231] Synthesis route:

[0232] Synthesis of intermediate 2-3: Compound 2-1 (2.00 g, 9.99 mmol) and triethylamine (2.89 g, 28.5 mmol) were dissolved in anhydrous ethanol (50 mL), and then compound 2-2 (2.71 g, 9.51 mmol) was added. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give compound 2-3, 3.36 g, yield 99%. 1 H NMR (400MHz, CDCl3) δ8.28 (s, 2H), 4.55-4.45 (m, 1H), 4.41 (d, J = 13.2Hz, 1H), 4.32 (s, 1H), 3.9 0(d,J=13.2Hz,1H),3.24-3.07(m,2H),3.06-2.94(m,1H),1.48(s,9H),1.12(d,J=6.8Hz,3H).

[0233] Synthesis of intermediate 2-4: Compound 2-3 (1.5 g, 4.20 mmol) was dissolved in anhydrous dichloromethane (10 mL), and 2 M dioxane hydrochloride solution (42 mL) was added. The mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and 30 mL of water was added. The pH was adjusted to approximately 11 with ammonia. The mixture was then extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 2-4, 1.23 g. MS-ESI calculated value [M+H] + 257.0 and 259.0, measured values ​​[M+H] + 256.9 and 258.9.

[0234] Synthesis of intermediate 2-6: Compound 2-5 (450 mg, 5.29 mmol) and thionyl chloride (3.15 g, 26.5 mmol, 1.92 mL) were added to anhydrous toluene (10 mL), and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and then anhydrous toluene (20 mL) and compound 2-4 (780 mg, 2.66 mmol) were added. The mixture was stirred at 110 °C for 12 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 2-6, 417 mg, was obtained by purification using a silica gel column (petroleum ether / ethyl acetate = 10 / 1–2 / 3), yielding 48%. 1H NMR (400MHz, CDCl3) δ8.31(s,2H),4.90-4.34(m,3H),4.08-3.93(s,0.5H),3.65-3.43(m,3H),3.29-2.89(m,2.5H),1.38-1.12(m,3H).

[0235] Synthesis of intermediate 2-7: Compound 2-6 (100 mg, 308 μmol), bis(phenylphosphine)boronic acid ester (86.2 mg, 339 μmol), potassium acetate (60.6 mg, 617 μmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (45.1 mg, 61.7 μmol) were dissolved in anhydrous dioxane (6 mL). The reaction mixture was stirred at 90°C for 12 hours under nitrogen protection. The reaction solution was filtered, and the residue was discarded to obtain crude compound 2-7, 89.0 mg. MS-ESI calculated value [M+H] + 290.1, measured value [M+H] + 290.2.

[0236] Synthesis of Compound 2: Crude compounds 2-7 (80.0 mg, 277 μmol), compound A (45.0 mg, 115 μmol), potassium carbonate (76.5 mg, 553 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (23.4 mg, 27.7 μmol) were dissolved in dioxane (4.5 mL) and water (0.5 mL). The reaction mixture was stirred at 100°C for 12 hours under nitrogen protection. The reaction solution was filtered, the residue was discarded, and the filtrate was concentrated under reduced pressure. The compound was purified by preparative separation using silica gel chromatography (dichloromethane / methanol = 10 / 1) and reversed-phase chromatography (column: Waters Xbridge C18 150*25mm*10um; mobile phase: A (water, 10mM NH4HCO3) and B (acetonitrile); gradient: B%: 22%-52%), yielding 2,900 mg of the compound, in 13% yield. 1 ¹H NMR (400MHz, CD₃OD) δ 8.61 (s, 2H), 8.40–8.34 (m, 1H), 7.73–7.67 (m, 2H), 7.56–7.10 (m, 4H), 6.42 (d, J = 7.2Hz, 1H), 5.20 (d, J = 7.2Hz, 1H), 4.95–4.91 (m, 1H), 4.85–4.60 (m, 4H), 4.49–3.51 (m, 2H), 3.48 (s, 3H), 3.29–2.64 (m, 4H), 1.33–1.16 (m, 3H). MS-ESI calculated values ​​[M+H] +599.2, measured value [M+H] + 599.2.

[0237] Example 3: Synthesis of Compound 3

[0238] Synthesis route:

[0239] Synthesis of intermediate 3-2: Compound 3-1 (2.00 g, 9.42 mmol) and triethylamine (2.86 g, 28.3 mmol) were dissolved in anhydrous ethanol (50 mL), and then compound 2-2 (2.68 g, 9.42 mmol) was added. The mixture was stirred at 80 °C for 12 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 3-2, 3.45 g, yield 99%. 1 H NMR (400MHz, CDCl3) δ8.26(s,2H),3.84-3.71(m,2H),3.68-3.47(m,4H),1.48(s,9H),1.05-0.93(m,2H),0.88-0.77(m,2H).

[0240] Synthesis of intermediate 3-3: Compound 3-2 (3.45 g, 9.34 mmol) was dissolved in anhydrous dichloromethane (10 mL), and 2 M dioxane hydrochloride solution (46.7 mL) was added. The mixture was stirred at 40 °C for 3 hours. After the reaction solution was evaporated to dryness, 30 mL of water was added, and the pH was adjusted to approximately 11 with ammonia. The mixture was then extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 3-3, 2.43 g, yield 97%. 1 H NMR (400MHz, CDCl3) δ8.25(s,2H),3.80-3.70(m,2H),3.62(s,2H),3.03-2.95(m,2H),0.59(s,4H).

[0241] Synthesis of intermediate 3-5: Compounds 3-3 (500 mg, 1.86 mmol), 3-4 (198 mg, 2.60 mmol), 2-(7-azobenzotriazine)-N,N,N,N'-tetramethylurea hexafluorophosphate (CAS: 148893-10-11.13 g, 2.97 mmol), and N,N-diisopropylethylamine (720 mg, 5.57 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL) and stirred at 25°C for 2 hours. 50 mL of water was added to the reaction mixture, followed by extraction three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The filter cake was dissolved in anhydrous tetrahydrofuran (20 mL) and water (10 mL), and sodium hydroxide (844 mg, 21.1 mmol) was added. The mixture was stirred at 25°C for 12 hours. 30 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by pulping (petroleum ether / ethyl acetate = 2 / 1) (10 mL) yielded compound 3-5, 590 mg, 97% yield. 1 H NMR (400MHz, DMSO-d6) δ8.45 (s, 2H), 4.63 (t, J = 5.6Hz, 1H), 4.41-4.00 (m, 2H), 3.94-3.48 (m, 6H), 1.14-0.65 (m, 4H).

[0242] Synthesis of Compound 3: Compounds 3-5 (30.5 mg, 93.1 μmol), crude intermediate A2 (64.0 mg, 133 μmol), potassium carbonate (36.8 mg, 266 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (11.3 mg, 13.3 μmol) were dissolved in dioxane (2 mL) and water (0.2 mL). The mixture was stirred at 100°C for 12 hours under nitrogen protection. The reaction solution was filtered, the residue was discarded, and the filtrate was evaporated to dryness. Compound 3 was purified by preparative separation using silica gel chromatography (dichloromethane / methanol = 10 / 1) and reversed-phase chromatography (column: Waters xbridge C18 150*25mm 10um; mobile phase: A (water, 10mM NH4HCO3) and B (acetonitrile); gradient: B%: 30%-50%) to obtain 15.1 mg of compound 3, yield 26%. 1¹H NMR (400MHz, CD₃OD) δ 8.57 (s, 2H), 8.36 (dd, J = 2.4, 7.2Hz, 1H), 7.74–7.63 (m, 2H), 7.53–7.08 (m, 4H), 6.41 (d, J = 7.2Hz, 1H), 5.20 (d, J = 7.2Hz, 1H), 4.47–4.16 (m, 2H), 4.11–3.65 (m, 6H), 3.60–3.52 (m, 1H), 3.48 (s, 3H), 2.89 (d, J = 14.0Hz, 1H), 1.17–0.90 (m, 4H). MS-ESI calculated values ​​[M+H] + 602.2, measured value [M+H] + 602.2.

[0243] Example 4: Synthesis of Compound 4

[0244] Synthesis route:

[0245] Synthesis of intermediate 4-2: Compound 3-3 hydrochloride (0.40 g, 1.31 mmol) and compound 4-1 (CAS: 1906-57-6, 0.41 g, 2.62 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (0.68 g, 5.24 mmol, 0.91 mL) and N,N,N,N-tetramethylurea hexafluorophosphonium salt (0.75 g, 1.96 mmol) were added at room temperature. The reaction mixture was stirred for 2 hours at room temperature. The reaction solution was quenched with water (50 mL), and then extracted three times with 20 mL of ethyl acetate each time. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1), compound 4-2, 0.38 g, yield 79%, was obtained. 1 H NMR(400MHz, CDCl3)δ8.28(s,2H),4.40-4.33(m,2H),4.01-3.89(m,2H),3.82(s, 2H),3.78-3.76(m,2H),1.42-1.37(m,3H),0.99-0.93(m,2H),0.93-0.87(m,2H).

[0246] Synthesis of intermediate 4-3: Compound 4-2 (0.33 g, 0.89 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and methyl magnesium bromide solution (3 M, 1.04 mL) was slowly added dropwise under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was then quenched by slowly adding 50 mL of saturated ammonium chloride aqueous solution under a nitrogen atmosphere at 0°C, followed by further stirring and quenching under a nitrogen atmosphere at 25°C for 1 hour. The mixture was filtered, and the filter cake was washed three times with 20 mL of ethyl acetate each time. The filtrate was extracted three times with 20 mL of ethyl acetate each time. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1), compound 4-3 was obtained, 0.15 g, yield 47%. 1 H NMR (400MHz, CDCl3) δ8.27(s,2H),3.89-3.87(m,4H),3.72(s,2H),1.48(s,6H),0.95(s,4H).

[0247] Synthesis of Compound 4: Compound 4-3 (40.0 mg, 0.11 mmol) and Compound A2 (54.0 mg, 0.11 mmol) were dissolved in dioxane (5 mL) and water (0.5 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (10 mg, 0.01 mmol) and potassium carbonate (38.9 mg, 0.28 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C for 12 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure and then purified by reverse-phase preparative separation (chromatographic column: Waters Xbridge C18 150*25mm*10um; mobile phase: A (water, 10mM NH4HCO3) and B (acetonitrile); gradient: B%: 25%-55%), yielding compound 4, 33.1 mg, with a yield of 46%. 1H NMR (400MHz, CDCl3) δ8.54(s,2H),8.49(d,J=8.0Hz,1H),7.77(d,J=8.4Hz,1H),7.57(d,J=1.2Hz,1H ),7.44-7.39(m,1H),7.34(dd,J=1.2,8.4Hz,1H),7.30(d,J=8.0Hz,1H),7.01-6.64(m,1H),6.27(d,J =7.2Hz, 1H), 4.97(d, J = 6.8Hz, 1H), 3.99-3.96(m, 2H), 3.94-3.92(m, 2H), 3.82(s, 2H), 3.52(s, 3H), 3.50-3.42(m, 1H), 2.89-2.86(m, 1H), 1.51(s, 6H), 1.02-1.00(m, 2H), 1.00(brs, 2H). MS-ESI calculated values ​​[M+H] + 630.3, measured value 630.3.

[0248] Example 5: Synthesis of Compound 5

[0249] Synthesis route:

[0250] Synthesis of intermediate 5-2: Compound 5-1 (CAS: 83400-91-3, 68.5 mg, 0.37 mmol), N,N-diisopropylethylamine (144 mg, 1.11 mmol, 0.19 mL), 1-hydroxybenzotriazole (75.3 mg, 0.56 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (107 mg, 0.56 mmol) were added to a solution of compound 3-3 (100 mg, 0.37 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 30°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL * 2). All extracted organic phases were combined and concentrated under reduced pressure to obtain a solid crude compound 5-2, 100 mg, which was directly used in the next reaction.

