Immunomodulators

Abstract

Disclosed in the present invention are immunomodulators. Specifically, the present invention relates to compounds that inhibit IL-17A and the use thereof as immunomodulators in the preparation of drugs. Disclosed in the present invention is the use of compounds represented by formula (I) or stereoisomers thereof in the preparation of drugs inhibiting IL-17A, thus providing a new option for clinically screening and / or preparing drugs for diseases related to the activity of IL-17A.

Description

An immunomodulator Technical Field

[0001] The present invention relates to an immunomodulator and application thereof in preparing medicines. Background Art

[0002] IL-17 (interleukin-17) is a proinflammatory cytokine that plays a role in inducing other inflammatory cytokines, chemokines and adhesion factors. The IL-17 family consists of cytokines involved in acute and chronic inflammatory responses, including IL-17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F. IL-17A is expressed by TH17 cells, which are involved in the pathogenesis of inflammation and autoimmune diseases. Human IL-17A is a glycoprotein with a molecular weight of approximately 17,000 daltons. IL-17A transmits signals to cells through the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al. Journal of immunology, 2008, 181: 2799-2805). The main function of IL-17A is to coordinate local tissue inflammation through the upregulation of proinflammatory and neutrophil migratory cytokines and chemokines (including IL-6, G-CSF, TNF-α, IL-1, CXCL1, CCL2, CXCL2), as well as matrix metalloproteinases to allow activated T cells to penetrate the extracellular matrix. Studies have shown that IL-17A plays an important role in severe asthma and chronic obstructive pulmonary disease (COPD), patients who are often unresponsive or respond poorly to currently available drugs (Al-Ramli et al. J Allergy Clin Immunol, 2009, 123: 1185-1187). Upregulated IL-17A levels have been implicated in many diseases, including rheumatoid arthritis (RA), bone erosions, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma, and multiple sclerosis (Gaffen, SL et al. Arthritis Research & Therapy, 2004, 6:240-247).

[0003] Immune function is critical for maintaining homeostasis and responding effectively to disease, and abnormal immune responses are established contributors to the pathophysiology of autoimmune diseases. In certain disease states, key pathways leading to these abnormal autoimmune responses have been identified as effective approaches for therapeutic intervention. IL-17A is a recognized proinflammatory cytokine that plays a key role in chronic inflammation and is a major driver of tissue damage. IL-17A induces normal immune and inflammatory responses to pathogens, but can also contribute to chronic autoimmune diseases, including psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis. Therefore, targeting the binding of IL-17A to IL-17R is an effective strategy for treating IL-17A-mediated autoimmune inflammatory diseases. Treatment of animals with IL-17A neutralizing antibodies reduced disease incidence and severity in autoimmune encephalomyelitis (Komiyama Y et al. J. Immunol., 2006, 177: 566-573). Clinical trials of IL-17A antibodies have shown promising results in IL-17A-mediated inflammatory diseases, including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis, and multiple sclerosis. The IL-17A antibody (Novartis's Cosentyx / secukinumab) was approved by the FDA for the treatment of psoriasis in January 2015.

[0004] Although multiple IL-17A antibodies are already on the market, there are relatively few known IL-17A small molecule modulators, especially improved and / or orally available IL-17A small molecule modulators. Therefore, the development of IL-17A small molecule modulators has important clinical therapeutic significance.

[0005] Summary of the Invention

[0006] The present invention first provides a compound represented by Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0007] in,

[0008] Indicates a single bond or a double bond;

[0009] X 1 Selected from C or N;

[0010] X 2 、X 3 are independently selected from O, N, NR X or CR X ;

[0011] X 4 、X 5 are independently selected from C or N;

[0012] Each R X are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, -OC 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -O(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -O(4-10 membered heterocycloalkyl), deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0013] Y 1 、Y 2 、Y 3 Each independently selected from N or CR Y ;

[0014] Each R Y are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-OC 1～6 Alkyl, -C 0～2 Alkylene-O (halogen substituted C 1～6 Alkyl), -C 0～2 Alkylene-O (3-10 membered cycloalkyl), -C 0～2 Alkylene-O(4-10 membered heterocycloalkyl);

[0015] Z is selected from C(O), S(O) or S(O)2;

[0016] R 1 Selected from -C 1～6 Alkyl, deuterium-substituted C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 2～6 Alkenyl, halogen-substituted C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C0～2 Alkylene-OR 11 、-C 0～2 Alkylene-NR 11 R 12 wherein alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 1a replace;

[0017] R 11 、R 12 are independently selected from hydrogen, deuterium, C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 1a replace;

[0018] Each R 1a are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR 1b 、-C 0～4 Alkylene-SR 1b 、-C 0～2 Alkylene-C(O)R 1b 、-C 0～2 Alkylene-C(O)NR 1b R 1c 、-C 0～2 Alkylene-NR 1b R 1c 、-C 0～2 Alkylene-NR 1b C(O)R 1c 、-C 0～4 Alkylene-S(O)2R 1b 、-C 0～4 Alkylene-NHS(O)2R 1b 、-C 0～4 Alkylene-S(O)R 1b 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 1d replace;

[0019] R 1b 、R 1c 、R 1d are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -SH, -S(C 1～6 Alkyl), -C 0～2 Alkylene-O(C 1～6 alkyl), -C(O)NH2, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0020] Alternatively, two R attached to the same carbon atom 1a , and the carbon atoms connected thereto together form a 3-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group; wherein the cycloalkyl group or heterocycloalkyl group is optionally replaced by one, two or three independent R 1e replace;

[0021] R 1e are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -SH, -S(C 1～6 Alkyl), -C 0～2 Alkylene-O(C 1～6 alkyl), -C(O)NH2, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0022] R 2 Selected from -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-12 membered bridged cycloalkyl), -C 0～2 Alkylene-(5-12 membered heterocyclic alkyl), -C 0～2 Alkylene-(5-12 membered spirocycloalkyl), -C 0～2 Alkylene-(5-12 membered spiroheterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-OR 21 、-C 0～2 Alkylene-NR 21 R 22 、-C 0～2 Alkylene-CN; wherein alkylene, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two, three or four independent R 2a replace;

[0023] R 21 、R 22 are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 2a replace;

[0024] Each R 2a are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR2b 、-C 0～2 Alkylene-C(O)R 2b 、-C 0～2 Alkylene-C(O)NR 2b R 2c 、-C 0～2 Alkylene-NR 2b R 2c 、-C 0～2 Alkylene-NR 2b C(O)R 2c 、-C 0～4 Alkylene-S(O)2R 2b 、-C 0～4 Alkylene -CN, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-12 membered bridged cycloalkyl), -C 0～2 Alkylene-(5-12 membered heterocyclic alkyl), -C 0～2 Alkylene-(5-12 membered spirocycloalkyl), -C 0～2 Alkylene-(5-12 membered spiroheterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, spiroalkyl, spiroheterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 2d replace;

[0025] or,

[0026] Two R attached to the same carbon atom 2a , together with the carbon atom to which it is connected, form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group;

[0027] R 2b 、R 2c are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 2dreplace;

[0028] Each R 2d are independently selected from hydrogen, deuterium, C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0029] R 3 Selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-OR 31 、-C 0～2 Alkylene-NR 31 R 32 wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 3a replace;

[0030] R 31 、R 32 are independently selected from hydrogen, deuterium, C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0031] Each R 3a are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0032] L is selected from C2～6 Alkylene, C 2～6 wherein,

[0033] 1) One or more methylene groups in the alkylene and alkenylene groups may be optionally replaced by O, NR L1 , C(O), S(O) or S(O)2; and / or

[0034] 2) Alkylene and alkenylene are optionally substituted by one, two, three or four independent R L replace;

[0035] Each R L1 Selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-OC 1～6 Alkyl, -C 0～2 Alkylene -CN, -C 0～2 Alkylene-C(O)(C 1～6 Alkyl), -C 0～2 Alkylene-O (3-10 membered cycloalkyl), -C 0～2 Alkylene-O (4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～4 Alkylene-N(C 1～6 Alkyl)(C 1～6 wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R L2 replace;

[0036] Each R L2 are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0037] Each R L are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OC 1～6Alkyl, -C 0～2 Alkylene-O (3-10 membered cycloalkyl), -C 0～2 Alkylene-O(4-10 membered heterocycloalkyl);

[0038] or,

[0039] Two R attached to the same carbon atom L , and the carbon atoms to which it is connected together form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group.

[0040] In some embodiments of the present invention, the compound represented by Formula I is represented by Formula II:

[0041] Among them, R 1 、R 2 、R 3 、Y 1 、Y 2 、Y 3 , Z, L, X 1 、X 2 、X 3 、X 4 、X 5 The definitions are as above.

[0042] In some embodiments of the present invention, X 1 、X 2 、X 3 、X 4 、X 5 The ring composed of is an aromatic heterocycle, and X 4 、X 5 Not N at the same time.

[0043] In some embodiments of the present invention,

[0044] X 1 C, X 2 NR X , X 3 N, X 4 C, X 5 is C;

[0045] Or, X 1 C, X 2 N, X 3 N, X 4 C, X 5 is N;

[0046] Or, X 1 C, X 2 N, X 3 CR X , X 4 N, X5 is C;

[0047] Or, X 1 N, X 2 N, X 3 CR X , X 4 C, X 5 is C;

[0048] Or, X 1 C, X 2 O, X 3 N, X 4 C, X 5 For C.

[0049] In some embodiments of the present invention, further, the compound represented by formula I is represented by the following formula:

[0050] Among them, R 1 、R 2 、R 3 、Y 1 、Y 2 、Y 3 , Z, and L are defined as described above.

[0051] In some embodiments of the present invention, further, the compound represented by formula I is represented by the following formula:

[0052] in,

[0053] R 4 、R 5 、R 6 are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR 1b 、-C 0～4 Alkylene-SR 1b 、-C 0～2 Alkylene-C(O)R 1b 、-C 0～2 Alkylene-C(O)NR 1b R 1c 、-C 0～4 Alkylene-NR 1b R 1c 、-C 0～2 Alkylene-NR 1b C(O)R 1c 、-C 0～4 Alkylene-S(O)2R1b 、-C 0～4 Alkylene-NHS(O)2R 1b 、-C 0～4 Alkylene-S(O)R 1b 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 1d replace;

[0054] R 1b 、R 1c 、R 1d are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -SH, -S(C 1～6 Alkyl), -C 0～2 Alkylene-O(C 1～6 alkyl), -C(O)NH2, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0055] Or, R 5 、R 6 The carbon atoms directly connected thereto together form a 3-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group; wherein the cycloalkyl group or heterocycloalkyl group is optionally replaced by one, two or three independent R 1e replace;

[0056] R 1e are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -SH, -S(C 1～6 Alkyl), -C 0～2 Alkylene-O(C1～6 alkyl), -C(O)NH2, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(4-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0057] R 2 、R 3 、Y 1 、Y 2 、Y 3 , L is defined as described in claim 1.

[0058] As a preference: the R 4 Selected from hydrogen, deuterium, halogen, -C 1～3 Alkyl, deuterium-substituted -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl;

[0059] R 5 、R 6 are independently selected from hydrogen, deuterium, halogen, -C 1～3 Alkyl, deuterium-substituted -C 1～3 Alkyl, halogen-substituted -C 1～3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 6-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle; wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 1d replace;

[0060] R 1d are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano;

[0061] Or, R 5 、R 6 The atoms directly connected thereto together form a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl groups are optionally replaced by one, two, or three independent R 1e replace.

[0062] In some embodiments of the present invention,

[0063] Y 1 、Y 2 、Y 3 Each independently selected from N or CR Y ;

[0064] Each R Y are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～3 Alkyl, 3-6 membered cycloalkyl, deuterium substituted -C 1～3 Alkyl, halogen-substituted -C 1～3 Alkyl, -C 0～2 Alkylene-OC 1～3 Alkyl, -C 0～2 Alkylene-O (halogen substituted C 1～3 alkyl).

[0065] Preferably,

[0066] Y 1 、Y 2 、Y 3 Each independently selected from N or CR Y ;

[0067] Each R Y Each of the following groups is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy.

[0068] In some preferred embodiments of the present invention,

[0069] Y 1 、Y 3 are independently selected from N or CH or CF; Y 2 Select N or CR Y ;

[0070] Each R Y Each of the following groups is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy.

[0071] Preferably, Z is selected from C(O) or S(O)2.

[0072] Preferably,

[0073] R 3 Selected from methyl, deuterated methyl, ethyl, perdeuterated ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxymethyl, methoxymethyl, deuterated methoxymethyl, amino, methylamino, dimethylamino, deuterated methylamino.

[0074] In some embodiments of the present invention, R 1Selected from benzene ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle; wherein the benzene ring and aromatic heterocycle are optionally replaced by one, two or three independent R 1a replace.

[0075] Alternatively, in some embodiments of the invention, R 1 Selected from -methylene-benzene ring, -methylene-5-membered aromatic heterocycle, -methylene-6-membered aromatic heterocycle, -methylene-9-membered aromatic heterocycle; wherein, methylene, benzene ring, aromatic heterocycle are optionally replaced by one, two or three independent R 1a replace.

[0076] Alternatively, in some embodiments of the invention, R 1 Selected from -difluoromethylene-benzene ring, -difluoromethylene-5-membered aromatic heterocycle, -difluoromethylene-6-membered aromatic heterocycle, -difluoromethylene-9-membered aromatic heterocycle; wherein the benzene ring and the aromatic heterocycle are optionally replaced by one R 1a replace.

[0077] Alternatively, in some embodiments of the invention, R 1 is selected from 8-membered fused heterocycloalkyl, 9-membered fused heterocycloalkyl, 10-membered fused heterocycloalkyl, 9-membered fused aromatic heterocycle, 10-membered fused aromatic heterocycle; wherein the fused heterocycloalkyl and fused aromatic heterocycle are optionally replaced by one, two or three independent R 1a replace.

[0078] Alternatively, in some embodiments of the invention, R 1 is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted by one, two or three independent R 1a replace.

[0079] Alternatively, in some embodiments of the invention, R 1 is selected from -methylene-3-membered cycloalkyl, -methylene-4-membered cycloalkyl, -methylene-5-membered cycloalkyl, -methylene-6-membered cycloalkyl, -methylene-4-membered heterocycloalkyl, -methylene-5-membered heterocycloalkyl, -methylene-6-membered heterocycloalkyl, -methylene-9-membered heterocycloalkyl; wherein methylene, cycloalkyl, heterocycloalkyl are optionally replaced by one, two or three independent R 1a replace.

[0080] Alternatively, in some embodiments of the invention, R 1is selected from -difluoromethylene-3-membered cycloalkyl, -difluoromethylene-4-membered cycloalkyl, -difluoromethylene-5-membered cycloalkyl, -difluoromethylene-6-membered cycloalkyl, -difluoromethylene-4-membered heterocycloalkyl, -difluoromethylene-5-membered heterocycloalkyl, -difluoromethylene-6-membered heterocycloalkyl, -difluoromethylene-9-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl groups are optionally replaced by one R 1a replace.

[0081] Alternatively, in some embodiments of the invention, R 1 Selected from methyl, difluoromethyl, trifluoromethyl, ethyl, monofluoroethyl, difluoroethyl, propyl, butyl, -C 0～2 Alkylene-OR 11 、-C 0～2 Alkylene-NR 11 R 12 , vinyl, propenyl, butenyl, pentenyl, hexenyl; wherein methyl, ethyl, propyl, butyl, vinyl, propenyl, butenyl, pentenyl, hexenyl are optionally replaced by one, two or three independent R 1a replace.

[0082] In some embodiments of the present invention, R 11 、R 12 are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, and halogen-substituted isopropyl.

[0083] Alternatively, in some embodiments of the invention, R 11 、R 12 Each independently selected from -C 0～2 Alkylene-(3-membered cycloalkyl), -C 0～2 Alkylene-(4-membered cycloalkyl), -C 0～2 Alkylene-(5-membered cycloalkyl), -C 0～2 Alkylene-(6-membered cycloalkyl), -C 0～2 Alkylene-(4-membered heterocycloalkyl), -C 0～2 Alkylene-(5-membered heterocycloalkyl), -C 0～2 Alkylene-(6-membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl are optionally substituted by one, two or three independent R 1a replace.