[0251] Synthesis of intermediate 5-3: Dilute hydrochloric acid (2 M, 2 mmol, 1 mL) was added to a THF (2 mL) solution of compound 5-2 (100 mg, 0.25 mmol). The mixture was stirred at 30 °C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give compound 4, 50.0 mg, in 56% yield. MS-ESI calculated value [M+H] + 357.0 and 359.0, measured values ​​[M+H] +357.0 and 359.0.

[0252] Synthesis of Compound 5: Compound 5-3 (20.0 mg, 0.06 mmol), Compound A2 (27.0 mg, 0.06 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (2.37 mg, 0.003 mmol), and potassium carbonate (15.5 mg, 0.11 mmol) were added to a mixed solution of dioxane (0.5 mL) and water (0.05 mL). The mixture was purged with nitrogen and stirred at 100°C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 5, 15.0 mg, was obtained by preparative separation and purification (chromatographic column: Waters xbridge 150*25mm 10um; mobile phase: H2O(10mM NH4HCO3)-ACN; gradient: B%: 28%-48%), with a yield of 42%. 1 H NMR(400MHz,CD3OD)δ8.62-8.57(m,2H),8.40-8.34(m,1H),7.73-7.66(m,2H) ,7.49-7.44(m,3H),7.44-7.12(m,1H),6.42(d,J=7.2Hz,1H),5.20(d,J=7.2Hz ,1H),4.63-4.40(m,1H),4.25-4.08(m,1H),4.00-3.87(m,2H),3.84-3.63(m,5 H), 3.60-3.53 (m, 1H), 3.48 (s, 3H), 2.90 (d, J = 13.6Hz, 1H), 1.53-0.75 (m, 4H). MS-ESI calculated value [M+H] + 632.2, Measured value [M+H] + 632.2.

[0253] Example 6: Synthesis of Compound 6

[0254] Synthesis route:

[0255] Synthesis of intermediate 6-2: Compound 6-1 (200 mg, 1.01 mmol) and compound 1-2 (195 mg, 1.01 mmol) were mixed in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (143 mg, 1.11 mmol) was added under a nitrogen stream. The mixture was stirred at 80°C for 2 hours. The reaction solution was diluted with water (10 mL) and then extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 420 mg of compound 6-2 as a red oil. 1 H NMR (400MHz, CDCl3) δ8.38(s,2H),3.94-3.71(m,1H),3.69-3.54(m,1H),3.51-3.29(m,2H),3.26-3.10(m,2H),2.62(s,2H),1.51(s,9H).

[0256] Synthesis of intermediate 6-3: Compound 6-2 (420 mg, 1.18 mmol) was added to a 2 M, 8 mL solution of dioxane hydrochloride and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to give 340 mg of compound 6-3 as a yellow solid, with a yield of 99%. MS-ESI calculated value [M+H] + 255.0 and 257.0, measured values ​​[M+H] + 254.9 and 256.9.

[0257] Synthesis of intermediate 6-4: Compound 6-3 (340 mg, 1.17 mmol) and N,N-diisopropylethylamine (754 mg, 5.83 mmol) were mixed in N,N-dimethylformamide (5 mL). Compound 1-5 (124 mg, 1.63 mmol) and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (621 mg, 1.63 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product and sodium hydroxide (276 mg, 6.90 mmol) were mixed and added to tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water (10 mL) and then extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to pure ethyl acetate) to give 240 mg of compound 6-4 as a yellow solid, yield 66%. 1¹H NMR (400MHz, DMSO-d⁶) δ 8.54 (s, 2H), 4.63 (t, J = 6.0Hz, 1H), 4.34–4.26 (m, 1H), 4.24–4.15 (m, 1H), 3.94 (td, J = 4.8, 13.2Hz, 1H), 3.68–3.61 (m, 1H), 3.27–3.21 (m, 1H), 3.15–3.09 (m, 2H), 2.45–2.38 (m, 2H). MS-ESI calculated values ​​[M+H] + 313.0 and 315.0, measured values ​​[M+H] + 312.9 and 314.9.

[0258] Synthesis of Compound 6: Compound 6-4 (30.0 mg, 95.8 μmol) and Compound A2 (40.0 mg, 83.1 μmol) were mixed in dioxane (1 mL) and water (0.2 mL). Under a nitrogen atmosphere, methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (16.2 mg, 19.2 μmol) and potassium carbonate (39.7 mg, 287 μmol) were added. The reaction mixture was stirred at 90°C for 14 hours. The reaction solution was concentrated under reduced pressure, and then purified by reversed-phase preparative separation (chromatographic column: Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile; gradient: B%: 28%-58%) to give compound 6, 24.3 mg, yield 49.8%. 1 H NMR(400MHz,DMSO-d6)δ8.71(s,2H),8.31-8.23(m,1H),7.88-7.51(m,3H),7. 50-7.45(m,3H),6.28(d,J=7.2Hz,1H),5.23(d,J=7.2Hz,1H),4.40-4.14(m,2 H),4.03-3.93(m,1H),3.81-3.71(m,1H),3.56-3.46(m,4H),3.41(s,3H),3.2 0-3.12(m,2H),2.82(d,J=13.6Hz,1H),1.26-1.14(m,1H),0.55-0.65(m,1H). MS-ESI calculated value [M+H] + 588.2, measured value [M+H] + 588.2.

[0259] Example 7: Synthesis of Compound 7

[0260] Synthesis route:

[0261] Synthesis of intermediate 7-2: Compound 7-1 (200 mg, 1.00 mmol) and compound 1-2 (193 mg, 1.00 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (258 mg, 2.00 mmol) was added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. The reaction solution was poured into water (3 mL), filtered, and the filter cake was washed with water (2 mL) and dried to give 320 mg of crude compound 7-2 as a white solid, with a yield of 90%. 1 ¹H NMR (400MHz, CDCl₃) δ 8.29 (s, 2H), 3.83 (dd, J = 5.6, 12.0Hz, 2H), 3.73 (d, J = 6.0Hz, 2H), 3.54 (t, J = 4.8Hz, 2H), 3.41–3.24 (m, 2H), 1.98–1.90 (m, 2H), 1.44 (d, J = 8.4Hz, 9H). MS-ESI calculated values ​​[M+H-56] + 301.0 and 303.0, measured value [M+H-56] + 300.9 and 302.9.

[0262] Synthesis of intermediate 7-3: Compound 7-2 (320 mg, 0.90 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (8.00 mmol, 4 mL, 2 M) was added at room temperature. The reaction mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure to give 260 mg of crude compound 7-3 as a white solid, yield 99%. MS-ESI calculated value [M+H] + 257.0 and 259.0, measured values ​​[M+H] + 256.9 and 258.9.

[0263] Synthesis of intermediate 7-4: Compound 7-3 (260 mg, 0.89 mmol), N,N-diisopropylethylamine (572 mg, 4.43 mmol), and compound 1-5 (101 mg, 1.33 mmol) were dissolved in N,N-dimethylformamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (505 mg, 1.33 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (30 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under vacuum to give the crude product. The crude product was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and sodium hydroxide (212 mg, 5.31 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (30 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed twice with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by silica gel column chromatography (ethyl acetate) yielded 230 mg of compound 7-4 as a colorless oily liquid, with a yield of 82%. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.44 (d, J = 5.2Hz, 2H), 4.51–4.45 (m, 1H), 4.06 (d, J = 5.6Hz, 1H), 3.97 (d, J = 5.6Hz, 1H), 3.85 (t, J = 5.6Hz, 1H), 3.82–3.76 (m, 1H), 3.75–3.69 (m, 2H), 3.66–3.60 (m, 1H), 3.49 (t, J = 5.6Hz, 1H), 3.45–3.41 (m, 2H), 1.81–1.68 (m, 2H). MS-ESI calculated values ​​[M+H] + 315.0 and 317.0, measured values ​​[M+H] + 314.9 and 316.9.

[0264] Synthesis of Compound 7: Compound 7-4 (25.0 mg, 0.08 mmol), Compound A2 (38.2 mg, 0.08 mmol), and potassium carbonate (32.9 mg, 0.23 mmol) were dissolved in dioxane (2 mL) and water (0.2 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (6.71 mg, 0.008 mmol) was added at room temperature. The reaction mixture was stirred at 100°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under vacuum. Compound 7, 12.0 mg, was obtained by reversed-phase preparative separation (chromatographic column: Phenomenex Luna C18150*25mm*10μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile); gradient: B%: 23%-53%), with a yield of 25%. 1 H NMR(400MHz, DMSO-d6)δ8.64(d,J=4.0Hz,2H),8.26(dd,J=3.2,6.4Hz,1H),7.87-7.58(m,3H),7.50-7.43(m ,3H),6.27(d,J=6.8Hz,1H),5.22(d,J=7.2Hz,1H),4.48(td,J=5.6,21.6Hz,1H),4.09(d,J=5.6Hz,1H),4.0 0 (d, J = 5.6 Hz, 1H), 3.94 (t, J = 6.8 Hz, 1H), 3.90-3.86 (m, 1H), 3.85-3.76 (m, 2H), 3.71-3.64 (m, 1H), 3.54 (d, J = 4.0 Hz, 1H), 3.51-3.46 (m, 2H), 3.41-3.39 (m, 1H), 3.35 (s, 3H), 2.82 (d, J = 14.0 Hz, 1H), 1.89-1.73 (m, 2H). MS-ESI calculated values ​​[M+H] + 590.2, measured value [M+H] + 590.2.

[0265] Example 8: Synthesis of Compound 8

[0266] Synthesis route:

[0267] Synthesis of intermediate 8-2: Compound 8-1 (200 mg, 1.01 mmol) and compound 1-2 (195 mg, 1.01 mmol) were dissolved in dimethyl sulfoxide (2 mL), and diisopropylethylamine (261 mg, 2.02 mmol) was added under a nitrogen atmosphere. The reaction was carried out at 80 °C for 2 hours. The reaction solution was diluted with water (3 mL), filtered, and the filter cake was dried under reduced pressure to give 330 mg of compound 8-2 as a yellow solid, with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ8.36 (s, 2H), 4.53-4.38 (m, 1H), 4.26 (d, J = 4.8Hz, 1H), 4.21-4.05 (m, 1H), 4.01-3.92 (m, 1H), 3.56(d,J=12.4Hz,1H), 3.44(dt,J=1.6,12.4Hz,1H), 2.80-2.72(m,1H), 2.70-2.64(m,1H), 1.40(d,J=19.2Hz,9H).

[0268] Synthesis of intermediate 8-3: Compound 8-2 (330 mg, 0.93 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (2 M, 4 mL) was added. The reaction was carried out at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to give 270 mg of compound 8-3 as a yellow solid, with a yield of 99%. MS-ESI calculated value [M+H] + 255.0 and 257.0, measured values ​​[M+H] + 255.0 and 257.0.

[0269] Synthesis of intermediate 8-4: Compound 8-3 (270 mg, 0.93 mmol) and diisopropylethylamine (598 mg, 4.63 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound 1-5 (106 mg, 1.39 mmol) and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (528 mg, 1.39 mmol) were added. The reaction was carried out at 25°C for 15 hours. The reaction solution was diluted with water (30 mL) and extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid was then dissolved in tetrahydrofuran (6 mL) and water (2 mL), and sodium hydroxide (215 mg, 5.36 mmol) was added. The reaction was carried out at 25°C for 2 hours. The reaction solution was diluted with water (30 mL), then extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 1 / 1 to pure ethyl acetate) gave 150 mg of compound 8-4 as a white solid, yield 51.7%. 1H NMR(400MHz, CDCl3)δ8.37(s,2H),4.71-4.48(m,2H),4.23-4.01(m,3H),4 .00-3.92(m,1H),3.88-3.78(m,2H),3.05-2.97(m,1H),2.92-2.83(m,1H).

[0270] Synthesis of Compound 8: Compound 8-4 (20.0 mg, 0.06 mmol) and Compound A2 (30.7 mg, 0.06 mmol) were dissolved in dioxane (2 mL) and water (0.2 mL). Potassium carbonate (20.5 mg, 0.19 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (10.8 mg, 0.01 mmol) were added under a nitrogen atmosphere. The reaction was carried out at 90°C for 15 hours. The reaction solution was filtered, concentrated under reduced pressure, and then purified by reversed-phase preparative separation (chromatographic column: Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile); gradient: B%: 26%-56%) to obtain compound 8, 26.5 mg, yield 69%. 1 H NMR(400MHz,DMSO-d6)δ8.70-8.67(m,2H),8.26(dd,J=2.4,6.8Hz,1H),7.88-7.59(m ,3H),7.52-7.43(m,3H),6.30-6.26(m,1H),5.23(d,J=7.2Hz,1H),5.20-5.10(m,1H) ,4.78(s,1H),4.48(s,1H),4.05-3.89(m,4H),3.83-3.68(m,2H),3.52-3.48(m,1H),3.39-3.36(m,3H),2.82(d,J=13.6Hz,1H),2.75-2.68(m,1H),1.62(d,J=8.8Hz,1H). MS-ESI calculated values ​​[M+H] + 588.2, measured value [M+H] + 588.2.

[0271] Example 9: Synthesis of Compound 9

[0272] Synthesis route:

[0273] Synthesis of intermediate 9-2: Compound 9-1 (100 mg, 0.47 mmol) and compound 1-2 (91.1 mg, 0.47 mmol) were dissolved in dimethyl sulfoxide (1 mL). N,N-diisopropylethylamine (122 mg, 0.94 mmol) was added at room temperature, and the mixture was stirred at 80°C for 2 hours. After the reaction solution cooled to room temperature, it was slowly poured into water (3 mL). The suspension was then filtered, and the filter cake was washed twice with water (1 mL). The filter cake was concentrated under reduced pressure to give 140 mg of compound 9-2 as a grayish-white solid, with a yield of 80%. 1 ¹H NMR (400MHz, CDCl₃) δ 8.29 (s, 2H), 4.48–4.21 (m, 4H), 3.24–3.01 (m, 2H), 2.01–1.86 (m, 2H), 1.72–1.64 (m, 2H), 1.49 (s, 9H). MS-ESI calculated values ​​[M+H-56] + 313.0 and 315.0, measured value [M+H-56] + 312.9 and 314.9.

[0274] Synthesis of intermediate 9-3: Compound 9-2 (140 mg, 0.38 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (2 M, 2 mL) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure to give 110 mg of compound 9-3 as a white solid, with a yield of 95%. MS-ESI calculated value [M+H] + 269.0 and 271.0, measured values ​​[M+H] + 268.9 and 270.9.

[0275] Synthesis of intermediate 9-4: Compound 9-3 (110 mg, 0.36 mmol) and N,N-diisopropylethylamine (233 mg, 1.80 mmol, 0.31 mL) were dissolved in N,N-dimethylformamide (2 mL). Compound 1-5 (38.3 mg, 0.50 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (192 mg, 0.50 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was slowly poured into water (30 mL) while stirring and quenching, and then extracted twice with ethyl acetate (20 mL). The organic phases were combined and concentrated under reduced pressure to give the crude product (110 mg, 0.34 mmol). The crude product (110 mg, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and sodium hydroxide (80.7 mg, 2.02 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was slowly poured into water (30 mL) while stirring and quenching, and then extracted twice with ethyl acetate (20 mL). The organic phases were combined and concentrated under reduced pressure. After purification by silica gel plate (ethyl acetate), 100 mg of compound 9-4, a white solid, was given, with a yield of 84.9%. 1 ¹H NMR (400MHz, CDCl₃) δ 8.31 (s, 2H), 4.84 (d, J = 6.0Hz, 1H), 4.54–4.39 (m, 2H), 4.27–4.14 (m, 2H), 4.06 (d, J = 6.0Hz, 1H), 3.16 (d, J = 13.2Hz, 1H), 3.05 (d, J = 12.8Hz, 1H), 2.01–1.89 (m, 2H), 1.86–1.80 (m, 1H), 1.78–1.72 (m, 1H). MS-ESI calculated values ​​[M+H] + 327.0 and 329.0, measured values ​​[M+H] + 326.9 and 328.9.

[0276] Synthesis of Compound 9: Compound 9-4 (30.0 mg, 91.7 μmol) and Compound A2 (44.1 mg, 91.7 μmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (7.76 mg, 9.17 μmol) and potassium carbonate (38.0 mg, 275 μmol) were added at room temperature. The reaction mixture was stirred at 100 °C for 14 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The mixture was purified by reverse-phase preparative separation (Phenomenex Luna C18 150*25 mm 10 μm; mobile phase: A (water, containing 0.225% formic acid) and B (acetonitrile); gradient: B%: 31%-61%). Compound 9 was obtained, 19.0 mg, in a yield of 33%. 1 H NMR (400MHz, CDCl3) δ8.56 (s, 2H), 8.50 (d, J = 8.4Hz, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.58 (s, 1H), 7.47-7 .39(m,1H),7.38-7.29(m,2H),7.05-6.64(m,1H),6.28(d,J=7.2Hz,1H),4.98(d,J=6.8Hz,1H),4.89( d, J = 4.0 Hz, 1H), 4.59 (t, J = 10.8 Hz, 2H), 4.28-4.17 (m, 2H), 4.13-4.05 (m, 1H), 3.53 (s, 3H), 3.51-3.44 (m, 1H), 3.23 (d, J = 12.8 Hz, 1H), 3.12 (d, J = 13.2 Hz, 1H), 2.89 (d, J = 13.6 Hz, 1H), 2.01-1.81 (m, 4H). MS-ESI calculated values ​​[M+H] + 602.2, measured value [M+H] + 602.2.

[0277] Example 10: Synthesis of Compound 10

[0278] Synthesis route:

[0279] Synthesis of intermediate 10⁻²: Compound 10⁻¹ (500 mg, 2.33 mmol) and compound 1⁻² (451 mg, 2.33 mmol) were dissolved in dimethyl sulfoxide (5 mL), and diisopropylethylamine (603 mg, 4.67 mmol) was added under a nitrogen atmosphere. The reaction was carried out at 80 °C for 2 hours. The reaction solution was diluted with water (8 mL), filtered, and the filter cake was dried under reduced pressure to give 850 mg of compound 10⁻² as a yellow solid, with a yield of 98%. 1 H NMR (400MHz, CDCl3) δ8.31(s,2H),3.86-3.78(m,4H),3.67-3.62(m,2H),1.49(s,9H),1.40(s,6H).

[0280] Synthesis of intermediate 10⁻³: Compound 10⁻² (850 mg, 2.29 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (2 M, 10 mL) was added. The reaction was carried out at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to give 700 mg of compound 10⁻³ as a yellow solid, with a yield of 99%. MS-ESI calculated value [M+H] + 271.0 and 273.0, measured values ​​[M+H] + 270.9 and 272.9.

[0281] Synthesis of intermediate 10⁻⁴: Compound 10⁻⁃ (0.70 g, 2.28 mmol) and diisopropylethylamine (1.47 g, 11.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), and compound 1-5 (0.26 g, 3.41 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (1.30 g, 3.41 mmol) were added. The reaction mixture was reacted at 25°C for 96 hours. The reaction solution was diluted with water (50 mL), the pH of the reaction solution was adjusted to 8 with sodium bicarbonate solid, and then extracted three times with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid was then dissolved in tetrahydrofuran (9 mL) and water (3 mL), and sodium hydroxide (0.51 g, 12.8 mmol) was added. The reaction mixture was reacted at 25°C for 2 hours. The reaction solution was diluted with water (30 mL), then extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then purified by reversed-phase preparative separation (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: A (water, 10 mM ammonium bicarbonate) and B (acetonitrile); gradient: B%: 20%-50%), yielding 0.07 g of compound 10⁻⁴ as a white solid, in 10% yield. 1H NMR (400MHz, CDCl3) δ8.34(s,2H),4.12(s,2H),3.91(s,2H),3.74-3.69(m,2H),3.57-3.50(m,2H),1.53(s,6H).

[0282] Synthesis of Compound 10: Compound 10-4 (15.0 mg, 0.05 mmol) and Compound A2 (21.9 mg, 0.05 mmol) were dissolved in dioxane (1 mL) and water (0.1 mL). Potassium carbonate (18.9 mg, 0.14 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (7.71 mg, 0.01 mmol) were added under a nitrogen atmosphere. The reaction was carried out at 90°C for 15 hours. The reaction solution was filtered, concentrated under reduced pressure, and then purified by reverse-phase preparative separation (chromatographic column: Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile; gradient: B%: 34%-64%) to obtain compound 10, 12.3 mg, yield 43%. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.66 (s, 2H), 8.26 (dd, J = 2.4, 6.8Hz, 1H), 7.88–7.57 (m, 3H), 7.50–7.45 (m, 3H), 6.27 (d, J = 6.8Hz, 1H), 5.22 (d, J = 7.2Hz, 1H), 4.06 (s, 2H), 3.95 (s, 2H), 3.66 (s, 5H), 3.53–3.48 (m, 2H), 3.32–3.30 (m, 1H), 2.82 (d, J = 13.6Hz, 1H), 1.43 (s, 6H). MS-ESI calculated values ​​[M+H] + 604.3, measured value [M+H] + 604.3.

[0283] Example 11: Synthesis of Compound 11

[0284] Synthesis route:

[0285] Synthesis of intermediate 11-2: Compound 11-1 (100 mg, 0.50 mmol) and compound 1-2 (97.6 mg, 0.50 mmol) were dissolved in dimethyl sulfoxide (1 mL), and N,N-diisopropylethylamine (130 mg, 1.01 mmol) was added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. The reaction solution was poured into water (3 mL), filtered, and the filter cake was washed with water (2 mL) and dried to give 150 mg of crude compound 11-2 as a white solid, with a yield of 84%. 1 ¹H NMR (400MHz, CDCl₃) δ 8.29 (s, 2H), 4.91 (s, 1H), 4.71–4.48 (m, 1H), 3.63–3.51 (m, 2H), 3.46–3.30 (m, 2H), 2.00–1.89 (m, 2H), 1.58 (s, 9H). MS-ESI calculated value [M+H-56] + 299.0 and 301.0, measured values ​​[M+H-56] + 298.9 and 300.9.

[0286] Synthesis of intermediate 11-3: Compound 11-2 (150 mg, 0.42 mmol) was dissolved in dichloromethane (0.5 mL), and dioxane hydrochloride solution (2 M, 2 mL) was added at room temperature. The reaction mixture was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure to give 120 mg of crude compound 11-3 as a white solid, yield 97%. MS-ESI calculated value [M+H] + 255.0 and 257.0, measured values ​​[M+H] + 254.9 and 256.9.

[0287] Synthesis of Intermediate 11-4: Compound 11-3 (120 mg, 0.41 mmol), N,N-diisopropylethylamine (266 mg, 2.06 mmol), and compound 1-5 (47.0 mg, 0.62 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (235 mg, 0.62 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (30 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases were concentrated under vacuum to give the crude product. The crude product was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and sodium hydroxide (92.0 mg, 2.30 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (20 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was then dissolved in ethyl acetate (3 mL), stirred at room temperature for 10 minutes, filtered, and the filter cake was dried to give 70.0 mg of the crude compound 11-4 as a reddish-brown solid, with a yield of 54.4%. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.45 (d, J = 2.0Hz, 2H), 4.93–4.79 (m, 2H), 4.72–4.58 (m, 1H), 4.16–4.00 (m, 1H), 3.95–3.81 (m, 1H), 3.54–3.48 (m, 2H), 3.45–3.42 (m, 1H), 3.29–3.20 (m, 1H), 2.03–1.81 (m, 2H). MS-ESI calculated values ​​[M+H] + 313.0 and 315.0, measured values ​​[M+H] + 312.9 and 314.9.