[0084] In some embodiments of the present invention, each R 1aare independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, methyl, ethyl, n-propyl, isopropyl, butyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, halogen-substituted butyl; wherein methyl, ethyl, n-propyl, isopropyl, butyl are optionally substituted by one, two or three independent R 1d replace;

[0085] Alternatively, in some embodiments of the invention, each R 1a Each independently selected from -C 0～2 Alkylene-(3-membered cycloalkyl), -C 0～2 Alkylene-(4-membered cycloalkyl), -C 0～2 Alkylene-(5-membered cycloalkyl), -C 0～2 Alkylene-(6-membered cycloalkyl), -C 0～2 Alkylene-(4-membered heterocycloalkyl), -C 0～2 Alkylene-(5-membered heterocycloalkyl), -C 0～3 Alkylene-(6-membered heterocycloalkyl), -(6-membered aromatic ring); wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring are optionally replaced by one, two or three independent R 1d replace;

[0086] Alternatively, in some embodiments of the invention, each R 1a Each independently selected from -C 0～4 Alkylene-OR 1b 、-C 0～4 Alkylene-SR 1b 、-C 0～4 Alkylene-S(O)2R 1b 、-C 0～4 Alkylene-S(O)R 1b 、-NHS(O)2R 1b 、-C 0～3 Alkylene-NR 1b R 1c , wherein the alkylene group is optionally replaced by one, two or three independent R 1d replace;

[0087] In some embodiments of the present invention, R 1b 、R 1c 、R 1d are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, butyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, halogen, cyano, =O, =S, nitro, -OH, -O(C1～6 alkyl), -CH2-O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl), -(3-membered cycloalkyl), -(4-membered cycloalkyl), -(5-membered cycloalkyl), -(6-membered cycloalkyl), -C(O)NH2.

[0088] Alternatively, two R attached to the same carbon atom 1a , and the carbon atoms connected thereto together form a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl groups are optionally replaced by one, two, or three independent R 1e replace;

[0089] R 1e are independently selected from hydrogen, deuterium, -C 1～3 Alkyl, deuterium-substituted -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, halogen.

[0090] Preferably, the R 1 Selected from

[0091] In some embodiments of the present invention, R 2 is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl; wherein the cycloalkyl group is optionally substituted by one, two, three or four independent R 2a replace.

[0092] Alternatively, in some embodiments of the invention, R 2 Selected from -C1 alkylene-(3-membered cycloalkyl), -C1 alkylene-(4-membered cycloalkyl), -C1 alkylene-(5-membered cycloalkyl), -C1 alkylene-(6-membered cycloalkyl), -C1 alkylene-(7-membered cycloalkyl), -C1 alkylene-(8-membered cycloalkyl), -C1 alkylene-(phenyl ring), -C1 alkylene-(aromatic heterocycle); wherein the alkylene, cycloalkyl, benzene ring, and aromatic heterocycle are optionally substituted by one, two, three, or four independent R 2a replace.

[0093] In some embodiments of the present invention, preferably, R 2 Selected from wherein ring V is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl; wherein the cycloalkyl group is optionally substituted by one, two or three independent R 2a Replacement; R 2a‘ is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl; wherein the cycloalkyl group is optionally substituted by one, two or three independent R 2d replace.

[0094] Alternatively, in some embodiments of the invention, R 2 is selected from 6-membered fused cycloalkyl, 9-membered fused cycloalkyl, 10-membered fused cycloalkyl, 11-membered fused cycloalkyl, 9-membered fused heterocycloalkyl, 10-membered fused heterocycloalkyl, 12-membered fused heterocycloalkyl, 8-membered spirocycloalkyl; wherein the fused cycloalkyl, fused heterocycloalkyl, spirocycloalkyl are optionally substituted by one, two, three or four independent R 2a replace.

[0095] Alternatively, in some embodiments of the invention, R 2 Selected from 5-membered bridged cycloalkyl, 6-membered bridged cycloalkyl, 7-membered bridged cycloalkyl, 8-membered bridged cycloalkyl, 9-membered bridged cycloalkyl, 10-membered bridged cycloalkyl, -C1 alkylene-(5-membered bridged cycloalkyl), -C1 alkylene-(6-membered bridged cycloalkyl), -C1 alkylene-(7-membered bridged cycloalkyl), -C1 alkylene-(8-membered bridged cycloalkyl), -C1 alkylene-(9-membered bridged cycloalkyl), -C1 alkylene-(10-membered bridged cycloalkyl).

[0096] In some embodiments of the present invention, R 21 、R 22 R is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, butyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, halogen-substituted butyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, -C1 alkylene-(3-membered cycloalkyl), -C1 alkylene-(4-membered cycloalkyl), -C1 alkylene-(5-membered cycloalkyl), -C1 alkylene-(6-membered cycloalkyl), -C1 alkylene-(7-membered cycloalkyl); wherein alkylene, cycloalkyl, heterocycloalkyl are optionally substituted by one, two or three independent R 2a replace.

[0097] In some embodiments of the present invention, each R 2aare independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, methyl, ethyl, n-propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, -S(O)2R 2b 、-OR 2b .

[0098] Alternatively, in some embodiments of the invention, each R 2a are independently selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, -C1 alkylene-(3-membered cycloalkyl), -C1 alkylene-(4-membered cycloalkyl), -C1 alkylene-(5-membered cycloalkyl), -C1 alkylene-(6-membered cycloalkyl), -C1 alkylene-(7-membered cycloalkyl); wherein alkylene, cycloalkyl, heterocycloalkyl are optionally substituted by one, two or three independent R 2d replace;

[0099] or,

[0100] Two R attached to the same carbon atom 2a , together with the carbon atom to which it is connected, form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group;

[0101] In some embodiments of the present invention, R 2b 、R 2c R is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, -C1 alkylene-(3-membered cycloalkyl), -C1 alkylene-(4-membered cycloalkyl), -C1 alkylene-(5-membered cycloalkyl), -C1 alkylene-(6-membered cycloalkyl), -C1 alkylene-(7-membered cycloalkyl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl are optionally substituted by one, two or three independent R 2d replace;

[0102] In some embodiments of the present invention, each R 2d are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, halogen, cyano, =O, =S, nitro, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C1～6 Alkyl)(C 1～6 alkyl).

[0103] Preferably, the R 2 Selected from

[0104] In some embodiments of the present invention, L is selected from C3 alkylene, C4 alkylene, C5 alkylene, C6 alkylene, C3 alkenylene, C4 alkenylene, C5 alkenylene, C6 alkenylene; wherein,

[0105] 1) One, two or three methylene groups in an alkylene or alkenylene group may be optionally replaced by O, NR L1 , C(O), S(O) or S(O)2; and / or

[0106] 2) Alkylene and alkenylene are optionally substituted by one, two, three or four independent R L replace.

[0107] Each R L1 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, -C 0～2 Alkylene -CN, -C 0～2 Alkylene-C(O)(C 1～6 Alkyl), -C 0～2 Alkylene-(3-membered cycloalkyl), -C 0～2 Alkylene-(4-membered cycloalkyl), -C 0～2 Alkylene-(6-membered cycloalkyl), -C 0～2 Alkylene-(6-membered heterocycloalkyl), -C 0～2 Alkylene-(6-membered aromatic ring), -C 0～2 Alkylene-OC 1～6 Alkyl, -C 0～4 Alkylene-N(C 1～6 Alkyl)(C 1～6 wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R L2 replace;

[0108] Each R L2 are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0109] Each R Lare independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, methyl, ethyl, n-propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, and halogen-substituted isopropyl;

[0110] or,

[0111] Two R attached to the same carbon atom L , and the carbon atoms connected to it together form a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, or a 6-membered cycloalkyl group.

[0112] Preferably, L is selected from

[0113] Among them, the aa end and X 4 In some specific embodiments of the present invention, the compound is specifically:

[0114] The present invention also provides the use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating IL-17-mediated diseases.

[0115] Furthermore, the IL-17-mediated disease is one or more diseases associated with inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.

[0116] The present invention also provides a pharmaceutical composition, which is a preparation prepared by adding any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0117] The present invention also provides any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in treating diseases or conditions such as psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma and / or COPD.

[0118] The present invention provides a pharmaceutical composition comprising any one of the above compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, diluent or excipient.

[0119] The present invention also provides the use of the aforementioned compound, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a medicament for treating IL-17-mediated diseases.

[0120] The present invention also provides a method for treating psoriasis, comprising administering an effective amount of any one of the above compounds or pharmaceutically acceptable salts thereof to a patient in need thereof.

[0121] The present invention also provides any one of the above compounds or a pharmaceutically acceptable salt thereof for use in therapy.

[0122] The present invention also provides a method for treating or preventing inflammation, cancer or autoimmune diseases in a patient, comprising administering a therapeutically effective amount of any one of the above compounds to a patient in need thereof.

[0123] The present invention also provides any one of the above compounds or pharmaceutically acceptable salts thereof for use in treating psoriasis.

[0124] The present invention also provides use of any of the above compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating psoriasis.

[0125] IL-17-mediated diseases, as defined herein, are diseases in which IL-17 plays a significant role in the pathogenesis of the disease. IL-17's primary function is to coordinate local tissue inflammation, thereby playing a role in various diseases. IL-17-mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.

[0126] "Cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer cells" refer to cells in the early, intermediate, or late stages of a multi-step tumor progression. Cancers include sarcomas, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer. In some embodiments, the compound of Formula I is used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.

[0127] Autoimmune diseases are caused by the body's immune response to substances and tissues normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Grave's disease, celiac disease, Crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barré syndrome, multiple sclerosis, and autoimmune retinopathy. Some embodiments of the present invention relate to treating autoimmune diseases such as psoriasis or multiple sclerosis.

[0128] Inflammatory diseases include a variety of conditions characterized by histopathological inflammation. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation caused by house dust mites, and interstitial cystitis. There is significant overlap between inflammatory diseases and autoimmune diseases. Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma. The immune system is often involved in inflammatory diseases, which are manifested in allergic reactions and some myopathies, and many immune system diseases lead to abnormal inflammation. IL-17A-mediated diseases also include autoimmune inflammatory diseases.

[0129] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0130] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0131] "Substitution" means that the hydrogen atoms in a molecule are replaced by other different atoms or groups; or the lone pair of electrons in the atoms in the molecule are replaced by other atoms or groups. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0132] "Optionally substituted" means that "substitution" can but must not occur, and the description includes instances where it occurs and instances where it does not occur.

[0133] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0134] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may optionally be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups can also be part of other groups, such as -O(C 1～6 alkyl).

[0135] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having the specified number of member atoms. a～b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0136] In the present invention, -C0~2 alkylene can be C0 alkylene, C1 alkylene (e.g., -CH2-), C2 alkylene (e.g., -CH2CH2-, etc.); C0 alkylene means that the group here does not exist and is connected in the form of a chemical bond, such as A-C0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.

[0137] As used herein, "cycloalkyl" and "cycloalkane" refer to saturated or partially saturated cyclic groups having carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused or bridged). The terms "cycloalkyl" and "cycloalkane" include cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Bicyclohexyl. The terms "cycloalkyl" and "cycloalkane" also include partially saturated cyclic groups formed by the fusion of an aromatic ring with a non-aromatic ring, where the attachment point can be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalene-5-yl and 5,6,7,8-tetrahydronaphthalene-5-yl.

[0138] The unsaturated group mentioned in the present invention refers to a group or molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, etc.; the unsaturated carbocyclic group of the present invention may or may not include an aromatic ring group, and the unsaturated heterocyclic group may or may not include a heteroaryl group, which can be freely selected by those skilled in the art.

[0139] "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least one site of vinyl unsaturation (>C=C<). For example, C a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0140] "Alkynyl" refers to a straight chain monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon radicals having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0141] "Halogen" is fluorine, chlorine, bromine or iodine.

[0142] "Halogen alkyl" or "halogen substituted alkyl" means that the hydrogen atoms in the alkyl group may be substituted by one or more halogen atoms. 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0143] "Heterocycloalkyl", "heterocycle", "heterocycloalkane" refers to a saturated or non-aromatic partially saturated ring having a single ring or multiple rings (fused or bridged) containing at least one heteroatom; wherein a heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It generally refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Bicyclic means consisting of two rings with two ring atoms in common, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl. The term "heterocycloalkyl" also includes partially saturated cyclic groups formed by the fusion of an aromatic ring containing at least one heteroatom with a non-aromatic ring, the site of attachment of which may be at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom, examples of which include

[0144] "Aromatic ring group" or "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. An aryl group is typically a monocyclic, bicyclic, or tricyclic aromatic group having multiple carbon atoms. Additionally, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0145] As used herein, "aromatic heterocyclic group" or "aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; a heteroatom includes nitrogen, oxygen, sulfur, or the like. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, there are one to three heteroatoms. Examples of heterocyclic aromatic groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0146] "Stereoisomers" include enantiomers and diastereomers;

[0147] The "-OR", "-NRR" and the like described in the present invention refer to that the R group is connected to the oxygen atom or nitrogen atom via a single bond.

[0148] In the present invention, the oxygen atom in "-C(O)R", "-S(O)2R", etc. is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the carbon atom or sulfur atom by a single bond.

[0149] The “=O” and “=S” mentioned in the present invention refer to an oxygen atom or a sulfur atom connected to a substitution position via a double bond.

[0150] The group description of the present invention It is used to describe the position of group substitution.

[0151] The "deuterated compound" of the present invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0152] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0153] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, including zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be sodium salts, potassium salts, hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0154] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0155] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0156] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0157] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0158] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AvanceIII 400 MHz and Bruker Avance NEO 600 MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0159] LC-MS analysis was performed using a Shimadzu LC-MS2020 (ESI) liquid chromatography-mass spectrometer. HPLC analysis was performed using a Shimadzu LC-20A high-pressure liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reverse-phase preparative chromatograph. Thin-layer chromatography (TLC) silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a 0.4 mm to 0.5 mm diameter. Column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as the carrier. Supercritical fluid chromatography (SFC) analysis and preparative analysis were performed using a Shimadzu SFC-30A instrument.

[0160] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0161] Unless otherwise specified, reactions were conducted under a nitrogen atmosphere. Unless otherwise specified, solutions in the examples are aqueous solutions. Unless otherwise specified, reactions were conducted at room temperature. Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C. Unless otherwise specified, M is moles per liter.

[0162] The reagents described in the examples are abbreviated as follows: DMF: N,N-dimethylformamide; DCM: dichloromethane; TFA: trifluoroacetic acid; MeOH: methanol; Cs2CO3: cesium carbonate; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride; LiAlH 4: lithium aluminum tetrahydride; TBS-Cl: tert-butyldimethylsilyl chloride; THF: tetrahydrofuran; NBS: N-bromosuccinimide; (Boc)2O: di-tert-butyl dicarbonate; Na2CO3: sodium carbonate; B2pin2: diboronic acid pinacol ester; AcOK: potassium acetate; Pd(dppf)2Cl2: 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; n-BuLi: n-butyllithium; MgSO4: sulfur magnesium sulfate; CsF: cesium fluoride; TMSCN: trimethylsilyl cyanide; EA / HCl: hydrogen chloride ethyl acetate solution; Cbz-Osu: benzyl-N-succinimidyl carbonate; K2CO3: potassium carbonate; H2O2: hydrogen peroxide; DMSO: dimethyl sulfoxide; NMP: N-methylpyrrolidone; LiOH.H2O: lithium hydroxide monohydrate; Pd(PPh3)4: tetrakistriphenylphosphine palladium; SOCl2: dichloromethane Sulfoxide; t-BuOK: potassium tert-butoxide; t-BuOH: tert-butanol; Pd / C: palladium on carbon; HCOONH4: ammonium formate; (COCl)2: oxalyl chloride; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DIAD: diisopropyl azodicarboxylate; PPh3: triphenylphosphine; Zn: zinc powder; NH4Cl: ammonium chloride; Ti(OEt)4: tetraisopropyl titanate; Raney Ni: Raney nickel; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(amphos)Cl2: dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II); Pd(OAc)2: palladium acetate; Pd(OH)2: palladium hydroxide; CyJohnphos: 2-(dicyclohexylphosphino)biphenyl; rac-BI-DIME: 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxy,phosphine pentane conjugate; CbzCl: benzyl chloroformate; NaBH(OAc)3: sodium triacetoxyborohydride; K3PO4: potassium phosphate; Py: pyridine; selectfluor: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate).

[0163] Preparation of intermediate A-1

[0164] To a solution of methyl 2-(5-methyl-1H-pyrazol-3-yl)acetate (2.83 g, 18.36 mmol) and DIPEA (11.86 g, 91.78 mmol, 15.99 mL) in DMF (60 mL) was added dropwise SEM-Cl (3.67 g, 22.03 mmol) at 0°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, concentrated to dryness, and purified by silica gel column chromatography to afford intermediate A-1-1 (4.6 g, 88% yield). MS (ESI) m / z = 285 [M+1] + .

[0165] To a solution of Intermediate A-1-1 (4.3 g, 15.12 mmol) in THF (150 mL) was added portionwise LiAlH4 (1.15 g, 30.24 mmol) at -78°C. The temperature was raised to room temperature and allowed to react for 1 hour. After the reaction, the temperature was lowered to -10°C and water (2 mL), 15% aqueous NaOH (2 mL), and water (6 mL) were added dropwise to quench the reaction. The mixture was stirred at room temperature for 10 minutes, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was concentrated to dryness to obtain Intermediate A-1-2 (3.8 g, 98% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 257 [M+1] + .

[0166] To a solution of intermediate A-1-2 (3.8 g, 14.82 mmol) in THF (50 mL) was added TBSCl (4.47 g, 29.64 mmol) and imidazole (2.02 g, 29.64 mmol) at 0°C and stirred at room temperature for 2 hours. After the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with saturated brine and concentrated to dryness. The crude product was purified by silica gel column chromatography to obtain intermediate A-1-3 (4.77 g, 87% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 371 [M+1] + .

[0167] To a solution of intermediate A-1-3 (4.77 g, 12.87 mmol) in DCM (60 mL) was added NBS (2.7 g, 15.17 mmol) and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, aqueous sodium bicarbonate was added to quench the reaction, and DCM was added for extraction. The organic layer was washed with brine and concentrated to dryness. The crude product was purified by silica gel column chromatography to obtain intermediate A-1 (5.5 g, 95% yield). MS (ESI) m / z = 449 [M+1] + .

[0168] Preparation of intermediate A-2

[0169] To a 50 mL single-necked flask, intermediate A-1-1 (206 mg, 724.27 μmol) and DCM (7 mL) were added, followed by the addition of NBS (141.80 mg, 796.69 μmol) at room temperature. The reaction was stirred overnight at room temperature. After completion, the reaction was quenched with aqueous sodium bicarbonate solution and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA 10:1 to 5 / 1) to afford intermediate A-2 (150 mg, 412.86 μmol, 57.0% yield). MS (ESI) m / z = 363 [M+1] + .

[0170] Preparation of intermediate A-3

[0171] To a solution of Intermediate A-2 (600 g, 1.65 mol) in 1,4-dioxane (6 L) were added pinacol borane (570.63 g, 4.46 mol), Pd(OAc)2 (11.22 g, 49.54 mmol), CyJohnphos (34.73 g, 99.09 mmol), and triethylamine (250.66 g, 2.48 mol, 345.50 mL) in that order. After the additions were complete, the atmosphere was evacuated and replaced with nitrogen three times. The mixture was heated to 90°C and stirred under nitrogen overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield Intermediate A-3 (540.6 g, 1.32 mol, 79.77% yield). MS (ESI) m / z = 411 [M+1] + .

[0172] Preparation of intermediate B-1

[0173] To a solution of methyl 2-bromo-5-aminobenzoate (11.5 g, 49.99 mmol) in MeOH (150 mL) was added (Boc)2O (24.00 g, 109.97 mmol) and Na2CO3 (15.89 g, 149.96 mmol). The mixture was stirred at room temperature overnight. After the reaction was complete, water and ethyl acetate were added for extraction, and the organic layer was washed with brine. The organic layer was concentrated to dryness and purified by silica gel column chromatography to obtain intermediate B-1-1 (13.9 g, 84% yield). MS (ESI) m / z = 330 [M+1] + .

[0174] To a solution of Intermediate B-1-1 (6.6 g, 19.99 mmol) in 1,4-dioxane (70 mL) were added B2pin2 (5.58 g, 21.99 mmol), AcOK (3.92 g, 39.98 mmol), and Pd(dppf)Cl2 (731.31 mg, 999.47 μmol) in that order. After the additions were complete, the atmosphere was evacuated and replaced with nitrogen three times. The mixture was heated to 80°C and stirred under nitrogen protection overnight. After the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to yield Intermediate B-1 (6.7 g, 89% yield). MS (ESI) m / z = 378 [M+1] + .

[0175] Preparation of intermediate B-2

[0176] To a solution of methyl 2-bromophenylacetate (10 g, 43.65 mmol) in concentrated sulfuric acid (42 mL) was added dropwise concentrated nitric acid (5.50 g, 87.31 mmol) in an ice-water bath. The mixture was stirred at 0°C for 30 minutes. After the reaction was complete, the mixture was slowly poured into ice water and extracted with ethyl acetate. The organic phases were combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to yield intermediate B-2-1 (9.8 g, 35.76 mmol, 81.91% yield). MS (ESI) m / z = 272 [M-1] - .

[0177] To a solution of intermediate B-2-1 (5 g, 18.24 mmol) in methanol / glacial acetic acid / water (72 mL / 3 mL / 18 mL) was added reduced iron powder (5.09 g, 91.22 mmol) in portions with stirring. After addition, the mixture was heated to reflux and stirred for 3 hours. After monitoring the reaction, the mixture was filtered through hot celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate B-2-2 (3.95 g, 16.19 mmol, 88.73% yield). MS (ESI) m / z = 244 [M+1] + .

[0178] To a solution of intermediate B-2-2 (3.95 g, 16.19 mmol) in tetrahydrofuran (80 mL) were added methanol (726.08 mg, 22.66 mmol) and lithium borohydride (916.89 mg, 42.09 mmol) at room temperature. After addition, the mixture was heated to 60°C and stirred for 2 hours. After completion of the reaction, the mixture was poured into ice water to quench the reaction and extracted with ethyl acetate. The organic phases were combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude intermediate B-2-3 (3.58 g, 14.89 mmol, 92.02% yield). MS (ESI) m / z = 216 [M+1] + .

[0179] To a solution of intermediate B-2-3 (3.58 g, 16.55 mmol) in tetrahydrofuran (80 mL) was added imidazole (2.25 g, 33.10 mmol) and TBSCl (4.99 g, 33.10 mmol) under ice-water bath. After addition, the mixture was heated to room temperature and stirred for 2 hours. After completion of the reaction, the mixture was poured into saturated ammonium chloride solution to quench the reaction and extracted with ethyl acetate. The organic phases were combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate B-2-4 (4.58 g, 13.87 mmol, 83.81% yield). MS (ESI) m / z = 330 [M+1] + .

[0180] To a 250 mL single-necked flask, add intermediate B-2-4 (3 g, 9.08 mmol), pinacol diboron (2.54 g, 9.99 mmol), potassium acetate (1.71 g, 18.16 mmol), and dioxane (50 mL). The mixture was evacuated and replaced with nitrogen three times with stirring. The temperature was raised to 90°C and stirred overnight. After the reaction, the mixture was cooled and the sample was directly purified by silica gel column chromatography to obtain intermediate B-2 (2.12 g, 5.60 mmol, 61.71% yield). MS (ESI) m / z = 378 [M+1] + .

[0181] Preparation of intermediate B-3

[0182] 2-Bromo-4-fluoro-5-nitrobenzoic acid (5 g, 18.94 mmol) and methanol (100 mL) were added dropwise to a 250 mL single-necked flask. Thionyl chloride (6.76 g, 56.82 mmol, 4.13 mL) was added dropwise in an ice-water bath. The mixture was heated to 60°C and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate and washed sequentially with aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate B-3-1 (5.03 g, 18.10 mmol, 95.58% yield). MS (ESI) m / z = 276 [M-1] - .

[0183] To a 250 mL single-necked flask, add intermediate B-3-1 (5 g, 17.98 mmol) and ethanol / glacial acetic acid / water (120 mL / 5 mL / 30 mL). Reduced iron powder (5.02 g, 89.92 mmol) was added portionwise with stirring at room temperature. After addition, the mixture was heated to reflux for 2 hours. After cooling slightly, the mixture was filtered through celite while hot and washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate and washed sequentially with aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate B-3-2 (4.3 g, 17.34 mmol, 96.40% yield). MS (ESI) m / z = 248 [M+1] + .

[0184] To a 250 mL single-necked flask, intermediate B-3-2 (3.97 g, 16.00 mmol), pinacol diboron (4.47 g, 17.61 mmol), potassium acetate (3.01 g, 32.01 mmol), and dioxane (100 mL) were added, followed by Pd(dppf)Cl2 (585.54 mg, 0.800 mmol). The mixture was evacuated and replaced with nitrogen three times with stirring. The temperature was raised to 85°C and stirred overnight. After the reaction, the mixture was cooled and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate B-3 (4.83 g, 13.59 mmol, 84.89% yield). MS (ESI) m / z = 296 [M+1] + .

[0185] Preparation of intermediate B-4

[0186] Referring to the synthesis method of intermediate B-1, methyl 4-amino-2-bromo-4-chlorobenzoate was used instead of intermediate B-1-1. The remaining reagents and operations were the same to obtain intermediate B-4. MS (ESI) m / z = 312 [M+1] + .

[0187] Preparation of intermediate C-1

[0188] To a solution of (methoxymethyl)triphenylphosphonium chloride (300 g, 4.09 mol) in dry THF (2.4 L) in an ice-water bath and under nitrogen, n-BuLi (2.5 M in hexane, 4.09 mol, 1.63 L) was added dropwise. The mixture was stirred at 0°C for 1 hour, gradually turning dark brown. A solution of dicyclopropyl ketone (300 g, 2.72 mol) in THF (0.6 L) was then added dropwise. The reaction mixture was heated to 60°C and stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with 30% aqueous NH4Cl, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product, which was isolated and purified by vacuum distillation to afford Intermediate C-1-1 (279 g, 74.2% yield) as a clear oil.

[0189] To a solution of Intermediate C-1-1 (279 g, 2.02 mol) in dry THF (1.7 L) was added 6 M HCl (1.7 L) in an ice-water bath. The reaction mixture was heated to 60°C and stirred at this temperature for 5 hours. After completion, the reaction was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude oil, Intermediate C-1-2 (239.6 g), which was used directly in the next reaction without further purification.

[0190] To a 5L three-necked flask, intermediate C-1-2 (239g, 1.92mol, based on 100% purity) and DCM (2.5L) were added, followed by (S)-(+)-p-methylbenzenesulfenamide (299g, 1.92mol), anhydrous magnesium sulfate (697g, 5.79mol), and tetrahydropyrrole (13.73g, 0.193mol). The reaction mixture was stirred overnight at room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40°C. Petroleum ether was added to the resulting filtrate, which was concentrated and separated and purified to obtain intermediate C-1-3 (217g, 43% yield). MS (ESI) m / z = 262 [M+1] + .

[0191] To a solution of intermediate C-1-3 (217 g, 0.83 mol) in n-hexane (2 L) was added CsF (252 g, 1.66 mol) with stirring. The mixture was cooled to 0°C under nitrogen, and then TMSCN (165 g, 1.66 mol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the mixture was concentrated to dryness, then slurried and filtered twice with n-hexane. The solid was then concentrated under reduced pressure to dryness to yield intermediate C-1-4 (168 g, 70% yield). MS (ESI) m / z = 289 [M+1]+ .

[0192] Intermediate C-1-4 (84 g, 2.92 mol) was dissolved in MeOH (840 mL) and HCl / EA (4 M, 146 ml, 0.583 mol) was added under ice-water bath. The mixture was stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure. The crude product was washed several times with petroleum ether, filtered, and the filter cake dried to obtain intermediate C-1-5 (54.4 g), which was used directly in the next reaction without purification. MS (ESI) m / z = 151 [M+1] + .

[0193] To a mixture of intermediate C-1-5 (54.4 g, 0.363 mol, based on 100% purity) in THF (300 mL) / H2O (300 mL) was added K2CO3 (100.74 g, 0.73 mol) and CbzOsu (90.39 g, 0.363 mol) under ice-water bath. The mixture was stirred at 25°C for 2 hours. After completion of the reaction, ethyl acetate was added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography to obtain intermediate C-1-6 (93.6 g, 0.330 mol, 90.8% yield) as a white solid. MS (ESI) m / z = 285 [M+1] + .

[0194] To a solution of intermediate C-1-6 (75.4 g, 0.264 mol) in DMSO (750 mL) was added K2CO3 (54.9 mg, 0.398 mol). The temperature was cooled to 10°C, and then H2O2 (90 g, 0.79 mol, 30% content) was added dropwise. The reaction solution was stirred at 25°C overnight. After completion, the reaction was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate C-1-7 (73.5 g, 0.242 mol, 91.6% yield), which was used directly in the next step without purification. MS (ESI) m / z = 303 [M+1] + .

[0195] Under nitrogen, n-BuLi (204 mL, 0.5 mol, 2.5 M solution in hexane) was added dropwise to a mixture of intermediate C-1-7 (73.5 g, 0.242 mol) in dry THF (500 mL) / NMP (150 mL) at -78°C. The reaction was stirred and maintained at -78°C for 1 hour. A solution of (Boc)2O (57.5 mg, 0.26 mol) in THF (250 mL) was then added, and the reaction was stirred and continued for 1 hour. After completion, the reaction was quenched by the careful and slow addition of cold 30% aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield crude intermediate C-1-8 (86 g, 0.214 mol), which was used directly in the next step without further purification. MS (ESI) m / z = 403 [M+1] + .

[0196] To a solution of intermediate C-1-8 (86 g, 0.214 mol) in tetrahydrofuran (800 mL) and H2O (200 mL) was added LiOH.H2O (17.89 g, 0.426 mol). The temperature was raised to 40°C and stirred at this temperature overnight. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was dissolved in water and impurities were extracted with ethyl acetate. The temperature was cooled in an ice-water bath and the pH was adjusted to 2-3 with 6M HCl. The product was then extracted with ethyl acetate and concentrated to obtain the crude product. The product was separated and purified by column chromatography to obtain intermediate C-1 (48 g, 0.158 mol, 74.07% yield). MS (ESI) m / z = 304 [M+1] + .

[0197] Preparation of intermediate C-2

[0198] At zero degrees Celsius, DIAD (2099 g, 10.39 mol) was added dropwise to a mixed solution of 3-fluorophenol (1063 g, 9.49 mol), ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (1435 g, 9.96 mol), and PPh3 (2741 g, 10.46 mol) in THF (15 L). The temperature was maintained below 0°C, and after completion of the addition, the mixture was allowed to warm to room temperature and allowed to react overnight. LCMS indicated completion of the reaction. The reaction solution was concentrated to dryness, and 12 L of a 15:1 PE:EA solution was added. The mixture was stirred for 30 minutes to precipitate a large amount of solid. The solid was passed through a short silica gel column, and the silica gel layer was rinsed with 15 L of a 15:1 PE:EA solution. The filtrate was concentrated to dryness to obtain intermediate C-2-1, which was used directly in the next reaction at 100%. MS (ESI) m / z = 239 [M+1] + .