[0288] Synthesis of Compound 11: Compound 11-4 (20.0 mg, 0.06 mmol), Compound A2 (30.7 mg, 0.06 mmol), and potassium carbonate (26.5 mg, 0.19 mmol) were dissolved in dioxane (2 mL) and water (0.2 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (5.41 mg, 0.006 mmol) was added at room temperature. The reaction mixture was stirred at 100°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under vacuum. Compound 11, 23.7 mg, was obtained by reversed-phase preparative separation (chromatographic column: Phenomenex Luna C18150*25mm*10μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile); gradient: B%: 13%-43%), with a yield of 63%. 1 H NMR(400MHz, DMSO-d6)δ8.63(d,J=2.4Hz,2H),8.26(dd,J=2.4,6.8Hz,1H),7.87-7.57(m, 3H),7.50-7.43(m,3H),6.27(d,J=7.2Hz,1H),5.22(d,J=7.2Hz,1H),4.99(d,J=27.2Hz,1 4.88-4.57 (m, 2H), 4.19-4.05 (m, 1H), 3.98-3.83 (m, 1H), 3.61-3.57 (m, 1H), 3.55-3.47 (m, 2H), 3.42 (d, J = 11.6 Hz, 2H), 3.35 (s, 3H), 2.82 (d, J = 13.6 Hz, 1H), 2.06-1.83 (m, 2H). MS-ESI calculated values ​​[M+H] + 588.2, measured value 588.2.

[0289] Example 12: Synthesis of Compound 12

[0290] Synthesis route:

[0291] Synthesis of intermediate 12-2: Compound 12-1 (200 mg, 1.01 mmol) and compound 1-2 (195 mg, 1.01 mmol) were mixed in dimethyl sulfoxide (2 mL). N,N-diisopropylethylamine (143 mg, 1.11 mmol) was added under a nitrogen stream, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into water (3 mL), filtered, and the precipitate was collected. The precipitate was washed twice with water (1 mL) and dried under vacuum to give 317 mg of compound 12-2 as a white solid, with a yield of 88%. 1¹H NMR (400MHz, CDCl₃) δ 8.36 (s, 2H), 4.55–4.35 (m, 2H), 4.04–3.91 (m, 2H), 3.54–3.36 (m, 2H), 2.83–2.72 (m, 1H), 1.61 (d, J = 8.8 Hz, 1H), 1.42 (s, 9H). MS-ESI calculated value [M+H-56] + And 301.0, measured value [M+H-56] + 298.9 and 300.9.

[0292] Synthesis of intermediate 12-3: Compound 12-2 (317 mg, 0.89 mmol) was added to a dioxane hydrochloride solution (8.00 mmol, 4 mL, 2 M), and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to give 227 mg of compound 12-3 as a yellow solid, with a yield of 100%. MS-ESI calculated value [M+H] + 255.0 and 257.0, measured values ​​[M+H] + 254.9 and 256.9.

[0293] Synthesis of Intermediate 12-4: Compound 12-3 (227 mg, 0.89 mmol, hydrochloride) and N,N-diisopropylethylamine (576 mg, 4.46 mmol) were mixed in N,N-dimethylformamide (3 mL). Compound 1-5 (68.0 mg, 0.89 mmol) and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (509 mg, 1.34 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product and sodium hydroxide (192 mg, 4.81 mmol) were mixed and added to tetrahydrofuran (6 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (30 mL) and then extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting solid was added to ethyl acetate (5 mL) and stirred at room temperature for 10 minutes. The mixture was then filtered again, and the filter cake was dried under vacuum to give 140 mg of compound 12-4 as a yellow solid, with a yield of 50.2%. 1¹H NMR (400MHz, CDCl₃) δ 8.37 (s, 2H), 4.60–4.45 (m, 2H), 4.19–4.10 (m, 2H), 4.06 (d, J = 10.8 Hz, 1H), 4.04–3.96 (m, 1H), 3.70–3.61 (m, 1H), 3.53–3.43 (m, 1H), 3.35 (d, J = 11.2 Hz, 1H), 3.07–2.74 (m, 2H). MS-ESI calculated values ​​[M+H] + 313.0 and 315.0, measured values ​​[M+H] + 312.9 and 314.9.

[0294] Synthesis of Compound 12: Compound 12-4 (30.0 mg, 95.8 μmol) and Compound A2 (40.0 mg, 83.1 μmol) were mixed in dioxane (2 mL) and water (0.4 mL). Under a nitrogen atmosphere, methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (8.11 mg, 9.58 μmol) and potassium carbonate (39.7 mg, 287 μmol) were added. The reaction mixture was stirred at 90°C for 14 hours. The reaction solution was concentrated under reduced pressure, and then purified by reversed-phase preparative separation (chromatographic column: Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile; gradient: B%: 23%-53%) to give compound 12 as a white solid, 24.3 mg, yield 49.8%. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.69 (s, 2H), 8.31–8.21 (m, 1H), 7.87–7.51 (m, 3H), 7.50 (s, 3H), 6.27 (d, J = 7.2Hz, 1H), 5.22 (d, J = 7.0Hz, 1H), 4.53–4.37 (m, 3H), 4.12–3.95 (m, 2H), 3.94–3.81 (m, 2H), 3.57–3.47 (m, 3H), 3.40–3.36 (m, 3H), 2.82 (d, J = 13.6Hz, 1H), 2.76–2.68 (m, 1H), 1.62 (d, J = 8.8Hz, 1H). MS-ESI calculated values ​​[M+H] + 588.2, measured value [M+H] + 588.2.

[0295] Example 13: Synthesis of Compound 13

[0296] Synthesis route:

[0297] Synthesis of intermediate 13-2: Compound 13-1 (200 mg, 0.94 mmol) was dissolved in dimethyl sulfoxide (2 mL), and compound 1-2 (182 mg, 0.94 mmol) and N,N-diisopropylethylamine (243 mg, 0.33 mmol) were added. The reaction was carried out under nitrogen protection at 80°C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phase was washed twice with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 340 mg of crude compound 13-2 as a brown solid. 1 ¹H NMR (400MHz, CDCl₃) δ 8.23 ​​(s, 2H), 4.71–4.53 (m, 2H), 3.90–3.59 (m, 2H), 3.12–2.92 (m, 2H), 1.95–1.86 (m, 2H), 1.79–1.74 (m, 2H), 1.39 (s, 9H). MS-ESI calculated value [M+H-56] + 313.0 and 315.0, measured value [M+H-56] + 313.0 and 315.0.

[0298] Synthesis of intermediate 13-3: Compound 13-2 (340 mg, 0.92 mmol) was dissolved in dichloromethane (3 mL), and a 2M dioxane hydrochloride solution (2 M, 6 mL) was added. The reaction was carried out under nitrogen protection at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure to give 247.6 mg of compound 13-3 as a white solid. MS-ESI calculated value [M+H] + 269.0 and 271.0, measured values ​​[M+H] + 269.0 and 271.0.

[0299] Synthesis of intermediate 13-4: Compound 13-3 (247.6 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound N,N-diisopropylethylamine (594 mg, 4.60 mmol), compound 1-5 (140 mg, 1.84 mmol), and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (699 mg, 1.84 mmol) were added. The reaction was carried out under nitrogen protection at 25°C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed once with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 300 mg of the intermediate compound, a brown oily substance. This intermediate compound was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and sodium hydroxide (220 mg, 5.50 mmol) was added. The reaction was carried out at 25°C for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and purified by column chromatography (ethyl acetate) to give 120 mg of compound 13-4 as a white solid, with a yield of 40%. MS-ESI calculated value [M+H] + 327.0 and 329.0, measured values ​​[M+H] + 327.0 and 329.0.

[0300] Synthesis of Compound 13: Compound 13-4 (40.8 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). Compound A2 (50.0 mg, 0.10 mmol), potassium carbonate (43.0 mg, 0.31 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (18.0 mg, 0.02 mmol) were added. The reaction was carried out under nitrogen protection at 90°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by reverse-phase preparative separation (Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile); gradient: B%: 32%-62%). Compound 13, 41.2 mg, was obtained in a yield of 68.5%. 1H NMR(400MHz,DMSO-d6)δ8.69(s,2H),8.31-8.24(m,1H),7.90-7.52(m,3H),7.51- 7.44(m,3H),6.28(d,J=7.2Hz,1H),5.24(d,J=7.2Hz,1H),4.88-4.71(m,2H),4.68 -4.52 (m, 1H), 4.29–4.10 (m, 2H), 3.98 (d, J = 15.6 Hz, 1H), 3.61–3.47 (m, 2H), 3.36 (s, 3H), 3.28 (s, 1H), 2.98–2.78 (m, 2H), 2.00–1.79 (m, 3H), 1.65 (t, J = 8.0 Hz, 1H). MS-ESI calculated values ​​[M+H] + 602.2, measured value [M+H] + 602.2.

[0301] Example 14: Synthesis of Compound 14

[0302] Synthesis route:

[0303] Synthesis of intermediate 14-2: Compound 14-1 (1.00 g, 4.71 mmol) and compound 1-2 (0.91 g, 4.71 mmol) were dissolved in dimethyl sulfoxide (10 mL). N,N-diisopropylethylamine (1.22 g, 9.42 mmol) was added at room temperature, and the mixture was stirred at 80 °C for 2 hours. After the reaction solution cooled to room temperature, it was slowly poured into water (30 mL). The suspension was then filtered, and the filter cake was washed twice with water (5 mL). The filter cake was concentrated under reduced pressure to give 1.70 g of compound 14-2 as a brown solid, with a yield of 98%. 1 ¹H NMR (400MHz, CDCl₃) δ 8.27 (s, 2H), 3.85–3.77 (m, 2H), 3.63 (s, 2H), 3.62–3.57 (m, 2H), 1.49 (s, 9H), 1.01–0.95 (m, 2H), 0.86–0.80 (m, 2H). MS-ESI calculated value [M+H-56] + 313.0 and 315.0, measured value [M+H-56] + 312.9 and 314.9.

[0304] Synthesis of intermediate 14-3: Compound 14-2 (1.70 g, 4.60 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride solution (2 M, 17 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure to give 1.40 g of compound 14-3 as a grayish-white solid, with a yield of 99%. MS-ESI calculated value [M+H] + 269.0 and 271.0, measured values ​​[M+H] + 269.0 and 271.0.

[0305] Synthesis of intermediate 14-5: Compound 14-3 (200 mg, 0.65 mmol) and N,N-diisopropylethylamine (423 mg, 3.27 mmol, 0.57 mL) were dissolved in N,N-dimethylformamide (4 mL). Compound 14-4 (100 mg, 0.98 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (373 mg, 0.98 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was slowly poured into water (30 mL) while stirring and quenching, and then extracted twice with ethyl acetate (20 mL). The organic phases were combined and concentrated under reduced pressure to give crude product (230 mg, 0.65 mmol). The crude product (230 mg, 0.65 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and sodium hydroxide (156 mg, 3.91 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was slowly poured into water (30 mL) while stirring and quenching, and then extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After purification by slurrying with ethyl acetate (5 mL), 110 mg of a grayish-white solid of compound 14-5 was obtained, with a yield of 48%. 1 ¹H NMR (400MHz, CDCl₃) δ 8.28 (s, 2H), 4.06–3.81 (m, 4H), 3.73 (s, 2H), 1.31–1.21 (m, 2H), 1.11–0.91 (m, 6H). MS-ESI calculated values ​​[M+H] + 353.0 and 355.0, measured values ​​[M+H] + 352.9 and 354.9.

[0306] Synthesis of intermediate 14-6: Compound 14-5 (66.0 mg, 187 μmol) and imidazole (25.4 mg, 374 μmol) were dissolved in dichloromethane (2 mL). A mixture of tert-butyldimethylchlorosilane (56.3 mg, 374 μmol) dissolved in dichloromethane (1 mL) was slowly added dropwise at 0°C. The reaction mixture was stirred at room temperature for 36 hours. The reaction mixture was quenched by slowly pouring it into water (30 mL), followed by extraction twice with dichloromethane (20 mL). The combined organic phases were concentrated under reduced pressure. After purification by silica gel plate (petroleum ether / ethyl acetate = 5 / 1), 40.0 mg of compound 14-6 was obtained, a colorless oily liquid, in 46% yield. 1 ¹H NMR (400MHz, CDCl₃) δ 8.29 (s, 2H), 4.06–3.98 (m, 2H), 3.91–3.82 (m, 2H), 3.72 (s, 2H), 1.23–1.20 (m, 2H), 0.94–0.90 (m, 6H), 0.84 (s, 9H), 0.03 (s, 6H). MS-ESI calculated values ​​[M+H] + 467.1 and 469.1, measured values ​​[M+H] + 467.1 and 469.1.

[0307] Synthesis of intermediate 14-7: Compound 14-6 (20.0 mg, 42.8 μmol) and compound A2 (20.6 mg, 42.8 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). Tetra(triphenylphosphine)palladium (4.94 mg, 4.28 μmol) and potassium carbonate (17.7 mg, 128 μmol) were added at room temperature. The reaction mixture was stirred at 90 °C for 14 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. After purification by silica gel plate (100% ethyl acetate), 20.0 mg of compound 14-7 as a white solid was given, in 63% yield. MS-ESI calculated value [M+H] + 742.3, Measured value [M+H] + 742.4.

[0308] Synthesis of Compound 14: Compound 14-7 (20.0 mg, 27.0 μmol) was dissolved in methanol (1 mL). Potassium fluoride (3.13 mg, 53.9 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. The mixture was purified by reverse-phase preparative separation (Unisil 3-100C18 Ultra 150*50 mm 3 μm; mobile phase: A (water, containing 0.225% formic acid) and B (acetonitrile); gradient: B%: 35%-65%). Compound 14, 9.01 mg, yield 53%. 1¹H NMR (400MHz, CDCl₃) δ 8.53 (s, 2H), 8.50 (d, J = 8.0Hz, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.57 (s, 1H), 7.46–7.39 (m, 1H), 7.36–7.29 (m, 2H), 7.03–6.65 (m, 1H), 6.30 (d, J = 7.2Hz, 1H), 5.06 (d, J = 7.2Hz, 1H), 4.12–3.70 (m, 6H), 3.55 (s, 3H), 3.53–3.46 (m, 1H), 2.90 (d, J = 13.6Hz, 1H), 1.35–1.25 (m, 2H), 1.12–0.96 (m, 6H). MS-ESI calculated values ​​[M+H] + 628.2, measured value [M+H] + 628.3.

[0309] Example 15: Synthesis of Compound 15

[0310] Synthesis route:

[0311] Synthesis of intermediate 15-2: Compound 15-1 (100 mg, 0.47 mmol) was dissolved in dimethyl sulfoxide (1 mL), and compound 1-2 (91.0 mg, 0.47 mmol) and N,N-diisopropylethylamine (121 mg, 0.94 mmol) were added. The reaction was carried out under nitrogen protection at 120°C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phase was washed once with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel plate (PE / EA = 3 / 1) yielded 92.0 mg of compound 15-2 as a colorless oil, with a yield of 53%. 1 ¹H NMR (400MHz, CDCl₃) δ 8.36 (s, 2H), 3.96 (s, 2H), 3.50 (s, 2H), 3.35 (s, 2H), 1.46 (s, 9H), 1.02–0.94 (m, 4H). MS-ESI calculated values ​​[M+H-56]. + 313.0 and 315.0, measured value [M+H-56] + 312.9 and 314.9.

[0312] Synthesis of intermediate 15-3: Compound 15-2 (180 mg, 0.48 mmol) was dissolved in dichloromethane (1 mL), and a 2M solution of dioxane hydrochloride (2 M, 2 mL) was added. The reaction was carried out under nitrogen protection at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure to give 131 mg of compound 15-3 as a white solid. MS-ESI calculated value [M+H]+ 269.0 and 271.0, measured values ​​[M+H] + 269.0 and 271.0.

[0313] Synthesis of Intermediate 15-4: Compound 15-3 (131 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (277 mg, 2.14 mmol), compound 1-5 (65.0 mg, 0.86 mmol), and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (325 mg, 0.86 mmol) were added. The reaction was carried out under nitrogen protection at 25°C for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed once with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 140 mg of the intermediate compound, a brown oily substance. This intermediate compound was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and sodium hydroxide (102 mg, 2.57 mmol) was added. The reaction was carried out at 25°C for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and purified by silica gel column chromatography (ethyl acetate) to give 100 mg of compound 15-4 as a white solid, in 65% yield. MS-ESI calculated value [M+H] + 327.0 and 329.0, measured values ​​[M+H] + 326.9 and 328.9.

[0314] Synthesis of Compound 15: Compound 15-4 (40.8 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). Compound A2 (50.0 mg, 0.10 mmol), potassium carbonate (43.0 mg, 0.31 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (18.0 mg, 0.02 mmol) were added. The reaction was carried out under nitrogen protection at 90°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by reverse-phase preparative separation (henomenex Luna C18 150*25mm*10μm; mobile phase: A (water, 0.225% formic acid) and B (acetonitrile); gradient: B%: 25%-55%). Compound 15 was given as a white solid, 38.0 mg, with a yield of 63.2%. 1¹H NMR (400MHz, DMSO-d⁶) δ 8.73 (s, 2H), 8.33–8.23 (m, 1H), 7.90–7.53 (m, 3H), 7.52–7.45 (m, 3H), 6.28 (d, J = 7.2Hz, 1H), 5.24 (d, J = 7.2Hz, 1H), 4.17–3.93 (m, 4H), 3.60–3.41 (m, 9H), 2.83 (d, J = 13.6Hz, 1H), 1.11–0.87 (m, 4H). MS-ESI calculated values ​​[M+H] + 602.2, measured value [M+H] + 602.3.

[0315] Example 16: Synthesis of Compound 16

[0316] Synthesis route:

[0317] Synthesis of intermediate 16-2: Compound 16-1 (200 mg, 0.88 mmol) was dissolved in dimethyl sulfoxide (6 mL), and N,N-diisopropylethylamine (343 mg, 2.65 mmol) and compound 1-2 (200 mg, 1.03 mmol) were added sequentially. The reaction mixture was reacted at 70 °C for 1 h. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed sequentially with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1–8:1) yielded 320 mg of compound 16-2 as a white solid, 95% yield. 1 ¹H NMR (400MHz, CDCl₃) δ 8.55–8.15 (m, 2H), 4.00–3.82 (m, 2H), 3.64 (d, J = 4.4 Hz, 2H), 3.56–3.40 (m, 2H), 2.51–2.36 (m, 2H), 1.98 (d, J = 2.8 Hz, 2H), 1.83–1.73 (m, 2H), 1.56–1.38 (m, 9H). MS-ESI calculated values ​​[M+H-100]. + 283.1 and 285.1, measured values ​​[M+H-100] + 282.9 and 284.9.

[0318] Synthesis of intermediate 16-3: Compound 16-2 (320 mg, 0.83 mmol) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride solution (2 M, 6 mL) was added. The reaction was carried out at 30°C for 1 hour. The reaction solution was concentrated to give compound 16-3, 226.5 mg of white solid. MS-ESI calculated value [M+H] +283.1 and 285.1, measured values ​​[M+H] + 282.9 and 284.9.

[0319] Synthesis of intermediate 16-4: Compound 16-3 (226.5 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (6 mL), and 2-(7-azobenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (0.59 g, 1.56 mmol) was added. The reaction mixture was stirred at 20 °C for 0.5 h. Then, N,N-diisopropylethylamine (0.61 g, 4.69 mmol) and compound 1-5 (65.0 mg, 0.86 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 16-4. The crude compound 16-4 was dissolved in tetrahydrofuran (10 mL) and water (3 mL), and sodium hydroxide (0.18 g, 4.51 mmol) was added. The reaction mixture was reacted at 20 °C for 2 hours. The reaction solution was poured into water (60 mL) and extracted with ethyl acetate (40 mL). The organic phase was washed successively with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) gave 0.18 g of compound 16-4 as a white solid, in 63.6% yield. MS-ESI calculated value [M+H] + 341.1 and 343.1, measured values ​​[M+H] + 341.0 and 343.0.

[0320] Synthesis of Compound 16: Compound 16-4 (50.0 mg, 0.15 mmol), Compound A2 (70.5 mg, 0.15 mmol), potassium carbonate (60.8 mg, 0.44 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (12.4 mg, 0.01 mmol) were placed in a 10 mL thumb flask. Dioxane (1 mL) and water (0.2 mL) were added at room temperature. The gas inside the flask was purged three times with nitrogen, and the reaction was stirred in a 90°C oil bath for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. Compound 16, 39.2 mg, was obtained by reversed-phase preparative separation (column: Waters xbridge 150*25mm 10μm; mobile phase: A (water, 10mM NH4HCO3) and B (acetonitrile); gradient: B%: 26%-56%), with a yield of 43%. 1H NMR(400MHz,DMSO-d6)δ8.66(s,2H),8.39-8.17(m,1H),7.87-7.50(m,3H),7.50-7.40(m ,3H),6.27(d,J=7.2Hz,1H),5.22(d,J=7.2Hz,1H),4.60(t,J=5.2Hz,1H),4.09(d,J=5.2 Hz, 2H), 3.99(s, 2H), 3.76-3.66(m, 2H), 3.56-3.41(m, 3H), 3.35(s, 3H), 2.82(d, J = 13.6Hz, 1H), 2.56-2.51(m, 1H), 2.49-2.45(m, 1H), 1.98(t, J = 9.2Hz, 2H), 1.87-1.61(m, 2H). MS-ESI calculated values ​​[M+H] + 616.2 Measured value [M+H] + 616.1.

[0321] Example 17: Synthesis of Compound 17

[0322] Synthesis route:

[0323] Synthesis of intermediate 17-3: Compound 17-2 (1.00 g, 11.1 mmol) was dissolved in anhydrous dichloromethane (30 mL), and imidazole (2.27 g, 33.3 mmol) and compound 17-1 (3.36 g, 12.2 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 hours. The reaction solution was washed three times with water (20 mL * 3), and the organic phase was dried over anhydrous sodium sulfate and filtered. The crude product was concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) yielded 1.90 g of a colorless oily compound 17-3, with a yield of 52%. 1 H NMR (400MHz, CDCl3) δ7.73-7.67(m,4H),7.48-7.37(m,6H),4.26(s,2H),3.69(s,3H),1.10(s,9H).

[0324] Synthesis of intermediate 17-4: Compound 17-3 (600 mg, 1.83 mmol) was dissolved in tetrahydrofuran (6 mL), and sodium hydroxide aqueous solution (1 M, 72.0 mg, 1.80 mmol, 1.8 mL) was slowly added. The mixture was stirred at 25 °C for 12 hours. The pH of the reaction solution was adjusted to 2 with 1 N dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (10 mL * 3). The combined organic phases were washed three times with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1) yielded 496 mg of compound 17-4 as a colorless oil, with a yield of 86%. 1 H NMR (400MHz, CDCl3-d) δ7.68-7.61(m,4H),7.52-7.39(m,6H),4.23(s,2H),1.12(s,9H).