[0199] To a mixture of intermediate C-2-1 (9.49 mol, calculated as 100% from the previous step) in 95% EtOH (8 L) / H₂O (1.6 L) was added LiOH (988.4 g, 23.72 mol), and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated, the crude product diluted with water, and concentrated HCl was added dropwise to adjust the pH to 3-4. The mixture was then extracted with DCM. The organic phases were combined, washed three times with water and saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness. Three liters of petroleum ether were added, stirred for 30 minutes, filtered, and the solid washed with petroleum ether. The solid was dried to give intermediate C-2-2 (1495 g, 7.12 mol, 75% yield for two steps), which was used directly in the next step without purification. MS (ESI) m / z = 211 [M+1] + .

[0200] Under nitrogen protection, oxalyl chloride (COCl) 2 (1365.2 g 10.75 mol) was added dropwise to a mixed solution of intermediate C-2-2 (1505 g 7.16 mol) in DCM (10 L) / DMF (50 mL) at zero degrees Celsius. The mixture was stirred at zero degrees Celsius for 3 hours, then cooled to -10°C, AlCl 3 (1904.56 g, 14.32 mol) was added in batches, and the reaction solution was slowly warmed to room temperature and stirred for another hour. The reaction solution was slowly poured into ice water, the organic phase was separated, and the aqueous phase was extracted 3 times with DCM. The organic phases were combined, washed 3 times with water, washed with saturated sodium bicarbonate solution until weakly alkaline, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude intermediate C-2-3 (1200 g, 6.25 mol, 85.3% yield), which was used directly in the next reaction without purification.

[0201] Under nitrogen, n-BuLi (2.5 M in hexane, 0.677 mol, 271 ml) was added dropwise to a solution of (methoxymethyl)triphenylphosphonium chloride (0.677 mol, 232.1 g) in anhydrous THF (1000 mL) in an ice bath. The mixture was stirred at 0°C for 1 hour, turning dark brown. A solution of intermediate C-2-3 (100 g, 0.521 mol) in THF was then added dropwise. The reaction mixture was heated to 60°C and stirred for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched with 30% aqueous NH4Cl, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (0-10% PE / EA) to afford C-2-4 (114.74 g, 0.521 mol, 100% yield) as a clear oil.

[0202] A solution of intermediate C-2-4 (114 g, 0.518 mmol) in THF (570 mL) was cooled to 0°C. 6M HCl (570 mL) was slowly added dropwise at a temperature below 10°C. The mixture was heated to 60°C and stirred at this temperature for 5 hours. After completion of the reaction, ethyl acetate was added for extraction. The combined organic phases were washed once with a 10% aqueous sodium bicarbonate solution and once with saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford intermediate C-2-5 (106.8 g, 0.518 mol, 100% yield) as an oil, which was used directly in the next reaction without further purification.

[0203] Intermediate C-2-5 (106.8 g, 0.518 mol), (S)-(+)-tert-butylsulfenamide (62.78 g, 0.518 mol), anhydrous THF (1000 mL) and (EtO)4Ti (236.3 g, 1.036 mol) were mixed in a 2000 mL single-necked bottle. Under nitrogen, the temperature was raised to 60°C and stirred for 5 hours. The mixture was cooled to room temperature, and water and ethyl acetate were added. The insoluble matter was filtered off. The filtrate was separated and the aqueous layer was extracted twice with ethyl acetate. The separated organic phases were combined and concentrated to obtain a brown oil, which was separated and purified by silica gel column chromatography (eluent: PE / EA 0-50%) to obtain intermediate C-2-6 (128 g, 0.414 mol, 80% yield) as a light yellow solid. MS (ESI) m / z = 310 [M+1] + .

[0204] To a solution of intermediate C-2-6 (128 g, 0.414 mol) in MTBE (2560 mL) was added CsF (125.78 g, 0.828 mol), followed by TMSCN (82.1 g, 0.828 mol) at room temperature. The reaction mixture was stirred at 20-25°C overnight. After completion of the reaction, a large amount of solid precipitated, which was filtered and dissolved in water and ethyl acetate. The organic phase was separated and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was added to MTBE (5 v / m) and heated to reflux for 1 hour. The temperature was then gradually lowered to room temperature and stirred for 2 hours. Filtering afforded intermediate C-2-7 (37.6 g, 0.112 mol, 27% yield) as an off-white solid. MS (ESI) m / z = 337 [M+1] + .

[0205] To a solution of intermediate C-2-7 (37.6 g, 0.112 mol) in MeOH (376 mL) was added dropwise HCl / EA (4 M, 56 ml, 0.224 mol). The mixture was stirred at room temperature for 2 h. After completion, the reaction solution was concentrated, and the crude product was washed once with methyl tert-butyl ether, filtered, and dried to obtain intermediate C-2-8 (25.52 g, 0.110 mol, 98% yield), which was used directly in the next step without purification. MS (ESI) m / z = 233 [M+1] + .

[0206] To a mixture of intermediate C-2-8 (25.52 g, 0.110 mol) in THF (153 mL) / H2O (77 mL) at room temperature were added K2CO3 (45.6 g, 0.330 mol) and Cbz-Osu (54.82 g, 0.220 mol). The mixture was stirred at 40°C overnight. After completion of the reaction, the mixture was extracted with ethyl acetate. The combined organic phases were concentrated to obtain a crude product which was separated and purified by MPLC to afford intermediate C-2-9 (38.66 g, 0.106 mol, 96.02% yield) as an oil. MS (ESI) m / z = 367 [M+1] + .

[0207] To a solution of intermediate C-2-9 (38.66 g, 0.106 mol) in DMSO (387 mL) was added K2CO3 (14.65 g, 0.106 mol), followed by the dropwise addition of H2O2 (24 g, 30%, 0.212 mol). The reaction mixture was stirred at 25°C for 2 hours. After completion, the reaction mixture was diluted with a large amount of water, resulting in the precipitation of a large amount of white solid. The solid was filtered, and the filter cake was thoroughly rinsed with water. The filter cake was then dissolved in an appropriate amount of ethyl acetate, washed once with water, and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford intermediate C-2-10 (39.93 g, 0.104 mol, 98% yield) as a solid. MS (ESI) m / z = 385 [M+1] + .

[0208] Under nitrogen, n-BuLi (96 ml, 0.239 mol, 2.5 M in hexane) was added dropwise to a mixture of intermediate C-2-10 (39.93 g, 0.104 mol) in anhydrous THF (400 mL) / NMP (80 mL) at -78°C. The reaction was stirred at -78°C for 1 hour. A solution of (Boc)2O (29.06 g, 0.135 mol) in THF was then added, and stirring continued for 1 hour. After completion, the reaction was quenched by the careful and slow addition of cold 30% aqueous NH4Cl. The product was extracted with ethyl acetate and concentrated to afford intermediate C-2-11 (50.4 g, 0.104 mol, 100.00% yield), which was used directly in the next step without further purification. MS (ESI) m / z = 485 [M+1] + .

[0209] To a mixture of intermediate C-2-11 (50.4 g, 0.104 mol) in THF (806 mL) / H2O (201 mL) was added LiOH monohydrate (8.67 g, 0.208 mol), the temperature was raised to 40 ° C and stirred at this temperature overnight. After the reaction was completed, the pH of the aqueous layer was adjusted to 3-4 with 2M HCl, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate, and diisopropylamine (12.6 g, 0.125 mol) was added dropwise at room temperature with stirring. After the addition, stirring was continued for 2 hours. A white solid was obtained by filtration. The solid was dissolved in appropriate amounts of water and ethyl acetate, and the mixture was added with 2M The pH of the aqueous layer was adjusted to 3-4 with HCl. The organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the pure intermediate C-2 (27 g, 70 mmol, 67.3% yield over two steps). MS (ESI) m / z = 386 [M+1] + . 1H NMR (400MHz, Methanol-d4) δ7.30 (q, J=7.7, 6.6Hz, 5H), 7.02 (dd, J=8.5, 6.6Hz, 1H), 6.52 ( dd,J=10.6,2.6Hz,1H),6.44(td,J=8.5,2.7Hz,1H),5.06(d,J=12.5Hz,1H),4.96(d,J=12.6 Hz, 1H), 4.68 (dd, J = 11.3, 2.0 Hz, 1H), 4.54 (d, J = 7.6 Hz, 1H), 3.27 (d, J = 1.8 Hz, 1H), 2.38 (d, J = 7.5 Hz, 1H), 0.94–0.79 (m, 2H), 0.75–0.64 (m, 1H), 0.63–0.53 (m, 2H), 0.46–0.35 (m, 1H). Optical rotation data: test temperature 25°C, sample concentration 0.002 g / 100 mL, solvent methanol, specific rotation -132.8°, chiral purity 98%.

[0210] Preparation of intermediate C-3

[0211] Synthesis method: Refer to the synthesis method in patent UCB-WO2020 / 11731,2020,A1 to obtain intermediate C-3, MS (ESI) m / z = 306 [M+1] + .

[0212] Preparation of intermediate C-4

[0213] Synthesis method: Refer to the synthesis method in patent WO2020 / 146194,2020,A1, except that the double bond reduction in the middle step is Pd / C reduction. The rest of the reagents and procedures are the same to obtain intermediate C-4, MS (ESI) m / z = 328 [M+1] + .

[0214] Preparation of intermediate C-5

[0215] To a three-necked flask, add (S)-(-)-NZ-aziridine-2-carboxylic acid methyl ester (10 g, 42.55 mmol), 2-trifluoromethyl-2-propanol (27.23 g, 212.77 mmol), and dichloromethane (90 mL). The atmosphere was replaced with nitrogen three times under vacuum. The reaction mixture was cooled to 0°C and a solution of boron trifluoride in ether (4 mL) was added dropwise. After the addition, the mixture was heated to room temperature and stirred for 6 hours. After the reaction was complete, the mixture was cooled in an ice-water bath, quenched with methanol, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate C-5-1 (400 mg, 1.10 mmol, 2.59% yield). MS (ESI) m / z = 364 [M+1] + .

[0216] To a single-necked flask, intermediate C-5-1 (400 mg, 1.10 mmol) and tetrahydrofuran / methanol (10 mL / 10 mL) were added. The mixture was cooled in an ice-water bath and a 10 mL aqueous solution of sodium hydroxide (79.27 mg, 1.98 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, the pH was adjusted to a weak base with 6N hydrochloric acid. The organic solution was concentrated under reduced pressure at 0°C to remove the organic solution. The mixture was diluted with water and extracted twice with ethyl acetate, which was discarded. The aqueous phase was again adjusted to pH 4 with 6N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate C-5 (298 mg, 853.13 μmol, 86.10% yield). MS (ESI) m / z = 350 [M+1] + .

[0217] Preparation of intermediate D-1

[0218] To a three-necked flask, methyl 1H-3-pyrazolecarboxylate (1.31 g, 10.41 mmol), triphenylphosphine (3.28 g, 12.49 mmol), and dry tetrahydrofuran (80 mL) were added. The atmosphere was evacuated and replaced with nitrogen three times. 1,1-Difluoro-2-propanol (1 g, 10.41 mmol) was then added via syringe. The reaction mixture was cooled to -5°C, and DIAD (2.52 g, 12.49 mmol) was added dropwise. After addition, the mixture was warmed to room temperature and stirred overnight. After completion of the reaction, intermediate D-1-1 was directly purified by silica gel column chromatography to afford intermediate D-1-1 (1.5 g, 3.82 mmol, 36.70% yield, 52% purity. The first isomer was less polar, while the other positional isomer was more polar. Due to impurities in this step, the structure was confirmed by NOE after hydrolysis in the next step. MS (ESI) m / z = 205 [M+1] + .

[0219] To a single-necked flask, intermediate D-1-1 (1.5 g, 3.82 mmol, 52% purity) and tetrahydrofuran / methanol (12 mL / 12 mL) were added. The mixture was cooled in an ice-water bath and a 12 mL aqueous solution of sodium hydroxide (305.62 mg, 7.64 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, the organic solution was concentrated under reduced pressure to remove the organic solution, diluted with water, and extracted twice with ethyl acetate, which was discarded. The aqueous phase was then adjusted to pH 4 with 6N hydrochloric acid to precipitate a large amount of white solid. This solid was filtered under reduced pressure, washed with water, and dried to obtain intermediate D-1 (0.56 g, 2.39 mmol, 62.44% yield, 81% purity; structure confirmed by NOE). MS (ESI) m / z = 191 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 7.66 (t, J = 2.3 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.27 (tdd, J = 55.6, 5.0, 2.4 Hz, 1H), 5.85–5.67 (m, 1H), 1.54 (dd, J = 7.0, 1.2 Hz, 3H). Preparation of intermediates D-2 to D-43

[0220] Referring to the synthetic route of intermediate D-1, in step 1, 1-difluoro-2-propanol was replaced with the corresponding alcohol in the table below. The remaining reagents and procedures were the same to obtain the corresponding intermediate in the table below.

[0221] Preparation of intermediate D-44

[0222] Referring to the synthetic route of intermediate D-1, (R)-(-)-1-benzyloxy-2-propanol was used instead of 1,1-difluoro-2-propanol in step 1. The remaining reagents and procedures were the same to obtain intermediate D-44-2. MS (ESI) m / z = 261 [M+1] + .

[0223] To a single-necked flask, intermediate D-44-2 (2 g, 7.68 mmol) and methanol (100 mL) were added, followed by Pd / C (200 mg, w / w 10%). After addition, the mixture was evacuated and replaced with hydrogen three times. The reaction was stirred at room temperature under a hydrogen balloon overnight. After completion of the reaction, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate D-44 (1.30 g, 7.64 mmol, 99.43% yield). MS (ESI) m / z = 171 [M+1] + .

[0224] Preparation of intermediate D-45

[0225] Referring to the synthetic route of intermediate D-44, 3-benzyloxy-1-propanol was used instead of (R)-(-)-1-benzyloxy-2-propanol in step 1. The remaining reagents and procedures were the same to obtain intermediate D-45. MS (ESI) m / z = 171 [M+1] + .

[0226] Preparation of intermediate D-46

[0227] To a three-necked flask, methyl 1-H-pyrazole-5-carboxylate (30 g, 237.88 mmol) and dry tetrahydrofuran (300 mL) were added. The atmosphere was replaced with nitrogen three times under vacuum, and the mixture was cooled to 0°C in an ice-water bath. Sodium hydride (14.27 g, 356.82 mmol) was then added portionwise. After addition, the atmosphere was replaced with hydrogen three times under vacuum, and the mixture was stirred at 0°C for 30 minutes. SEMCl (47.59 g, 285.46 mmol) was then added dropwise at 0°C. After addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was cooled to 0°C in an ice-water bath, and the reaction mixture was slowly poured into icy ammonium chloride solution to quench the reaction. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate D-46-1 (55 g, 214.53 mmol, 90.18% yield). MS (ESI) m / z = 257 [M + 1] + .

[0228] To a single-necked flask, add intermediate D-46-1 (60 g, 234.03 mmol) and tetrahydrofuran / methanol (100 mL / 300 mL). Cool in an ice-water bath and add a 200 mL solution of lithium hydroxide (29.46 g, 702.10 mmol). After addition, warm to room temperature and stir for 2 hours. After completion, concentrate under reduced pressure to remove the organic solution, dilute with water, extract twice with ethyl acetate, and discard. The aqueous phase is then adjusted to pH 4 with 6N hydrochloric acid to precipitate a large amount of white solid. Filter under reduced pressure, wash with water, and dry to obtain intermediate D-46-2 (50 g, 206.32 mmol, 88.16% yield). MS (ESI) m / z = 243 [M+1] + .

[0229] To a single-necked flask, add intermediate D-46-2 (62 g, 255.83 mmol) and DMF (1000 mL). Cool in an ice-water bath, then add potassium carbonate (45.96 g, 332.58 mmol). Warm to room temperature and stir for 30 minutes. Then cool in an ice-water bath and add benzyl bromide (113.77 g, 665.16 mmol) dropwise. Warm to room temperature and stir overnight. After completion, pour into ice water and extract twice with ethyl acetate. The organic phase is washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to yield intermediate D-46-3 (60 g, 180.47 mmol, 70.54% yield). MS (ESI) m / z = 333 [M+1] + .

[0230] To a single-necked flask, add intermediate D-46-3 (20 g, 60.24 mmol) and dichloromethane (150 mL). Cool in an ice-water bath, then add trifluoroacetic acid (150 mL). After addition, warm to room temperature and stir for 1 hour, then concentrate to dryness under reduced pressure. The crude product is dissolved in dichloromethane and the pH is adjusted to 8 with sodium bicarbonate solution while stirring. The organic phase is separated, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to yield intermediate D-46-4 (10.98 g, 54.34 mmol, 90.20% yield). MS (ESI) m / z = 203 [M+1] + .

[0231] Referring to the synthetic route of intermediate D-1, N-tert-butyl-3-hydroxyazetidine was used instead of 1,1-difluoro-2-propanol in step 1. The remaining reagents and procedures were the same to obtain intermediate D-46-5. MS (ESI) m / z = 314 [M+1] + .

[0232] To a single-necked flask, intermediate D-46-5 (300 mg, 957.26 μmol) and methanol (10 mL) were added, followed by Pd / C (45 mg, w / w 15%) and Pd(OH)2 (45 mg, w / w 15%). After addition, the atmosphere was replaced with hydrogen three times under vacuum, and the reaction was stirred at room temperature under a hydrogen balloon for 3 hours. After completion of the reaction, the mixture was filtered over celite, washed with methanol, and the filtrate was concentrated to dryness under reduced pressure to yield intermediate D-46 (190 mg, 850.98 μmol, 88.90% yield). MS (ESI) m / z = 224 [M+1] + .

[0233] Preparation of intermediate D-47

[0234] Referring to the synthetic route of intermediate D-44, 2-benzyloxy-1-ethanol was used instead of (R)-(-)-1-benzyloxy-2-propanol in step 1. The remaining reagents and procedures were the same to obtain intermediate D-47-1. MS (ESI) m / z = 157 [M+1] + .

[0235] Referring to the synthetic route of intermediate D-46, intermediate D-47-1 was used instead of intermediate D-46-2 in step 3. The remaining reagents and procedures were the same to obtain intermediate D-47-2. MS (ESI) m / z = 247 [M+1] + .

[0236] To a single-necked flask, intermediate D-47-2 (498.98 mg, 2.80 mmol) and acetonitrile (20 mL) were added, followed by cuprous iodide (88.94 mg, 466.98 μmol). 2-Fluorosulfonyldifluoroacetic acid (498.98 mg, 2.80 mmol) was dissolved in acetonitrile (5 mL) and added dropwise. After addition, the mixture was heated to 50°C and stirred for 2 hours. After completion, the reaction was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate D-47-3 (145 mg, 489.42 μmol, 26.20% yield). MS (ESI) m / z = 297 [M+1] + .

[0237] Referring to the synthetic route of intermediate D-46, intermediate D-47-3 was used instead of intermediate D-46-5 in step 6. The remaining reagents and procedures were the same to obtain intermediate D-47. MS (ESI) m / z = 207 [M+1] + .

[0238] Preparation of intermediate D-48

[0239] Benzyloxyethanol (3 g, 19.71 mmol), dichloromethane (100 mL), and triethylamine (7.98 g, 78.85 mmol, 11.00 mL) were added to a three-necked flask. The mixture was cooled to 0°C in an ice-water bath and methylsulfonyl chloride (4.52 g, 39.42 mmol) was added dropwise. After the mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, water was added to quench the reaction and the mixture was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield intermediate D-48-1 (5.7 g, 19.55 mmol, 99.20% yield).

[0240] To a single-necked flask, add intermediate D-48-1 (5.7 g, 19.55 mmol) and DMF (50 mL), followed by sodium azide (1.29 g, 19.80 mmol). After addition, heat to 90°C and stir for 12 hours. After completion, cool the reaction, quench with aqueous sodium bicarbonate, and extract with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield intermediate D-48-2 (2.95 g, 16.65 mmol, 84.07% yield).

[0241] To a single-necked flask, intermediate D-48-2 (2.95 g, 16.65 mmol) and toluene (40 mL) were added, followed by methyl propiolate (1.40 g, 16.65 mmol). After addition, the mixture was heated to 100°C and stirred for 12 hours. After completion of the reaction, the mixture was cooled and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography, and the least polar product spot was collected. Intermediate D-48-3 (749 mg, 2.87 mmol, 17.22% yield) was obtained, as confirmed by H-NMR and NOE. MS (ESI) m / z = 262 [M+1] + . 1 H NMR (600MHz, Methanol-d4) δ8.15(s,1H),7.29–7.19(m,3H),7.17–7.12(m,2H),4.96(t,J=5.3Hz,2H),4.43(s,2H),3.87(t,J=5.3Hz,2H),3.83(s,3H).

[0242] To a single-necked flask, intermediate D-48-3 (749 mg, 2.87 mmol) and methanol (20 mL) were added, followed by Pd / C (150 mg, w / w 20%) and Pd(OH)2 (150 mg, w / w 20%). After addition, the atmosphere was replaced with hydrogen three times under vacuum, and the reaction was stirred at room temperature under a hydrogen balloon for 12 hours. After completion of the reaction, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate D-48-4 (541 mg, 2.84 mmol, 99.24% yield). MS (ESI) m / z = 172 [M+1] + .

[0243] Referring to the synthetic route of intermediate D-47 step 2, intermediate D-48-4 was used instead of intermediate D-47-2 in step 2. The remaining reagents and procedures were the same to obtain intermediate D-48-5. MS (ESI) m / z = 222 [M+1] + .

[0244] Referring to the synthetic route of intermediate D-1, step 2, intermediate D-48-5 was used instead of intermediate D-1-1 in step 2. The remaining reagents and procedures were the same to obtain intermediate D-48. MS (ESI) m / z = 208 [M+1] + .

[0245] Preparation of intermediate D-49

[0246] To a single-necked flask, intermediate D-43-1 (189 mg, 943.78 μmol) and dichloromethane (6 mL) were added, the temperature was lowered to 0°C, and m-CPBA (210.77 mg, 1.04 mmol) was added. After the addition, the mixture was heated to room temperature and stirred for 3 hours. After completion of the reaction, the temperature was lowered to 0°C, and a saturated sodium sulfite solution was added to quench the reaction. The mixture was then extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate D-49-1 (190 mg, 818.06 μmol, 86.68% yield). MS (ESI) m / z = 233 [M+1] + .

[0247] To a single-necked flask, add intermediate D-49-1 (730 mg, 3.14 mmol) and tetrahydrofuran / methanol (5 mL / 5 mL). Cool in an ice-water bath and add a 5 mL solution of lithium hydroxide monohydrate (395.68 mg, 9.43 mmol). After addition, warm to room temperature and stir for 2 hours. After completion, concentrate under reduced pressure to remove the organic solution, dilute with water, extract twice with ethyl acetate, and discard. The aqueous phase is then adjusted to pH 4 with 6N hydrochloric acid to precipitate a large amount of white solid. Filter under reduced pressure, wash with water, and dry to obtain intermediate D-49 (650 mg, 2.98 mmol, 94.76% yield). MS (ESI) m / z = 219 [M+1] + .

[0248] Preparation of intermediate D-50

[0249] To a single-necked flask, add Intermediate D-45 (2 g, 11.76 mmol) and DMF (39 mL). Cool in an ice-water bath, then add potassium carbonate (3.25 g, 23.52 mmol). Warm to room temperature and stir for 30 minutes. Then cool in an ice-water bath and dropwise add iodomethane (1.84 g, 12.94 mmol). After addition, warm to room temperature and stir overnight. After completion of the reaction, pour into ice water and extract twice with ethyl acetate. The organic phase is washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to yield Intermediate D-50-1 (2.09 g, 11.36 mmol, 96.64% yield). MS (ESI) m / z = 185 [M+1] + .

[0250] To a three-necked flask, oxalyl chloride (206.73 mg, 1.63 mmol) and DCM (4 mL) were added. The mixture was cooled to -60°C in a dry ice-ethanol bath, and DMSO (254.52 mg, 3.26 mmol) was added dropwise. The mixture was stirred at this temperature for 30 minutes. Then, a dichloromethane solution of Intermediate D-50-1 (100 mg, 542.91 μmol) was added dropwise. After the addition, the mixture was stirred at this temperature for 1 hour. Triethylamine (329.62 mg, 3.26 mmol) was then added dropwise. After the addition, the mixture was gradually heated to 0°C and stirred for 30 minutes. After the reaction was complete, the mixture was poured into ice water and extracted twice with dichloromethane. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude Intermediate D-50-2 (100 mg, 542.91 μmol).

[0251] To a single-necked flask, intermediate D-50-2 (100 mg, 542.91 μmol) and tetrahydrofuran (2 mL) were added, followed by cesium fluoride (4.17 mg, 27.45 μmol) and trifluoromethyltrimethylsilane (85.86 mg, 603.81 μmol). The mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate D-50-3 (40 mg, 158.61 μmol, 28.90% yield). MS (ESI) m / z = 253 [M+1] + .

[0252] To a single-necked flask, intermediate D-50-3 (40 mg, 158.61 μmol) and tetrahydrofuran / methanol (1 mL / 1 mL) were added. The mixture was cooled in an ice-water bath and a 1 mL aqueous solution of lithium hydroxide monohydrate (19.97 mg, 475.83 μmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion, the reaction was concentrated under reduced pressure to remove the organic solution, diluted with water, extracted twice with ethyl acetate, and discarded. The aqueous phase was adjusted to pH 4 with 6N hydrochloric acid and extracted twice with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain intermediate D-50 (25 mg, 104.97 μmol, 66.18% yield). MS (ESI) m / z = 239 [M+1] + .

[0253] Preparation of intermediate D-51

[0254] To a single-necked flask, add intermediate D-39-1 (280 mg, 1.31 mmol) and dichloromethane (6 mL). The temperature was lowered to 0°C, and m-CPBA (247.55 mg, 1.44 mmol) was added. After the addition, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, the temperature was lowered to 0°C, and a saturated sodium sulfite solution was added to quench the reaction. The mixture was then extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate D-51-1 (248.39 mg, 1.08 mmol, 82.54% yield). MS (ESI) m / z = 231 [M+1] + .

[0255] To a single-necked flask, intermediate D-51-1 (200 mg, 868.49 μmol) and THF / MeOH / H2O (3 mL / 3 mL / 3 mL) were added, followed by hydrated lithium hydroxide (3.25 g, 23.52 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the organic solvent was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 4 with 6N HCl. The mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain crude intermediate D-51 (120 mg, 554.90 μmol, 63.89% yield). MS (ESI) m / z = 217 [M+1] + , and used directly in the next step without purification.

[0256] Preparation of intermediate D-52

[0257] To a three-necked flask, triethyl 2-fluoro-2-phosphorylacetate (1 g, 4.13 mmol) and dry THF (10 mL) were added. The atmosphere was replaced with nitrogen three times under vacuum. The temperature was then cooled to -60°C in a dry ice-ethanol bath. n-Butyllithium (1.65 mL, 4.13 mmol) was added dropwise. The reaction was maintained at this temperature and stirred for 10 minutes. Isobutyraldehyde (238.19 mg, 3.30 mmol) was then added dropwise. The mixture was gradually warmed to room temperature and stirred for 1 hour. After completion, the reaction was quenched by pouring into saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude intermediate D-52-1 (436 mg, 2.72 mmol, 65.92% yield), which was used directly in the next step without purification.

[0258] To a single-necked flask, intermediate D-52-1 (436 mg, 2.72 mmol) and THF / EtOH / H2O (8 mL / 0.8 mL / 3 mL) were added, followed by hydrated lithium hydroxide (125.75 mg, 2.99 mmol). The mixture was stirred at room temperature for 2 hours. After completion, the pH was adjusted to 4 with 6N HCl in an ice-water bath. The mixture was extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude intermediate D-52 (337 mg, 2.55 mmol, 93.70% yield). MS (ESI) m / z = 131 [M-1] + , and used directly in the next step without purification.

[0259] Preparation of intermediate D-53

[0260] Referring to the synthetic route of intermediate D-52, cyclopropylcarboxaldehyde was used instead of isobutylaldehyde in step 1. The remaining reagents and procedures were the same to obtain intermediate D-53. MS (ESI) m / z = 129 [M-1] + , and used directly in the next step without purification.

[0261] Preparation of intermediate D-54

[0262] Referring to the synthetic route of intermediate D-52, acetone was used instead of isobutyraldehyde in step 1. The remaining reagents and procedures were the same to obtain intermediate D-54. MS (ESI) m / z = 117 [M-1] + , and used directly in the next step without purification.

[0263] Preparation of intermediate D-55

[0264] To a single-necked flask, methyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate (1 g, 4.59 mmol) and DMF (15 mL) were added, followed by zinc cyanide (807.76 mg, 6.88 mmol) and tetrakistriphenylphosphine (264.85 mg, 229.31 μmol). The atmosphere was evacuated and replaced with nitrogen three times. The temperature was raised to 95°C and stirred for 16 hours. After completion, the reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate D-55-1 (680 mg, 4.14 mmol, 90.32% yield).

[0265] 1 H NMR (600MHz, Chloroform-d) δ6.89 (d, J = 4.3 Hz, 1H), 6.74 (d, J = 4.3 Hz, 1H), 4.07 (s, 3H), 3.87 (s, 3H).

[0266] To a single-necked flask, intermediate D-55-1 (630 mg, 3.84 mmol) and THF / H2O (6 mL / 6 mL) were added, followed by hydrated lithium hydroxide (319.76 mg, 7.68 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the organic solvent was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 4 with 6N HCl. A large amount of white solid precipitated, which was filtered, washed with water, and dried to obtain intermediate D-55 (527 mg, 3.51 mmol, 91.47% yield). MS (ESI) m / z = 151 [M+1]. + .

[0267] Preparation of intermediate D-56

[0268] Methyl 3-pyrazolecarboxylate (1.40 g, 11.09 mmol) and acetonitrile (50 mL) were added to a single-necked flask, followed by the addition of cesium carbonate (3.62 g, 11.09 mmol) while stirring. Ethyl trifluoromethanesulfonate (1.97 g, 11.09 mmol) was then added dropwise in an ice-water bath. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate D-56-1 (1.94 g, 9.34 mmol, 84.21% yield). MS (ESI) m / z = 209 [M+1] + .

[0269] Referring to the synthetic route of intermediate D-1, intermediate D-56-1 was used instead of intermediate D-1-1 in step 2. The remaining reagents and procedures were the same to obtain intermediate D-56. MS (ESI) m / z = 195 [M+1] +.

[0270] Preparation of intermediate D-57

[0271] To a 30 mL microwave tube, ethyl 1-isopropyl-1H-pyrazole-5-carboxylate (500 mg, 2.74 mmol) and acetonitrile / glacial acetic acid (6.9 mL / 2.3 mL) were added, followed by selectfluor (1.46 g, 4.12 mmol). After addition, nitrogen was bubbled through the tube for 1 minute. The mixture was returned to a microwave reactor, heated to 100°C, and stirred for 6 hours. HPLC and TLC indicated only half the reaction had occurred. The reaction was quenched with water, the pH adjusted to 8 with potassium carbonate solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate D-57-1 (0.2 g, 998.95 μmol, 36.41% yield). MS (ESI) m / z = 201 [M+1]. + .

[0272] Referring to the synthetic route of intermediate D-1, intermediate D-57-1 was used instead of intermediate D-1-1 in step 2. The remaining reagents and procedures were the same to obtain intermediate D-57. MS (ESI) m / z = 173 [M+1] + .