[0325] Synthesis of intermediate 17-6: Compound 17-5 (1.00 g, 4.20 mmol) and compound 3-1 (0.94 g, 4.41 mmol) were dissolved in anhydrous dioxane (10 mL), and then N,N-diisopropylethylamine (1.63 g, 12.6 mmol) was added. The mixture was stirred at 100 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) gave 1.40 g of compound 17-6 as a yellow solid, in 90% yield. 1 ¹H NMR (400MHz, CDCl₃-d) δ 7.34–7.28 (m, 1H), 6.78–6.71 (m, 1H), 3.73–3.65 (m, 2H), 3.63–3.54 (m, 2H), 3.50 (s, 2H), 1.48 (s, 9H), 1.07–1.01 (m, 2H), 0.88–0.82 (m, 2H). MS-ESI calculated values ​​[M+H] + 369.1 and 371.1, measured values ​​[M+H] + 369.1 and 371.0.

[0326] Synthesis of intermediate 17-7: Compound 17-6 (400 mg, 1.08 mmol) was dissolved in anhydrous dichloromethane (4 mL), and dioxane hydrochloride solution (2 N, 4 mL) was slowly added dropwise. The reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to give 330 mg of compound 17-7 as a white solid, hydrochloride.

[0327] Synthesis of intermediate 17-8: Compound 17-7 (90.0 mg, 0.29 mmol, hydrochloride) and compound 17-4 (102 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (152 mg, 1.18 mmol) and 2-(7-azobenzotriazine)-N,N,N,N'-tetramethylurea hexafluorophosphate (134 mg, 0.35 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 hours. The reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL * 3), and the combined organic phases were washed three times with saturated brine (10 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1) yielded 130 mg of a colorless oily compound 17-8, with a yield of 79%. 1 ¹H NMR (400MHz, CDCl₃-d) δ 7.78–7.66 (m, 4H), 7.47–7.31 (m, 7H), 6.84–6.67 (m, 1H), 4.61–4.22 (m, 2H), 3.97–3.72 (m, 2H), 3.68–3.01 (m, 4H), 1.12 (s, 9H), 0.98–0.84 (m, 4H). MS-ESI calculated values ​​[M+H] + 565.2 and 567.2, measured values ​​[M+H] + 565.2 and 567.1.

[0328] Synthesis of intermediate 17-9: Compound 17-8 (60.0 mg, 0.11 mmol) and compound A2 (51.1 mg, 0.11 mmol) were dissolved in dioxane (4 mL) and water (0.4 mL). Potassium carbonate (44.0 mg, 0.32 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (8.98 mg, 0.01 mmol) were added sequentially, and the mixture was stirred at 100 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (dichloromethane / methanol = 50 / 1) yielded 64.0 mg of compound 17-9 as a yellow oil, in 72% yield. MS-ESI calculated value [M+H] + 840.3, measured value [M+H] + 840.3.

[0329] Synthesis of compound 17: Compound 17-9 (30.0 mg, 0.04 mmol) was dissolved in anhydrous methanol (2 mL), and potassium fluoride (6.22 mg, 0.11 mmol) was added. The mixture was stirred at 25 °C for 12 hours. After filtration, the filtrate was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: A (water, containing 0.025% formic acid) and B (acetonitrile); gradient: B%: 14%-44%) to obtain compound 17, 9.00 mg, yield 42%. 1 H NMR(400MHz, CDCl3-d)δ8.55-8.43(m,1H),8.07-8.01(s,1H),7.94-7.87(m,1H),7 .82-7.76(m,1H),7.71-7.64(m,1H),7.45-7.37(m,1H),7.35-7.29(m,1H),7.09-6 0.71 (m, 2H), 6.32-6.25 (m, 1H), 5.02-4.92 (m, 1H), 4.45-4.13 (m, 2H), 4.05-3.80 (m, 2H), 3.78-3.59 (m, 4H), 3.56-3.42 (m, 5H), 2.94-2.84 (m, 1H), 1.29-1.03 (m, 4H). Calculated value [M+H] + 602.1, Measured value [M+H] + 602.2.

[0330] Bioactivity test

[0331] Biological Example 1: Determination of the inhibitory effect of the compound of the present invention on TNF-α-induced NF-κB activation.

[0332] Test compounds: The test compounds selected were the compounds from the embodiments of this invention, comparative compound 1, and the positive reference compound, wherein the structure of the positive reference compound is as follows: It is the compound disclosed in WO2018197503A1 (Example 6), and was prepared using the same method as that patent. In this application, it is named compound C.

[0333] Comparative compound 1 was prepared according to Example 136 in CN107108672B, and its structure is as follows:

[0334] Methods: A stable cell line expressing the NF-κB luciferase reporter gene, HCT116-NF-κB, was constructed in HCT116 cells to detect the effect of the test compound on TNF-α-induced NF-κB activation. HCT116-NF-κB cells were spaced at 1 × 10⁻⁶ cells per well.5 Cells were seeded at a density of [number] cells per well into 48-well cell culture plates (culture medium composition: DMEM (GIBCO cat#1995500BT), 10% fetal bovine serum (CellMax cat#SA211.02), 1% penicillin / streptomycin (GIBCO cat#15140-122)) and cultured for 16 h in a 37°C incubator with 5% CO2. Compounds were prepared using DMSO and serially diluted, then added to the wells and incubated for 30 min to test the final concentrations between 30 μM and 0.5 nM. Subsequently, cytokine TNF-α (Sino Biological cat#10602-HNAE) was added to a final concentration of 1.5 ng / mL, and the plates were incubated for 8 hours in a 37°C incubator with 5% CO2 before discarding the culture medium. Add 50 μL of 1×passive lysis buffer (Promega CAT#E1941) to each well of the cell culture plate. After lysing the cells for 15 minutes, transfer 10 μL of the lysate to a 1.5 mL EP tube, followed by adding 10 μL of [unspecified ingredient]. After thoroughly mixing the test reagent (Promega cat#E2520) for 5 minutes, the fluorescence intensity in the cell lysate was detected using a Promega Glomax Luminometer (Promega Glomax 2030-100).

[0335] Data analysis was performed by calculating the average signal from the three wells of the cell plate. The compound inhibition rate was calculated as shown below, and then a curve was plotted with the compound concentration (Log value) on the X-axis and the inhibition rate on the Y-axis. The curve was fitted using GraphPad software, and the IC50 was calculated. 50 The results are shown in Table 1 below, where "A" represents IC. 50 The value is in the range of 0 to 30 nM.

[0336] Calculation formula: %inhibition = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100%, Note: the positive control group is the group with added TNF-α stimulation but no compound; the negative control group is the group without TNF-α stimulation and no compound.

[0337] Table 1. IC50 of the compounds of this invention on TNF-α-induced NF-κB. 50 value

[0338] Experimental Example 2: Pharmacokinetic assay of the compound of the present invention in mice after intravenous and oral administration.

[0339] Three SPF-grade male ICR mice (Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 20-25g, were used in each treatment group. The intravenous administration group received 1 mg / kg of medication, while the oral administration group received 5 mg / kg of medication after fasting overnight. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. Blood samples were placed on ice, and plasma was separated within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8℃). The separated plasma was stored at -80℃. Plasma samples from each time point were mixed with 5 times the volume of 50% methanol-acetonitrile solution containing internal standard. The mixture was vortexed for 5 minutes, centrifuged at 4000 rpm and 4°C for 10 minutes, and the supernatant was mixed with an equal volume of water. The mixture was then analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 software, and the results are shown in Table 2.

[0340] Table 2: Results of Pharmacokinetic Studies in Mice

[0341] The above pharmacokinetic results in mice indicate that the compound of the present invention exhibits a lower clearance rate than the positive reference compound C, and under oral administration conditions, the compound of the present invention has a higher C60% clearance rate compared to the positive reference compound C. max and exposure levels.

[0342] Experimental Example 3: Determination of the inhibitory effect of the compounds of the present invention on five different CYP-450 enzymes

[0343] Methods: DMSO serial dilutions of the compounds and standard inhibitors for each CYP enzyme were prepared; human liver microparticles frozen at -80°C were thawed on ice. 20 μL of a mixture of substrates for five different CYP enzymes (phosphate buffer as a control) was added to each well of a plate. The mixture contained 100 μM phenacetin (1A2), 50 μM diclofenac (2C9), 300 μM (S)-methoxyphentol (2C19), 50 μM dextromethorphan (2D6), and 20 μM midazolam (3A4). Then, 2 μL of the compound and positive inhibitor were added to the corresponding wells, and 2 μL of solvent was added to the wells without inhibitor and as a blank. The five different CYP enzymes used positive inhibitors and their working concentrations are as follows: 1A2-3 μM α-naphthylflavonoid, 2C9-3 μM sulfadiazine, 2C19-1 μM (+)-N-3-benzylphenylethyl lactourethrin, 2D6-3 μM quinine, and 3A-M-3 μM ketoconazole.

[0344] Prepare human liver microparticle working solution: Add 158 μL of human liver microparticles to all wells of the plate and incubate at 37°C for 10 minutes. Prepare reduced nicotinamide adenine dinucleotide phosphate (NADPH) solution: Add 20 μL of NADPH to all wells of the plate, mix well, and incubate at 37°C for 10 minutes. At the endpoint, add 400 μL of pre-chilled stop solution acetonitrile. Centrifuge all samples at 4000 rpm for 20 minutes to precipitate proteins. Transfer 200 μL of supernatant to 100 μL of HPLC solution, shake for 10 minutes, and then perform LC-MS / MS analysis.

[0345] The residual proportion of the substrate and the concentration of the test compound were plotted using XL fit or SigmaPlot, and the IC50 was determined using nonlinear regression analysis with four-parameter or three-parameter fitting. 50 The measured IC 50 As shown in Table 4 below.

[0346] Table 3. Inhibitory effects of the compounds of this invention on five different CYP-450 enzymes.

[0347] In this field, CYP-450 enzymes with inhibitory activity below 10 μM are generally considered to pose a risk of CYP inhibition. The inhibition assays of the five different CYP-450 enzymes described above indicate that the positive reference compound C has a high risk of inhibiting CYP1A2, with a measured IC50 value... 50 The value was 2.17 μM; compared with compound 1, which showed a higher risk of inhibiting CYP2C9, the measured IC50 value was 2.17 μM. 50 The value was 3.88 μM. The inhibitory activity IC50 of the compound of this invention against five different CYP-450 enzymes was [missing value]. 50 The values ​​are all greater than 10 μM, indicating a low risk of inhibition.

[0348] Experimental Example 4: Determination of the inhibitory effect of the compound of the present invention on human hERG channels

[0349] Methods: Prepare CHO-hERG cells. When the cell density reaches 60-80%, digest and centrifuge them, add external fluid, and count to ensure a cell density of 5 x 10⁻⁶ cells / mL. 5 / mL. Single-cell high-impedance sealing and whole-cell pattern formation were performed using a SyncroPatch 38 instrument. After obtaining whole-cell recordings, cells were clamped at -80 mV. Before a 2-second +40 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 1 second, and then back to -80 mV. This voltage stimulation was applied every 10 seconds. After recording for 1 minute, extracellular fluid was applied for 3 minutes of recording, and then the drug administration process began. The compound concentration started from the lowest test concentration, and each test concentration was administered for 3 minutes. After all concentrations (0.16 / 0.49 / 1.48 / 4.44 / 13.33 / 40 μM) were administered, a positive control compound was given. At least 2 cells were tested for each concentration (n≥2). Experimental data were analyzed using DataControl 384 software, and dose-response curve fitting was performed to determine the IC50 of the compound on hERG inhibition. 50 The data is shown in Table 4.