[0273] Preparation of intermediate D-58

[0274] Referring to the synthetic route of intermediate D-1, 1H-3-pyrazolecarboxylic acid methyl ester was substituted for 1,2,4-triazole-3-carboxylic acid methyl ester in step 1, and 1,1-difluoro-2-propanol was substituted for isopropanol. The remaining reagents and procedures were the same. D-58-1 was confirmed by hydrogen spectrum and NOE to obtain intermediate D-58. MS (ESI) m / z = 156 [M+1] + . D-58-1: 1H NMR (600MHz, Methanol-d4) δ8.05 (s, 1H), 5.55 (p, J = 6.6 Hz, 1H), 3.99 (s, 3H), 1.51 (d, J = 6.6 Hz, 6H).

[0275] Preparation of intermediate D-59

[0276] Referring to the synthetic route of steps 5 and 6 of intermediate D-46, in step 5, oxetane-3-methanol was used instead of N-tert-butyl-3-hydroxyazetidine. The remaining reagents and procedures were the same to obtain intermediate D-59. MS (ESI) m / z = 183 [M+1] + .

[0277] Preparation of intermediate E-1

[0278] To a single-necked flask, intermediate B-3-2 (247 g, 995.77 mmol) and DCM (2 L) were added. DMAP (24.4 g, 199.72 mmol) was then added under ice-water bath conditions. Boc anhydride (24.4 g, 199.72 mmol) was then added. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate E-1-1A (280.8 g, 626.39 mmol, 62.91% yield). MS (ESI) m / z = 448 [M+1]. + and intermediate E-1-1B (79.5 g, 228.34 mmol, 22.93% yield, MS (ESI) m / z = 348 [M+1] + .

[0279] To a single-necked flask, add intermediate E-1-1A (280.8 g, 626.39 mmol) and tetrahydrofuran (2 L). Methanol (28 g, 873.91 mmol) and lithium borohydride (41 g, 1.88 mol) were then added at room temperature. The mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate E-1-2 (153.7 g, 480.08 mmol, 76.64% yield). MS (ESI) m / z = 320 [M+1]. + .

[0280] To a single-necked flask, intermediate E-1-2 (13.56 g, 42.35 mmol) and dichloromethane (140 mL) were added, followed by portionwise addition of DMP (21.56 g, 50.83 mmol) in an ice-water bath. The reaction was stirred at room temperature for 2 hours. After completion, the reaction was quenched by the addition of 1M Na2S2O3 solution and 1M NaHCO3 solution, stirred for 30 minutes, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate E-1-3 (12 g, 37.72 mmol, 89.06% yield). MS (ESI) m / z = 318 [M+1] + .

[0281] To a single-necked flask, intermediate E-1-3 (4.42 g, 13.89 mmol) and methanol (50 mL) were added. Methylamine hydrochloride (862.97 mg, 27.79 mmol) was added at room temperature and stirred for 1 hour. The mixture was cooled to 0°C in an ice-water bath and sodium borohydride (1.05 g, 27.79 mmol) was added portionwise. After addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was cooled, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain crude intermediate E-1-4 (4.62 g, 13.87 mmol, 99.80% yield). MS (ESI) m / z = 333 [M+1]. + , and used directly in the next step without purification.

[0282] To a single-necked flask, intermediate E-1-4 (4.28 g, 12.85 mmol) and tetrahydrofuran / water (40 mL / 20 mL) were added. Sodium bicarbonate (2.16 g, 25.69 mmol) was then added at room temperature, followed by Boc anhydride (4.21 g, 19.27 mmol). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate E-1-5 (5.33 g, 12.30 mmol, 95.76% yield). MS (ESI) m / z = 433 [M+1] + .

[0283] To a single-necked flask, add intermediate E-1-5 (5.0 g, 11.57 mmol), intermediate A-3 (4.75 g, 11.57 mmol), dioxane, and water (100 mL / 20 mL). Pd2(dba)3 (264.76 mg, 289.25 μmol), rac-BI-DIME (190.97 mg, 578.50 μmol), and potassium phosphate (4.91 g, 23.14 mmol) were added. The atmosphere was evacuated and replaced with nitrogen three times. The temperature was gradually raised to 100°C and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column to obtain intermediate E-1-6 (4.32 g, 6.78 mmol, 58.64% yield). MS (ESI) m / z = 637 [M+1] + .

[0284] To a single-necked flask, intermediate E-1-6 (4.0 g, 6.29 mmol) and ethyl acetate (15 mL) were added. 4 M HCl in ethyl acetate (142 mL) was added under an ice-water bath, and the mixture was gradually warmed to room temperature with stirring for 1 hour. After the reaction was complete, the mixture was cooled in an ice-water bath and slowly poured into saturated sodium bicarbonate solution, maintaining a slightly alkaline pH. The mixture was then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to yield intermediate E-1-7 (1.51 g, 3.47 mmol, 55.15% yield). MS (ESI) m / z = 437 [M+1]. + .

[0285] To a single-necked flask, intermediate E-1-7 (1.51 g, 3.47 mmol) and tetrahydrofuran / water (10 mL / 10 mL) were added. Lithium hydroxide hydrate (0.29 g, 6.93 mmol) was added at room temperature and stirred for 2 hours. After the reaction, the pH was adjusted to neutral with 2M HCl in an ice-water bath and the mixture was concentrated to dryness under reduced pressure to obtain the crude intermediate E-1-8 (1.46 g, 3.47 mmol, calculated based on theoretical yield). MS (ESI) m / z = 423 [M+1] + .

[0286] To a single-necked flask, intermediate E-1-8 (1.46 g, 3.47 mmol) and DMF (18 mL) were added, followed by HATU (1.58 g, 4.16 mmol) and DIPEA (1.34 g, 10.41 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to yield intermediate E-1 (0.99 g, 2.45 mmol, 70.58% yield). MS (ESI) m / z = 405 [M+1]. + .

[0287] Preparation of Intermediates E-2 to E-15

[0288] Referring to the synthetic route of intermediate E-1, in step 4, methylamine hydrochloride is replaced by the corresponding amine in the table below. The remaining reagents and procedures are the same to obtain the corresponding intermediate.

[0289] Preparation of intermediate E-16

[0290] To a three-necked flask, intermediate E-1 (0.5 g, 1.24 mmol) and dry tetrahydrofuran (20 mL) were added. The mixture was evacuated and replaced with nitrogen three times. Borane tetrahydrofuran solution (7.44 mL, 7.44 mmol) was added via syringe. The temperature was gradually raised to 60°C and stirred for 6 hours. The reaction mixture was cooled, quenched by the addition of methanol dropwise in an ice-water bath, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate E-16 (0.28 g, 0.72 mmol, 58.0% yield). MS (ESI) m / z = 391 [M+1]. + .

[0291] Preparation of Intermediate E-17 to Intermediate E-15

[0292] Referring to the synthesis method of intermediate E-16, the corresponding macrocyclic amide in the table below was used to replace intermediate E-1. The remaining reagents and operations were the same to obtain the corresponding intermediate.

[0293] Preparation of intermediate E-29

[0294] Intermediate 118-3 (5.6 g, 16.12 mmol) and methanol (50 mL) were added to a single-necked flask. Ammonium acetate (6.21 g, 80.62 mmol) was added at room temperature, and the temperature was raised to 50°C with stirring for 3 hours. After cooling, sodium cyanoborohydride (2.03 g, 32.25 mmol) was added portionwise, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by MPLC to give intermediate E-29-1 (5.2 g, 14.93 mmol, 92.58% yield). MS (ESI) m / z = 348 [M+1] + .

[0295] To a single-necked flask, intermediate E-29-1 (250 mg, 717.66 μmol) and DCM (8 L) were added. Triethylamine (145.24 g, 1.44 mmol) and Boc anhydride (187.95 mg, 861.19 μmol) were then added at room temperature. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, water was added to quench the reaction and the product was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate E-29-2 (180 mg, 401.37 μmol, 55.93% yield). MS (ESI) m / z = 448 [M+1] + .

[0296] Referring to the synthetic route of intermediate E-1, intermediate E-29-2 was used in place of intermediate A-3 in step 7, and intermediate B-3 was used in place of intermediate E-1-5. The remaining reagents and procedures were the same to obtain intermediate E-29. MS (ESI) m / z = 405 [M+1] + .

[0297] Preparation of intermediate E-30

[0298] Referring to the synthetic route of intermediate E-1, 2-amino-5-bromoisonicotinate was used instead of intermediate B-3-2 in step 1. The remaining reagents and procedures were the same to obtain intermediate E-30-2. MS (ESI) m / z = 303 [M+1] + .

[0299] To a single-necked flask, intermediate E-30-2 (18.2 g, 60.04 mmol) and dichloromethane (300 mL) were added. Triethylamine (12.15 g, 120.07 mmol, 16.75 mL) was then added dropwise in an ice-water bath. Methanesulfonyl chloride (7.56 g, 66.04 mmol) was then added dropwise. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed sequentially with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain crude intermediate E-30-3 (18.8 g, 49.31 mmol, 82.14% yield). MS (ESI) m / z = 381 [M+1] + , and used directly in the next step without purification.

[0300] To a single-necked flask, intermediate E-30-3 (10 g, 26.32 mmol) and DMF (130 mL) were added. Cyclopropylamine (18 g, 31.58 mmol) was then added at room temperature, followed by sodium carbonate (5.58 g, 52.64 mmol) and sodium iodide (3.95 g, 26.32 mmol). After addition, the mixture was stirred at room temperature overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate E-30-4 (7.69 g, 22.55 mmol, 85.68% yield). MS (ESI) m / z = 342 [M+1] + .

[0301] To a single-necked flask, intermediate E-30-4 (1.98 g, 5.78 mmol) and tetrahydrofuran / water (15 mL / 15 mL) were added. Sodium carbonate (1.84 g, 17.35 mmol) and benzyl chloroformate (1.48 g, 8.67 mmol) were then added at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate E-30-5 (2.2 g, 4.62 mmol, 79.87% yield). MS (ESI) m / z = 476 [M+1] + .

[0302] Referring to the synthetic route of intermediate E-1, intermediate E-30-5 was used instead of intermediate E-1-5 in step 6. The remaining reagents and procedures were the same to obtain intermediate E-30-6. MS (ESI) m / z = 680 [M+1] + .

[0303] To a single-necked flask, intermediate E-30-6 (1.57 g, 2.31 mmol) and methanol (30 mL) were added. Palladium on carbon (471 mg, w / w 30%) was added at room temperature. After addition, the mixture was evacuated and replaced with hydrogen three times. The mixture was stirred at room temperature for 3 hours. After the reaction, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude intermediate E-30-7 (966 mg, 1.77 mmol, 76.65% yield). MS (ESI) m / z = 546 [M+1] + .

[0304] Referring to the synthetic route of intermediate E-1, intermediate E-30-7 was used instead of intermediate E-1-6 in step 7. The remaining reagents and procedures were the same to obtain intermediate E-30. MS (ESI) m / z = 414 [M+1] + .

[0305] Preparation of Intermediates E-31 to E-36

[0306] Referring to the synthesis method of intermediate E-30, in step 4, the corresponding amine in the table below is used instead of cyclopropylamine. The remaining reagents and procedures are the same to obtain the corresponding intermediate.

[0307] Preparation of Intermediate E-37 to Intermediate E-42

[0308] Referring to the synthesis method of intermediate E-16, the corresponding pyridine macrocyclic amide in the table below was used to replace intermediate E-1. The remaining reagents and operations were the same to obtain the corresponding intermediate.

[0309] Preparation of intermediate E-43

[0310] Referring to the synthetic route of intermediate E-1, intermediate E-37 was used instead of intermediate B-3-2 in step 1. The remaining reagents and procedures were the same to obtain intermediate E-43-1. MS (ESI) m / z = 550 [M+1] + .

[0311] To a single-necked flask, intermediate E-43-1 (500 mg, 0.91 mmol) and methanol (9 mL) were added. Palladium on carbon (150 mg, w / w 30%) and palladium hydroxide (150 mg, w / w 30%) were added at room temperature. After the addition, the atmosphere was replaced with hydrogen three times under vacuum and stirred at room temperature for 6 hours. After the reaction, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude intermediate E-43-2 (384.59 mg, 0.84 mmol, 92% yield). MS (ESI) m / z = 460 [M+1] + .

[0312] To a single-necked flask, intermediate E-43-2 (384.59 mg, 0.84 mmol) and dichloromethane (8 mL) were added. Triethylamine (93.32 mg, 0.92 mmol) and acetic anhydride (85.68 mg, 0.84 mmol) were then added at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC to afford intermediate E-43-3 (331.71 mg, 0.66 mmol, 78.82% yield). MS (ESI) m / z = 502 [M+1] + .

[0313] Referring to the synthetic route of intermediate E-1, intermediate E-43-3 was used instead of intermediate E-1-6 in step 7. The remaining reagents and procedures were the same to obtain intermediate E-43. MS (ESI) m / z = 402 [M+1] + .

[0314] Preparation of intermediate E-44

[0315] Referring to the synthetic route of intermediate E-1, benzylamine was used instead of methylamine hydrochloride in step 4. The remaining reagents and procedures were the same to obtain intermediate E-44. MS (ESI) m / z = 481 [M+1] + .

[0316] Preparation of intermediate E-45

[0317] Referring to the synthesis method of intermediate E-16, intermediate E-44 was used instead of intermediate E-1. The remaining reagents and operations were the same to obtain intermediate E-45. MS (ESI) m / z = 467 [M+1] + .

[0318] Preparation of intermediate E-46

[0319] Referring to the synthesis method of intermediate E-43, intermediate E-45 was used instead of intermediate E-37. The remaining reagents and operations were the same to obtain intermediate E-46-2. MS (ESI) m / z = 477 [M+1] + .

[0320] Intermediate E-46-2 (400 mg, 0.84 mmol) and dichloromethane (8 mL) were added to a single-necked flask. DIPEA (271 mg, 2.10 mmol) and bromoacetonitrile (109.96 mg, 0.92 mmol) were added at room temperature. After addition, the mixture was stirred at room temperature overnight. After the reaction was complete, the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC to obtain intermediate E-46-3 (297.15 mg, 0.58 mmol, 68.69% yield). MS (ESI) m / z = 516 [M+1] + .

[0321] Intermediate E-46-3 (297.15 mg, 0.58 mmol) and dichloromethane (5 mL) were added to a single-necked flask. TFA (0.5 mL) was added under ice-water bath conditions. After the addition, the mixture was reacted at room temperature for 3 hours. After the reaction was complete, the mixture was poured into an aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by reverse phase MPLC to obtain intermediate E-46. MS (ESI) m / z = 416 [M+1] + .

[0322] Preparation of intermediate E-47

[0323] To a single-necked flask, intermediate 118-3 (1.0 g, 2.89 mmol) and DCE (20 mL) were added, followed by 2',2-difluoroethylamine (0.35 g, 4.34 mmol). The mixture was stirred at 40°C overnight, cooled to room temperature, and sodium triacetoxyborohydride (1.53 g, 7.23 mmol) was added portionwise. The mixture was stirred at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC to afford intermediate E-47-1 (800.33 mg, 1.95 mmol, 67.38% yield). MS (ESI) m / z = 412 [M+1]. + .

[0324] To a single-necked flask, intermediate E-47-1 (3 g, 4.36 mmol) and THF / H2O (20 mL / 20 mL) were added, followed by sodium bicarbonate (733.35 mg, 8.73 mmol) and CbzOsu (1.09 g, 4.36 mmol). The mixture was stirred at room temperature overnight. Water was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate E-47-2 (0.93 g, 1.70 mmol, 38.99% yield). MS (ESI) m / z = 546 [M+1]. + .

[0325] To a single-necked flask, E-47-2 (900 mg, 1.65 mmol), intermediate B-3 (487.16 g, 1.65 mmol), Cs2CO3 (1.08 g, 3.30 mmol), and 1,4-dioxane (15 mL) / water (3 mL) were added, followed by Pd(dppf)Cl2 (120.88 mg, 165.14 μmol). After addition, the atmosphere was evacuated and replaced with nitrogen three times. The reaction was stirred at 90°C overnight. After completion of the reaction, the mixture was cooled, extracted with water and ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate E-47-3 (738.74 mg, 1.17 mmol, 70.56% yield). MS (ESI) m / z = 635 [M+1] + .

[0326] To a single-necked flask, intermediate E-47-3 (738.74 mg, 1.17 mmol) and methanol (10 mL) were added. Palladium on carbon (221 mg, w / w 30%) was added at room temperature. After addition, the atmosphere was replaced with hydrogen three times under vacuum. The reaction was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude intermediate E-47-4 (530.2 mg, 1.06 mmol, 91% yield). MS (ESI) m / z = 501 [M+1] + .

[0327] Referring to the synthesis method of steps 2 to 4 of Example 1, intermediate E-47-4 was used instead of intermediate 1-1 in step 2. The remaining reagents and procedures were the same to obtain intermediate E-47. MS (ESI) m / z = 455 [M+1] + .

[0328] Preparation of intermediate E-48

[0329] Referring to the synthesis method of intermediate E-30, 1-trifluoromethylethylamine was used instead of cyclopropylamine in step 4. The remaining reagents and procedures were the same to obtain intermediate E-48. MS (ESI) m / z = 470 [M+1] + .

[0330] Preparation of intermediate E-49

[0331] Referring to the synthesis method of intermediate E-16, intermediate E-48 was used instead of intermediate E-1. The remaining reagents and operations were the same to obtain intermediate E-49. MS (ESI) m / z = 456 [M+1] + .

[0332] Preparation of intermediate E-50

[0333] Referring to the synthesis method of intermediate E-16, intermediate E-34 was used instead of intermediate E-1. The remaining reagents and operations were the same to obtain intermediate E-50. MS (ESI) m / z = 450 [M+1] + .

[0334] Preparation of intermediate E-51

[0335] Referring to the synthesis method of intermediate E-30, 2,2,2-trifluoro-1,1-dimethylethylamine was used instead of cyclopropylamine in step 4. The remaining reagents and procedures were the same to obtain intermediate E-51. MS (ESI) m / z = 484 [M+1] + .

[0336] Preparation of intermediate E-52

[0337] Referring to the synthesis method of intermediate E-30, 1-(trifluoromethyl)cyclopropylamine was used instead of cyclopropylamine in step 4. The remaining reagents and procedures were the same to obtain intermediate E-52. MS (ESI) m / z = 482 [M+1] + .

[0338] Preparation of intermediate E-53

[0339] Referring to the synthesis method of intermediate E-16, intermediate E-51 was used instead of intermediate E-1. The rest of the reagents and operations were the same to obtain intermediate E-53. MS (ESI) m / z = 470 [M+1] + .

[0340] Preparation of intermediate E-54

[0341] Referring to the synthesis method of intermediate E-16, intermediate E-52 was used instead of intermediate E-1. The remaining reagents and operations were the same to obtain intermediate E-54. MS (ESI) m / z = 468 [M+1] + .

[0342] Preparation of intermediate E-55

[0343] Referring to the synthetic route of intermediate E-1, 2,2,2-trifluoro-1,1-dimethylethylamine was used instead of methylamine hydrochloride in step 4. The remaining reagents and procedures were the same to obtain intermediate E-55. MS (ESI) m / z = 501 [M+1] + .

[0344] Preparation of intermediate E-56

[0345] Referring to the synthesis method of intermediate E-16, intermediate E-55 was used instead of intermediate E-1. The remaining reagents and operations were the same to obtain intermediate E-56. MS (ESI) m / z = 487 [M+1] + .

[0346] Preparation of intermediate E-57

[0347] Referring to the synthetic route of intermediate E-1, 1-(trifluoromethyl)cyclopropylamine was used instead of methylamine hydrochloride in step 4. The remaining reagents and procedures were the same to obtain intermediate E-57. MS (ESI) m / z = 499 [M+1] + .

[0348] Preparation of intermediate E-58

[0349] Referring to the synthesis method of intermediate E-16, intermediate E-57 was used instead of intermediate E-1. The remaining reagents and operations were the same to obtain intermediate E-58. MS (ESI) m / z = 485 [M+1] + .

[0350] Preparation of Example 1

[0351] To a mixture of Intermediate B-1 (4 g, 8.90 mmol), Intermediate A-1 (4.03 g, 10.68 mmol), and Cs2CO3 (5.80 g, 17.79 mmol) in 1,4-dioxane (40 mL) / water (8 mL) was added Pd(PPh3)4 (1.03 g, 889.73 μmol). Nitrogen was bubbled through the mixture to deoxygenate the mixture. The mixture was microwaved at 120°C for 1 hour. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, concentrated to dryness, and purified by silica gel column chromatography to afford Intermediate 1-1 (2.5 g, 45% yield). MS (ESI) m / z = 620 [M+1] + .

[0352] To Intermediate 1-1 (2.5 g, 4.03 mmol) in dry THF (50 mL) was added dropwise LiAlH4 (382.60 mg, 10.08 mmol, 1 M solution in THF) at -78°C. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 2 hours. After completion of the reaction, ice water (0.7 mL), 15% aqueous NaOH (0.7 mL), and water (2.1 mL) were added sequentially at -10°C to quench the reaction. The reaction mixture was filtered, the filter cake washed with ethyl acetate, and the filtrate concentrated to dryness to afford Intermediate 1-2 (1.5 g, 63% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 592 [M+1] + .

[0353] To a solution of Intermediate 1-2 (1.5 g, 2.53 mmol) in DCM (60 mL) was added dichlorothionyl (2.7 g, 15.17 mmol) dropwise at 0°C. The mixture was allowed to react for 1 hour. After completion of the reaction, aqueous sodium bicarbonate was added to quench the reaction. Ethyl acetate was added for extraction, and the organic layer was washed with brine and concentrated to dryness to afford Intermediate 1-3 (189 mg, 19% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 396 [M+1] + .

[0354] To a solution of Intermediate 1-3 (189 mg, 477.28 μmol) in t-BuOH (4 mL) was added t-BuOK (58.91 mg, 525.00 μmol). The temperature was raised to 80°C and the reaction was allowed to react for 1 hour. After the reaction was concentrated to dryness, water and ethyl acetate were added for extraction. The organic layer was washed with brine and concentrated to dryness for purification to afford Intermediate 1-4 (159 mg, 93% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 360 [M+1] + .

[0355] To a solution of Intermediate C-1 (125 mg, 412.06 μmol) and DIPEA (176.86 mg, 1.37 mmol, 238.35 μL) in DMF (4 mL) was added HATU (169 mg, 444.47 μmol). After stirring at room temperature for 5 minutes, Intermediate 1-4 (123 mg, 342.11 μmol) was added. After addition, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, concentrated to dryness, and purified by silica gel column chromatography to afford Intermediate 1-5 (215 mg, 97% yield). MS (ESI) m / z = 645 [M+1] + .

[0356] To a solution of intermediate 1-5 (51 mg, 79.09 μmol) and formic acid amine (49.87 mg, 790.85 μmol) in MeOH (1 mL) was added Pd / C (20 mg, 10% w / w). The reaction was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite and washed with methanol. The filtrate was concentrated to dryness under reduced pressure. The crude product was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate 1-6 (40 mg, 99% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 511 [M+1] + .

[0357] To a solution of 2-isopropyl-3-pyrazolecarboxylic acid (16 mg, 103.78 μmol) and DIPEA (40.49 mg, 313.27 μmol, 54.56 μL) in DMF (1 mL) was added HATU (42 mg, 110.46 μmol). After stirring at room temperature for 5 minutes, Intermediate 1-6 (40 mg, 78.32 μmol) was added. After addition, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, concentrated to dryness, and purified by MPLC to afford Intermediate 1-7 (50 mg, 99% yield). MS (ESI) m / z = 647 [M+1] + .

[0358] To a solution of Intermediate 1-7 (50 mg, 77.29 μmol) in DCM (0.8 mL) was added TFA (0.8 mL). The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated to dryness and purified by MPLC to afford Example 1 (15 mg, 38% yield). MS (ESI) m / z = 517 [M+1] + . 1H NMR (400MHz, Methanol-d4) δ7.72–7.64(m,2H),7.52(d,J=2.0Hz,1H),7.41–7.27(m,1H),6.80(d,J=2.1Hz,1H),5.41(hept,J=6.7Hz,1H),4 .91(d,J=7.5Hz,1H),4.33(m,2H),3.72(s,2H),2.69(s,2H),2.26(s,3H),1.45(dd,J=6.7,5.5Hz,6H),0.97–0.73(m,3H),0.61–0.21(m,8H).

[0359] Preparation of Examples 2 to 7

[0360] Referring to the synthetic route of Example 1, the corresponding carboxylic acid intermediates in the table below were used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and operations were the same to obtain the corresponding structural example compounds in the table.

[0361] Preparation of Examples 8 to 10

[0362] Referring to the synthetic route of Example 1, the corresponding amino acids in the table below were used instead of intermediate C-1 in step 5, and 1-ethylpyrazole-5-carboxylic acid was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 7. The remaining reagents and operations were the same to obtain the corresponding structural example compounds in the table.

[0363] Preparation of Example 11

[0364] Referring to the synthetic route of Example 1, intermediate C-4 was used instead of intermediate C-1 in step 5, and 1-ethylpyrazole-5-carboxylic acid was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 7. The remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=70 / 30; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 11a (P1, SFC t R =3.054), MS(ESI)m / z=527[M+1] + . 1H NMR (600 MHz, Methanol-d4) δ 7.87–7.64 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 4.59–4.48 (m, 3H), 4.38 (d, J = 57.2 Hz, 2H), 3.96–3.57 (m, 2H), 2.74 (t, J = 49.5 Hz, 2H), 2.30 (s, 3H), 2.14–2.02 (m, 3H), 2.02–1.95 (m, 1H), 1.91–1.74 (m, 3H), 1.63–1.44 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H). Example 11b (P2, SFC t R =4.824), MS(ESI)m / z=527[M+1] + . 1 H NMR (600MHz, Methanol-d4) δ7.75–7.66(m,2H),7.50(d,J=2.1Hz,1H),7.35(d,J= 8.3Hz,1H),6.89(d,J=2.1Hz,1H),4.59–4.48(m,3H),4.34(s,2H),3.90–3.57(m,2 H),2.89–2.54(m,2H),2.29(s,3H),2.10(tt,J=16.5,10.3Hz,3H),1.99(d,J=13. 8Hz,1H),1.80(dt,J=31.7,13.3Hz,3H),1.63–1.43(m,2H),1.37(t,J=7.1Hz,3H).

[0365] Preparation of Example 12

[0366] To a 500 mL three-necked flask, add Intermediate A-1 (11 g, 24.47 mmol) and dry tetrahydrofuran (150 mL). Vacuum and replace with nitrogen three times, cool to -70°C, and add n-butyllithium (24.47 mmol, 9.7 mL) dropwise. Stir and react at this temperature for 1 hour. Add a solution of isopropyl pinacol borate (9.10 g, 48.94 mmol) in dry tetrahydrofuran (80 mL) dropwise. After addition, warm to room temperature and stir for 1 hour. After completion of the reaction, pour into saturated ammonium chloride solution to quench the reaction, and extract with ethyl acetate. The organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to yield Intermediate 12-1 (8.28 g, 11.66 mmol, 47.67% yield). MS (ESI) m / z = 497 [M+1] + .

[0367] To a mixture of intermediate 12-1 (5.00 g, 10.07 mmol), methyl 2-amino-5-bromoisonicotinate (1.94 g, 8.39 mmol), and Cs2CO3 (5.47 g, 16.78 mmol) in 1,4-dioxane (80 mL) / water (20 mL) was added Pd(PPh3)4 (484.82 mg, 419.40 μmol). After addition, the atmosphere was evacuated and replaced with nitrogen three times. The mixture was stirred at 100°C for 6 hours. After completion of the reaction, the mixture was cooled, extracted with water and ethyl acetate, and the organic layer was washed with brine and concentrated to dryness. The crude product was purified by silica gel column chromatography to afford intermediate 12-2 (1.40 g, 1.88 mmol, 22.47% yield). MS (ESI) m / z = 521 [M+1] + .

[0368] Referring to the synthetic method of steps 2 to 4 of Example 1, intermediate 12-2 was used instead of intermediate 1-1. The remaining reagents and procedures were the same to obtain intermediate 12-5. MS (ESI) m / z = 361 [M+1] + .

[0369] To a solution of intermediate 12-5 (80 mg, 221.90 μmol) and intermediate C-1 (134.63 mg, 443.80 μmol) in pyridine (2 mL) was added EDCI (127.61 mg, 665.70 μmol). The mixture was stirred at 60°C for 2 hours. After completion of the reaction, the mixture was cooled and concentrated to dryness under reduced pressure. The crude product was purified by MPLC (H2O / CH3CN, 0.05% TFA) to afford intermediate 12-6 (30 mg, 46.45 μmol, 20.93% yield). MS (ESI) m / z = 646 [M+1] + .

[0370] Referring to the synthetic method of steps 6 to 8 of Example 1, intermediate 12-6 was used instead of intermediate 1-5. The remaining reagents and operations were the same to obtain Example 12. MS (ESI) m / z=518[M+1] + . 1H NMR (600MHz, Methanol-d4) δ8.30 (s, 1H), 8.22 (s, 1H), 7.53 (d, J = 2.0Hz, 1H), 6.81 ( d,J=2.1Hz,1H),5.45–5.35(m,1H),4.98(d,J=7.3Hz,1H),4.66–4.13(m,2H),3.92–3 .57(m,2H),2.88–2.58(m,2H),2.31(s,3H),1.45(dd,J=8.5,6.6Hz,6H),0.96–0.79 (m,3H),0.59–0.42(m,3H),0.42–0.32(m,2H),0.32–0.28(m,2H),0.28–0.22(m,1H).

[0371] Preparation of Example 13

[0372] To a 250 mL single-necked eggplant-shaped flask, methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (3.47 g, 12.83 mmol) and DCM (70 mL) were added, followed by the addition of NBS (4.57 g, 25.67 mmol) at room temperature. The reaction was stirred overnight at room temperature. After completion, the reaction was quenched with aqueous sodium bicarbonate and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford Intermediate 13-1 (791 mg, 2.26 mmol, 17.65% yield). MS (ESI) m / z = 349 [M+1] + .

[0373] To a mixture of Intermediate 13-1 (741 mg, 2.12 mmol), Intermediate B-2 (1.60 g, 4.24 mmol), and Cs2CO3 (1.38 g, 4.24 mmol) in 1,4-dioxane (20 mL) / water (4 mL) was added Pd(dppf)Cl2 (77.61 mg, 106.07 μmol). After addition, the atmosphere was evacuated and replaced with nitrogen three times. The mixture was stirred at 80°C for 12 hours. After completion of the reaction, the mixture was cooled, extracted with water and ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford Intermediate 13-2 (332 mg, 638.68 μmol, 30.11% yield). MS (ESI) m / z = 520 [M+1] + .

[0374] Referring to the synthetic route of Example 1, intermediate 13-2 was used instead of intermediate 1-1 in step 2, and the remaining reagents and operations were the same to obtain Example 13, MS (ESI) m / z = 517 [M+1]+ . 1 H NMR(600MHz, Methanol-d4)δ7.64–7.49(m,3H),7.28(s,1H),6.82(d,J=2.0H z,1H),4.92(d,J=7.7Hz,1H),4.23(d,J=72.7Hz,1H),3.64(s,1H),3.25–3.2 0(m,1H),2.77(t,J=5.1Hz,2H),2.31(s,3H),1.48(dd,J=8.0,6.6Hz,6H),1. 33(t,J=7.3Hz,2H),1.00–0.74(m,3H),0.62–0.36(m,5H),0.35–0.24(m,3H).