[0350] Table 4. Inhibitory effect of the compounds of this invention on human hERG

[0351] The above hERG inhibition test results indicate that the positive reference compound C has a high risk of inhibiting hERG, and the measured IC50 value is [not specified]. 50 The value was 3.88 μM, while the IC50 of the compound of this invention for inhibiting hERG was [value missing]. 50 The values ​​are all greater than 10 μM, indicating a low risk of inhibition.

[0352] Experimental Example 5: Determination of the in vitro metabolic stability of the compounds of the present invention in human, canine, and mouse liver microsomes:

[0353] Methods: Preparation of experimental materials: The compounds of this invention, as well as the control compounds testosterone, diclofenac, and propafenone, were prepared into 10 mM stock solutions using DMSO. Mouse (IPHASE), dog (IPHASE), and human (Discovery Life) liver microsomes were prepared and diluted to 0.56 mg / mL with 100 mM phosphate buffer. NADPH powder (BONTAC) was weighed and diluted to 10 mM with 10 mM MgCl2. A low-temperature acetonitrile solution containing 250 nM tolbutamide and 250 nM labetalol was prepared as a stop solution.

[0354] Preheat empty incubation plates T60 and control plates NCF60 (without NADPH, buffer replaced) at 37°C for 10 minutes. Transfer 445 μL of microsome working solution to the preheated incubation plates T60 and NCF60, and then incubate at 37°C for 10 minutes. Transfer 54 μL of microsome working solution to the Blank60 plate, and then add 6 μL of NADPH cofactor and 180 μL of stop solution to each well. Add 5 μL of compound working solution to the incubation plates (T60 and NCF60) containing microsomes. Add 50 μL of phosphate buffer solution to the NCF60 incubation plate and incubate the plate at 37°C for 60 minutes. Add stop solution (180 μL) and NADPH working solution (6 μL) to the T0 plate. Then transfer 54 μL of the mixture from the 'T60' incubation plate to the T0 plate. Add 44 μL of NADPH working solution to the T60 incubation plate and incubate at 37 °C for 60 min. At 5, 15, 30, 45, and 60 min, transfer 60 μL of each sample from the compound plate to a well containing 180 μL of stop solution (two replicates per sample at each time point), and mix well. Vortex all sample plates for 10 min, then centrifuge at 3220 × g for 20 min at 4 °C. Transfer 80 μL of the supernatant to 240 μL of pure water and mix using a plate shaker for 10 min. Seal and shake each bioanalytical plate for 10 min before LC-MS / MS analysis.

[0355] The percentage remaining after incubation (%Remaining) is calculated using the following formula: %Remaining = (Ratio of peak area of ​​analyte to internal standard at each time point / Ratio of peak area of ​​analyte to internal standard at time zero) × 100. The half-life (T1 / 2) is then calculated using a first-order kinetic equation: T1 / 2 = Ln² / k e =0.693 / k e k e This represents the elimination rate constant, expressed by k. e Calculation of in vitro intrinsic clearance of liver microsomes (CL) int ) and liver intrinsic clearance (CLint, liver).

[0356] CL int =k e / Microsomal protein content (microsomal concentration during incubation, mg / mL);

[0357] CL int,liver＝ CL int × Microsomal protein content in liver (mg / g liver) × Liver weight to body weight ratio (g liver / kg body weight).

[0358] Conclusion: The compounds of this invention have good metabolic stability.

[0359] Experimental Example 6: Determination of the kinetic solubility of the compounds of the present invention

[0360] Methods: Preparation of stock solution: The test compound and the control compound were dissolved in DMSO to prepare a 10 mM solution.

[0361] Solubility determination: 15 μL of the stock solution for each sample was sequentially added to the corresponding 96-well vial (1.5 mL glass flat-bottomed bottle - Bio Tech Solutions); 485 μL of phosphate-buffered saline was added to each vial of the uncapped solubility plate; a stir bar (V&P Scientific) was added to each vial, and the vials were sealed with molded PTFE / silicone stoppers (Bio Tech Solutions). The solubility plate was then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C and 1100 RPM for 2 hours; after 2 hours, the stoppers were removed, and the stir bar was removed using a large magnet. The samples were then transferred from the solubility plate to a filter plate (Millipore); all samples were filtered using a vacuum device. Take 10 μL of the sample from the filtrate, then add 10 μL of DMSO and 980 μL of a 1:1 mixture of water and acetonitrile containing internal standards (100 nM tolbutamide, 200 nM labetalol, and 100 nM ketoprofen). Transfer 200 μL of this dilution to a new 96-well plate for LC-MS / MS analysis. The dilution factor can be adjusted based on solubility values ​​and LC-MS signal response.

[0362] Preparation of 3 μM standard: 15 μL of the 10 mM DMSO standard master plate was transferred to another empty plate, and 485 μL of DMSO was added to this plate to obtain a 300 μM standard solution. From the 300 μM DMSO standard plate, 10 μL was transferred to another empty plate, and 10 μL of phosphate-buffered saline and 980 μL of a 1:1 mixture of water and acetonitrile containing internal standards (100 nM tolbutamide, 200 nM labetalol, and 100 nM ketoprofen) were added to this plate to obtain a final 3 μM standard solution. 200 μL of this diluted solution was transferred to a new 96-well plate for LC-MS / MS analysis.

[0363] Sample analysis procedure: Place the sample plate into the autosampler. Evaluate the sample by LC-MS / MS analysis.

[0364] Data Analysis: All calculations were performed using Microsoft Excel. The filtrate was analyzed, and quantification was performed using standards of known concentrations via LC-MS peak identification and quantification. The solubility values ​​of the test compound and the control compound were calculated using the following formula: [Sample Concentration] = (Sample Peak Area Ratio × Sample Dilution Factor × [Standard Concentration]) / Standard Peak Area Ratio

[0365] Conclusion: The compounds of this invention exhibit good thermodynamic solubility.

[0366] While the embodiments disclosed in this application are as described above, the content is merely for the purpose of facilitating understanding of this application and is not intended to limit this application. Any person skilled in the art to which this application pertains may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application; however, the scope of protection of this application shall still be determined by the scope defined in the appended claims.

Claims

A compound having the formula (IA), its stereoisomer, or a pharmaceutically acceptable salt thereof: in, Ring A is selected from 4-10 membered heterocyclic alkyl groups, wherein the 4-10 membered heterocyclic alkyl group contains at least one nitrogen atom attached to a carbonyl group; X 1 X 2 X 3 and X 4 Each is independently selected from N and CR 6 And specify X 1 X 2 X 3 and X 4 At most two values ​​in the set are N at the same time; Q is selected from Z 1 Z 2 and Z 3 Each is independently selected from N and CR 7 And stipulate Z 1 Z 2 and Z 3 At most two values ​​in the set are N at the same time; R 1 Selected from -C 1-3 alkylene -OH, -C 1-3 Alkylene-CN, -C 3-6 Cycloalkyl-OH, -C 3-6 Cycloalkyl-CN,-NR 8 R 9 -OC 1-3 alkylene-OH and -OC 1-3 Alkylene-CN, -OC 3-6 Cycloalkyl-OH and -OC 3-6 Cycloalkyl-CN, wherein the C 1-3 Alkylene and C 3-6 Each cycloalkyl group is independently and optionally bound by one or more R a Replaced; R 2 Each is independently selected from hydrogen, halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-6 Alkyl and N(C) 1-6 alkyl)2, wherein the C 1-6 Alkyl and C 1-6 Alkoxy groups are each independently and optionally separated by one or more R groups. b Replaced; R 3 Each is independently selected from hydrogen and halogens; R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by one, two, or three R groups. c Replaced; R 5 Selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Haloalkoxy, -SC 1-6 Alkyl, -SC 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Haloalkenyl; R 6 Selected from hydrogen, halogen, cyano and C 1-6 alkyl; R 7 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. d Replaced; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. e Replaced; m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; n is an integer selected from 0, 1, 2, and 3; R a R b R c R d and R e Each is independently selected from halogen, cyano, amino, hydroxyl, C 1-3 Alkyl, -C 1-3 alkylene-OH, C 1- 3-alkoxy group, NHC 1-3 Alkyl and N(C) 1-3 Alkyl)2. The compound represented by formula (IA) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by formula (IA) has the structural features of formula (I): Wherein, ring A is selected from 4-10 membered heterocyclic alkyl groups, and the 4-10 membered heterocyclic alkyl group contains at least one nitrogen atom attached to a carbonyl group; X 1 and X 2 Each is independently selected from N and CR 6 ; Q is selected from Z 1 Z 2 and Z 3 Each is independently selected from N and CR 7 And stipulate Z 1 Z 2 and Z 3 At most two values ​​in the set are N at the same time; R 1 Selected from -C 1-3 alkylene -OH, -C 1-3 Alkylene-CN, -C 3-6 Cycloalkyl-OH, -C 3-6 Cycloalkyl-CN,-NR 8 R 9 -OC 1-3 alkylene-OH and -OC 1-3 Alkylene-CN, -OC 3-6 Cycloalkyl-OH and -OC 3-6 Cycloalkyl-CN, wherein the C 1-3 Alkylene and C 3-6 Each cycloalkyl group is independently and optionally bound by one or more R a Replaced; R 2 Each is independently selected from hydrogen, halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-6 Alkyl and N(C) 1-6 alkyl)2, wherein the C 1-6 Alkyl and C 1-6 Alkoxy groups are each independently and optionally separated by one or more R groups. b Replaced; R 3 Each is independently selected from hydrogen and halogens; R 4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by one, two, or three R groups. c Replaced; R 5 Selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Haloalkoxy, -SC 1-6 Alkyl, -SC 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Haloalkenyl; R 6 Selected from hydrogen, halogen, cyano and C 1-6 alkyl; R 7 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. d Replaced; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is independently and optionally surrounded by one, two, or three R's. e Replaced; m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; n is an integer selected from 0, 1, 2, and 3; R a R b R c R d and R e Each is independently selected from halogen, cyano, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, NHC 1-3 Alkyl and N(C) 1-3 Alkyl)2. The compound of formula (IA) as claimed in claim 1 or 2, its stereoisomers or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by formula (IA) satisfies one or more of the following conditions: (1) The halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (2) The C 1-3 The alkyl group is independently methyl, ethyl, n-propyl or isopropyl, preferably methyl; (3) The C 1-3 The alkoxy group is independently methoxy, ethoxy, n-propoxy, or isopropoxy, preferably methoxy; (4) The C 1-3 The alkylene group is -CH2-, -CH2CH2- or -CH2CH2CH2-, preferably -CH2-; (5) The C 3-6 Cycloalkylene is (6) The C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl; (7) The C 1-6 Haloalkyl is a C that is substituted with one or more halogens. 1-3 Alkyl groups, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3; (8) The C 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy; (9) The C 1-6 Haloalkoxy groups are C atoms that are substituted with one or more halogens. 1-3 Alkyl groups, such as -OCH2F, -OCH2Cl, -OCHF2, -OCHCl2, -OCCl3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3 or -OCF2CF3, preferably -OCHF2; (10) The -SC 1-6 The alkyl group is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, or tert-butylthio, preferably methylthio; (11) The -SC 1-6 The haloalkyl group is -SC substituted with one or more halogens. 1-3 Alkyl groups, such as -SCH2F, -SCH2Cl, -SCHF2, -SCHCl2, -SCCl3, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3 or -SCF2CF3, preferably -SCHF2; (12) The C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (13) The heteroatom of the 3-6 membered heterocyclic alkyl group is selected from N, O or S, and the number of heteroatoms is 1 or 2; preferably, the heteroatom of the 3-6 membered heterocyclic alkyl group is O, and the number of heteroatoms is 1. (14) The 3-6 membered heterocyclic alkyl group is an oxocyclic butyl group, an azacyclic butyl group, or a tetrahydrofuranyl group; (15) The C 2-6 The alkenyl group is independently C 2-4 Alkenyl, such as vinyl, propenyl or butenyl, preferably vinyl; (16) The C 2-6 The haloalkenyl group is a halovinyl group, for example: (17) The heteroatom of the 4-10 member heterocyclic alkyl group is selected from N, O or S, and contains at least one nitrogen atom, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom of the 4-10 member heterocyclic alkyl group is N, and the number of heteroatoms is 1 or 2. The 4-10 member heterocyclic alkyl group in (18) is a monocyclic heterocyclic alkyl group or a polycyclic monocyclic heterocyclic alkyl group, wherein the number of rings of the polycyclic group can be bicyclic or tricyclic, and the polycyclic group can be fused, spirocyclic or bridged; preferably, the 4-10 member heterocyclic alkyl group is a 4-7 member monocyclic heterocyclic alkyl group or a 7-10 member bicyclic heterocyclic alkyl group; Preferably, the 4-6 membered monocyclic heterocyclic alkyl group is... Preferably, the 6-9 membered bicyclic heterocyclic alkyl group is... The compound of formula (IA) as claimed in claim 1 or 2, its stereoisomers or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by formula (IA) satisfies one or more of the following conditions: (1)R 1 Selected from -C 1-3 alkylene -OH, -C 1-3 Alkylene-CN, -C 3-6 Cycloalkyl-OH, -C 3-6 Cycloalkyl-CN and -NR 8 R 9 Wherein C 1-3 Alkylene and C 3-6 Each cycloalkyl group is independently and optionally bound by one or more R a Replaced; preferably, R 1 Selected from More preferably, R 1 Selected from More preferably, R 1 for (2) Ring A is selected from 4-6 member monocyclic heterocyclic alkylene and 6-9 member bicyclic heterocyclic alkylene, wherein the bicyclic ring is a fused ring, a spiro ring or a bridged ring, and the 4-6 member monocyclic heterocyclic alkylene and 6-9 member bicyclic heterocyclic alkylene contain at least one nitrogen atom connected to a carbonyl group; Preferably, ring A is selected from The above One nitrogen terminus is attached to a carbonyl group; More preferably, ring A is selected from in One nitrogen terminus is attached to a carbonyl group; (3)R 2 Each is independently selected from hydrogen, halogen, hydroxyl, and C. 1-3 Alkyl; preferably, R 2 Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, and methyl; more preferably, R 2 Each is independently selected from hydrogen, methyl, and hydroxyl; more preferably, R 2 Each is independently selected from hydrogen and methyl; (4) m is selected from 0, 1 and 2; (5)X 1 and X 2 Each is independently selected from N or CH; preferably, X 1 and X 2 Let N be the number of people in the group. (6)R 6 Selected from hydrogen and fluorine; (7)R 3 Each is independently selected from hydrogen, fluorine, chlorine, bromine, and iodine; preferably, R 3 Each is independently selected from hydrogen and fluorine; more preferably, R 3 It is hydrogen; (8) n is selected from 0 and 1; (9)R 4 Selected from H, C 1-3 alkyl, Preferably, R 4 C 1-3 Alkyl; more preferably, R 4 It is methyl; (10)Q is (11)Z 1 Z 2 and Z 3 Each independently for CR 7 Preferably, Z 1 Z 2 and Z 3 For CH; (12)R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups; preferably, R 5 C 1-3 Haloalkoxy; more preferably, R 5 for (13)R 7 Each is independently selected from hydrogen, fluorine, chlorine, bromine, and iodine; preferably, R 7 Each is independently hydrogen; (14)R 8 and R 9 Each is independently selected from hydrogen and C. 1-3 alkyl; and (15)R a R b R c R d and R e Each is independently selected from halogens, hydroxyl groups, and C. 1-3 Alkyl; preferably, R a R b R c R d and R e Each is independently selected from fluorine, chlorine, hydroxyl, and methyl; more preferably, R a Selected from hydroxyl and methyl. The compound represented by formula (IA) as claimed in claim 2, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by formula (IA) satisfies one or more of the following conditions: (1) Structural Unit Selected from Preferably, structural unit for (2)R 5 Selected from Preferably, R 5 for (3) Structural Unit Selected from Preferably, structural unit Selected from More preferably, structural unit Selected from and (4) structural unit Selected from Preferably, structural unit for The compound of formula (IA) as claimed in claim 1 or 2, its stereoisomers or pharmaceutically acceptable salts thereof, is characterized in that, Structural unit Selected from Preferably, structural unit Selected from More preferably, structural unit for The compound represented by formula (IA) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by formula (IA) satisfies one or more of the following conditions: (1) Structural Unit Selected from Preferably, structural unit for (2)R a R b R c R d and R e Each is independently selected from halogens, hydroxyl groups, -CH2OH, and C. 1-3 alkyl; Preferably, R a Selected from -CH2OH and methyl, R b R c R d and R e Each is independently selected from fluorine, chlorine, hydroxyl, and methyl; (3) Structural Unit Selected from The compound represented by formula (IA) according to any one of claims 1-7, its stereoisomer, or a pharmaceutically acceptable salt thereof, is characterized in that, The compound represented by formula (IA) satisfies one of the following schemes: Option 1: The compound represented by formula (IA) has the structural features of formula (IV): Among them, R 1 Ring A, R 2 R 4 R 5 X 2 m and Q are as defined in any one of claims 1-7; Option 2: The compound represented by formula (IA) has the structural features of formula (IV): in, R 1 Selected from Ring A is a 4-6 member monocyclic heterocyclic alkylene group and a 6-9 member bicyclic heterocyclic alkylene group, wherein the bicyclic alkylene group is a fused ring, a spiro ring, or a bridged ring, and the 4-6 member monocyclic heterocyclic alkylene group and the 6-9 member bicyclic heterocyclic alkylene group contain at least one nitrogen atom attached to a carbonyl group; R 2 Each is independently selected from hydrogen and methyl; m is selected from 0 and 1; X 2 For N or CH; Q is selected from R 4 For H, C 1-3 Alkyl or 3-6 membered heterocyclic alkyl; R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups; Option 3: The compound represented by formula (IA) has the structural features of formula (IV): in, R 1 Selected from Ring A is selected from in One nitrogen terminus is attached to a carbonyl group; R 2 Each is independently selected from hydrogen, methyl, and hydroxyl; m is selected from 0 and 1; X 2 For N or CH; Q is selected from R 4 For H, C 1-3 Alkyl or 3-6 membered heterocyclic alkyl; R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups; Option 4: The compound represented by formula (IA) has the structural features of formula (IV): in, R 1 for Ring A is R 2 Each is independently selected from hydrogen, methyl, and hydroxyl; m is selected from 0 and 1; X 2 Let N be the number of people in the group. Q is R 4 C 1-3 alkyl; R 5 Selected from Option 5: The compound represented by formula (IA) has the structural features of formula (IV): in, Structural unit for X 2 For N or CH; Q is selected from R 4 For H, C 1-3 Alkyl or 3-6 membered heterocyclic alkyl; R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups; Option Six: The compound represented by formula (IA) has the structural features of formula (V): R 1 Selected from Q is selected from R 4 Selected from H, C 1-3 Alkyl or 3-6 membered heterocyclic alkyl; R 5 Selected from C 1-3 Haloalkoxy, -SC 1-3 Halogenated alkyl groups and halogenated vinyl groups; Option Seven: The compound represented by formula (IA) has the structural features of formula (V): R 1 Selected from Q is R 4 C 1-3 alkyl; R 5 Selected from Option 8: The compound represented by formula (IA) has the structural features of formula (IIIA): in, R 1 Selected from Ring A is a 4-6 member monocyclic heterocyclic alkylene group and a 6-9 member bicyclic heterocyclic alkylene group, wherein the bicyclic alkylene group is a fused ring, a spiro ring, or a bridged ring, and the 4-6 member monocyclic heterocyclic alkylene group and the 6-9 member bicyclic heterocyclic alkylene group contain at least one nitrogen atom attached to a carbonyl group; R 2 Each is independently selected from hydrogen and methyl; m is an integer selected from 0, 1, and 2; X 1 and X 2 Let N, X 3 and X 4 For CH; or, X 1 and X 4 Let N, X 2 and X 3 For CH; Q is selected from R 4 C 1-3 alkyl; R 5 Selected from C 1-3 Halogenated alkoxy groups and -SC 1-3 Halogenated alkyl groups; Option Nine: The compound represented by formula (IA) has the structural features of formula (IIIA): in, R 1 Selected from Ring A is selected from in One nitrogen terminus is attached to a carbonyl group; R 2 Each is independently selected from hydrogen and methyl; m is an integer selected from 0, 1, and 2; X 1 and X 2 Let N, X 3 and X 4 For CH; or, X 1 and X 4 Let N, X 2 and X 3 For CH; Q is R 4 C 1-3 alkyl; R 5 Selected from C 1-3 Halogenated alkoxy groups and -SC 1-3 Halogenated alkyl groups. The compound represented by formula (IA) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, is characterized in that, The compound represented by formula (IA) is any of the following compounds: Preferably, the compound represented by formula (IA) is any of the following compounds: A method for preparing a compound of formula (IA) according to any one of claims 1-9, the method comprising the following steps: (1) Compound (IA) and compound (IB) undergo a coupling reaction under the catalysis of a transition metal to obtain compound (IA); in, LG 1 Represents boric acid or borate esters, such as boric acid or pinacol borate ester; LG 2 Represents a leaving group, such as chlorine, bromine, or iodine, and LG 1 and LG 2 The structures represented can be interchanged; in equations (IA), (IB), and (IA), rings A and X... 1 X 2 X 4 X 4 R 1 R 2 R 3 R 4 R 5 Q, Z 1 Z 2 Z 3 The definitions of m and n are as described in any one of claims 1-9; Preferably, the transition metal is, for example, palladium, or, more specifically, palladium methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium; Preferably, the compound of formula (IA) is a compound of formula (I-A1), and the compound of formula (IA) is a compound of formula (I); Among them, LG 1 Ring A, X 1 X 2 R 1 R 2 R 3 R 4 R 5 Q, Z 1 Z 2 Z 3 The definitions of m and n are as described in any one of claims 1-9. A pharmaceutical composition comprising a compound of formula (IA) as described in any one of claims 1-9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. The use of a compound of formula (IA) as described in any one of claims 1-9, its stereoisomers or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 11, wherein the use is at least one of the following: (1) Application in the preparation of TNF-α inhibitors; (2) Use in medicines for the prevention and / or treatment of TNF-α-related diseases; (3) Use in medicines for the prevention and / or treatment of diseases, wherein the diseases are pain, nociceptive disorders, tumors, immune diseases, inflammatory diseases, neurodegenerative diseases, metabolic diseases or cardiovascular diseases. The application as described in claim 12, characterized in that, The application meets one or both of the following conditions: (1) The TNF-α-related diseases mentioned above are pain, nociceptive disorders, tumors, immune diseases, inflammatory diseases, neurodegenerative diseases, metabolic diseases or cardiovascular diseases; Preferably, the immune disease is an autoimmune disease; Preferably, the TNF-α-related diseases are rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, uveitis, multiple sclerosis, Behcet's disease, hidradenitis suppurativa, vasculitis, neurogenic tuberous disease, Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. (2) The diseases mentioned are rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, uveitis, multiple sclerosis, Behcet's disease, hidradenitis suppurativa, vasculitis, neurogenic tuberous disease, Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis.

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