[0375] Preparation of Example 14

[0376] Referring to the synthetic route of Example 13, 1-ethylpyrazole-5-carboxylic acid was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 8. The remaining reagents and procedures were the same to obtain Example 14. MS (ESI) m / z = 503 [M+1] + . 1 H NMR (600MHz, Methanol-d4) δ7.63–7.48(m,3H),7.35–7.24(m,1H),6.89(d,J=2.2 Hz,1H),4.92(d,J=7.6Hz,1H),4.80–4.50(m,3H),4.17(s,2H),3.82–3.51(m,1H), 2.77(t,J=5.1Hz,2H),2.31(s,3H),1.41(t,J=7.2Hz,3H),0.97–0.76(m,3H),0.5 8(tt,J=8.5,4.6Hz,1H),0.55–0.46(m,2H),0.45–0.36(m,2H),0.35–0.24(m,3H).

[0377] Preparation of Example 15

[0378] Referring to the synthetic route of Example 1, intermediate B-3 was used instead of intermediate B-1 in step 1, and the remaining reagents and procedures were the same to obtain Example 15, MS (ESI) m / z = 535 [M+1] + . 1H NMR (400MHz, Methanol-d4) δ8.04(d,J=8.0Hz,1H),7.53(d,J=2.0Hz,1H),7.19(d,J= 11.2Hz,1H),6.80(d,J=2.1Hz,1H),5.48–5.33(m,1H),5.01(d,J=7.1Hz,1H),4.31(s ,2H),3.72(s,2H),2.70(s,2H),2.28(s,3H),1.46(dd,J=6.7,4.8Hz,6H),1.02–0.79 (m,3H),0.61–0.53(m,1H),0.53–0.41(m,3H),0.41–0.35(m,1H),0.35–0.21(m,3H).

[0379] Preparation of Examples 16 to 21

[0380] Referring to the synthetic route of Example 15, in step 7, the corresponding carboxylic acid intermediate in the table below was used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and procedures were the same to obtain the corresponding structural example compounds in the table.

[0381] Preparation of Example 22

[0382] Methylamine hydrochloride (30 g, 217.38 mmol) was added to a solution of 2-bromo-5-nitrobenzaldehyde (25 g, 108.69 mmol) in methanol (500 mL). After the addition, the mixture was stirred at room temperature for 1 hour. The temperature was then cooled to 0°C in an ice-water bath, and sodium borohydride (8.22 g, 217.38 mmol) was added portionwise. After the addition, the mixture was heated to room temperature and stirred for 2 hours. The temperature was then lowered to 0°C and quenched by the addition of 30% ammonium chloride solution. The reaction was stirred for 10 minutes, and the mixture was concentrated under reduced pressure to an appropriate amount. Ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by silica gel column chromatography afforded Intermediate 22-1 (23 g, 93.85 mmol, 86.35% yield). MS (ESI) m / z = 245 [M+1] + .

[0383] To a solution of Intermediate 22-1 (23 g, 93.85 mmol) in THF / H₂O (230 mL / 100 mL) were added sodium bicarbonate (15.77 g, 187.70 mmol) and (Boc)₂O (30.72 g, 140.77 mmol). After the addition, the reaction was stirred at room temperature overnight. Water (100 mL) was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to afford Intermediate 22-2 (32.3 g, 93.57 mmol, 99.70% yield). MS (ESI) m / z = 345 [M+1] + .

[0384] To a solution of Intermediate 22-2 (32 g, 92.70 mmol) in EtOH / H₂O (640 mL / 128 mL) was added ammonium chloride (39.67 g, 741.62 mmol), followed by the addition of zinc powder (30.72 g, 140.77 mmol) in portions under an ice-water bath. After the addition, the reaction was stirred at room temperature overnight, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure. Water and ethyl acetate were added, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford Intermediate 22-3 (20 g, 63.45 mmol, 68.45% yield). MS (ESI) m / z = 315 [M+1] + .

[0385] To a 500 mL single-necked flask were added intermediate 22-3 (23 g, 72.97 mmol), pinacol diboronate (22.24 g, 87.56 mmol), potassium acetate (14.32 g, 145.94 mmol), Pd(dppf)Cl2 (5.34 g, 7.30 mmol), and dioxane (230 mL). The mixture was evacuated and replaced with nitrogen three times with stirring. The temperature was raised to 100°C and stirred overnight. After the reaction, the mixture was cooled, concentrated to an appropriate volume, and ethyl acetate was added and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford intermediate 22-4 (22.9 g, 63.21 mmol, 86.63% yield). MS (ESI) m / z = 363 [M+1] + .

[0386] To a 500 mL single-necked flask were added Intermediate 22-4 (22.43 g, 61.93 mmol), Intermediate A-2 (15 g, 42.19 mmol), sodium carbonate (8.5 g, 82.57 mmol), Pd(dppf)Cl2 (1.51 g, 2.06 mmol), and dioxane / water (230 mL / 50 mL). The atmosphere was evacuated and replaced with nitrogen three times with stirring. The temperature was raised to 100°C and stirred overnight. After the reaction, the mixture was cooled, concentrated to an appropriate volume, and ethyl acetate was added and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford Intermediate 22-5 (12.41 g, 23.95 mmol, 58% yield). MS (ESI) m / z = 519 [M+1] + .

[0387] To a solution of Intermediate 22-5 (2 g, 3.86 mmol) in DCM (100 mL) was added TFA (10 mL) under ice-water bath conditions. The mixture was stirred at room temperature until the reaction was complete. The reaction was concentrated to dryness and purified by MPLC (H2O / CH3CN, 0.05% NH4HCO3) to afford Intermediate 22-6 (1.53 g, 3.66 mmol, 94.98% yield). MS (ESI) m / z = 419 [M+1] + .

[0388] To a 50 mL glass air tube, add intermediate 22-6 (649 mg, 1.55 mmol), methanol (10 mL), and trimethylacetic acid. After complete addition, heat to 90°C and stir for 12 hours. Some of the starting material remains unreacted, so the mixture is concentrated to dryness under reduced pressure. The residue is dissolved in dichloromethane, washed sequentially with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product is purified by silica gel column chromatography to afford intermediate 22-7 (688 mg, 889.90 μmol, 57.40% yield, 50% purity). MS (ESI) m / z = 387 [M+1] + .

[0389] Referring to the synthetic route of Example 1, intermediate 22-7 was used instead of intermediate 1-4 in step 5, and the remaining reagents and operations were the same to obtain Example 22, MS (ESI) m / z = 544 [M+1] + . 1H NMR (600MHz, Methanol-d4) δ7.78(d,J=2.4Hz,1H),7.61(dd,J=8.5,2.3Hz,1H),7.54(d,J =2.1Hz,1H),7.44(s,1H),6.83(d,J=2.0Hz,1H),5.48–5.38(m,1H),4.93(d,J=7.7Hz,1H) ,4.51(q,J=14.7Hz,2H),4.02(d,J=41.7Hz,2H),2.95(s,3H),2.35(s,3H),1.47(dd,J=9. 1,6.7Hz,6H),0.98–0.78(m,3H),0.62–0.45(m,3H),0.44–0.37(m,2H),0.35–0.23(m,3H).

[0390] Preparation of Example 23

[0391] Referring to the synthetic route of Example 22, 1-ethylpyrazole-5-carboxylic acid was used instead of 1-isopropylpyrazole-5-carboxylic acid in Step 9. The remaining reagents and procedures were the same to obtain Example 23. MS (ESI) m / z = 530 [M+1] + . 1 H NMR(600MHz, Methanol-d4)δ7.77–7.69(m,1H),7.58(s,1H),7.44(d,J=62.0H z,2H),6.86(t,J=3.5Hz,1H),4.90(d,J=7.6Hz,1H),4.58–4.40(m,4H),3.99(d ,J=67.6Hz,2H),2.91(s,3H),2.32(s,3H),1.44–1.30(m,3H),0.95–0.73(m,3H) ),0.59–0.52(m,1H),0.52–0.41(m,2H),0.41–0.33(m,2H),0.33–0.20(m,3H).

[0392] Preparation of Example 24

[0393] To Intermediate 22-6 (638 mg, 825.22 μmol) in dry THF (20 mL) was added dropwise LiAlH₄ (62.63 mg, 1.65 mmol, 1 M solution in THF) at -78°C. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 1 hour. After completion of the reaction, ice water (0.08 mL), 15% aqueous NaOH (0.08 mL), and water (0.24 mL) were added sequentially at -10°C to quench the reaction and stir for 10 minutes. The reaction mixture was filtered through Celite, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to dryness to afford Intermediate 24-1 (235 mg, 630.74 μmol, 76.43% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 373 [M+1] + .

[0394] Referring to the synthetic route of Example 1, intermediate 24-1 was used instead of intermediate 1-4 in step 5, and the remaining reagents and operations were the same to obtain Example 24, MS (ESI) m / z = 530 [M+1] + . 1 H NMR (600MHz, Methanol-d4) δ7.76–7.61(m,2H),7.56–7.50(m,1H),7.34(s,1H),6.82(d,J=2.1Hz,1H),5.43(hept,J=6.8Hz,1H),4.92(d,J=7.6Hz,1 H),3.67(s,2H),3.07–2.56(m,4H),2.45(s,3H),2.25(s,3H),1.48(dd,J= 7.8,6.7Hz,6H),0.97–0.77(m,3H),0.64–0.35(m,5H),0.33–0.24(m,3H).

[0395] Preparation of Example 25 and Example 26

[0396] Referring to the synthetic route of Example 24, in step 4, the corresponding pyrazole carboxylic acid in the table below was used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and procedures were the same to obtain the corresponding structural example compounds in the table.

[0397] Preparation of Example 27

[0398] Referring to the synthetic method of step 4 to step 5 of Example 22, 5-amino-2-bromobenzonitrile was used instead of intermediate 22-3 in step 4. The remaining reagents and procedures were the same to obtain intermediate 27-2. MS (ESI) m / z = 401 [M+1] + .

[0399] To a 50 mL single-necked flask, intermediate 27-2 (300 mg, 748.98 μmol) and methanol (6 mL) were added Raney nickel (60 mg, 748.98 μmol). The atmosphere was replaced with hydrogen three times under vacuum and stirred at room temperature overnight. The reaction mixture was filtered through celite, the filter cake was washed with methanol, and the filtrate was concentrated to dryness to obtain intermediate 27-3 (218 mg, 538.83 μmol, 71.94% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 405 [M+1] + .

[0400] Referring to the synthetic method of steps 7 to 11 of Example 22, intermediate 27-3 was used instead of intermediate 22-6 in step 7. The remaining reagents and procedures were the same to obtain Example 27. MS (ESI) m / z=530[M+1] + . 1 H NMR (600MHz, Methanol-d4) δ7.80(d,J=2.3Hz,1H),7.63(d,J=8.3Hz,1H),7.54(d,J=2.0Hz,1H),7.37(d,J=8.3Hz,1H),6.81(d,J=2.0Hz,1H),5.48–5.35( m,1H),4.91(d,J=7.7Hz,1H),4.05(s,2H),3.55(s,2H),2.32(s,3H),1.47(dd ,J=8.8,6.7Hz,6H),0.98–0.75(m,3H),0.62–0.35(m,5H),0.34–0.23(m,3H).

[0401] Preparation of Example 28

[0402] Referring to the synthetic route of Example 27, 1-ethylpyrazole-5-carboxylic acid was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 7. The remaining reagents and procedures were the same to obtain Example 28. MS (ESI) m / z=516[M+1] + . 1H NMR(600MHz,Methanol-d4)δ7.80(d,J=2.3Hz,1H),7.63(d,J=8.3Hz,1H),7.5 2(d,J=2.1Hz,1H),7.37(d,J=7.4Hz,1H),6.88(d,J=2.1Hz,1H),4.92(d,J=7.6 Hz,1H),4.56(qd,J=7.1,2.5Hz,2H),4.05(s,2H),3.55(s,2H),2.32(s,3H),1 .40(t,J=7.2Hz,3H),0.98–0.76(m,3H),0.65–0.35(m,5H),0.35–0.23(m,3H).

[0403] Preparation of Example 29

[0404] Referring to the synthetic method of steps 1 to 4 of the synthetic route of Example 1, intermediate B-4 was used instead of intermediate B-1 in step 1. The remaining reagents and procedures were the same to obtain intermediate 29-4. MS (ESI) m / z = 394 [M+1] + .

[0405] To a solution of Intermediate 29-4 (600 mg, 1.53 mmol) and Intermediate C-1 (601.37 g, 1.98 mmol) in pyridine (16 mL) was added EDCI (1.18 g, 6.12 mmol). The reaction was stirred at room temperature overnight and concentrated to dryness under reduced pressure. The crude product was dissolved in ethyl acetate, washed sequentially with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by MPLC (H2O / CH3CN, 0.05% NH4HCON3) to afford Intermediate 29-5 (902 mg, 1.33 mmol, 86.98% yield). MS (ESI) m / z = 679 [M+1] + .

[0406] To a solution of Intermediate 29-5 (800 mg, 1.18 mmol) in dichloromethane (11 mL) were added triethylamine (83.42 mg, 0.83 mmol) and PdCl2 (41.44 mg, 0.24 mmol). After addition, the mixture was cooled to 0°C in an ice-water bath. A solution of triethylsilane (684.40 mg, 5.90 mmol) in dichloromethane (3 mL) was added dropwise. After completion, the mixture was stirred at 0°C under nitrogen atmosphere until the reaction was complete. The reaction mixture was filtered through Celite, washed with dichloromethane, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by MPLC (H2O / CH3CN, 0.05% NH4HCON3) to afford Intermediate 29-6 (464.62 mg, 0.85 mmol, 72.38% yield). MS (ESI) m / z = 545 [M+1] + .

[0407] Referring to the synthetic method of steps 7 to 8 of the synthetic route of Example 1, intermediate 29-6 was used instead of intermediate 1-6 in step 7. The remaining reagents and operations were the same to obtain Example 29. MS (ESI) m / z = 551 [M+1] + . 1 H NMR (600MHz, DMSO-d6) δ12.47(d,J=28.7Hz,1H),9.68(s,1H),8.44(d,J=8.7Hz,1H),7.81 (s,1H),7.55–7.36(m,2H),6.90(d,J=1.9Hz,1H),5.51–5.28(m,1H),4.93(t,J=8.8,7.2Hz ,1H),4.20(s,2H),3.60(s,2H),2.72–2.52(m,2H),2.18(d,J=35.6Hz,3H),1.36(dd,J=16. 6,6.6Hz,6H),1.02–0.78(m,3H),0.51–0.45(m,1H),0.43–0.28(m,4H),0.28–0.17(m,3H).

[0408] Preparation of Example 30 to Example 31

[0409] Referring to the synthetic route of Example 29, the corresponding pyrazole carboxylic acid in the following table was used instead of 1-isopropylpyrazole-5-carboxylic acid in Step 7. The remaining reagents and procedures were the same to obtain the corresponding example compounds.

[0410] Preparation of Example 32

[0411] To a solution of cyclopropanol (6.59 mg, 113.48 μmol) and N,N'-disuccinimidyl carbonate (29.07 mg, 113.48 μmol) in acetonitrile (1 mL) was added triethylamine (9.57 mg, 94.57 μmol, 13.19 μL) at room temperature. The mixture was stirred at room temperature for 2 hours. A solution of Intermediate 15-6 (50 mg, 94.57 μmol) in DMF (0.5 mL) was then added. The mixture was stirred at room temperature overnight. The reaction solution was directly purified by MPLC (H2O / CH3CN, 0.05% TFA) to afford Intermediate 32-1 (14 mg, 22.85 μmol, 24.16% yield). MS (ESI) m / z = 613 [M+1] + .

[0412] To a solution of Intermediate 32-1 (14 mg, 22.85 μmol) in DCM (1 mL) was added TFA (1 mL). The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated to dryness and purified by MPLC to afford Example 32 (5 mg, 8.38 μmol, 36.69% yield). MS (ESI) m / z = 483 [M+1] + . 1 H NMR (600MHz, Methanol-d4) δ8.02(d,J=7.9Hz,1H),7.21(d,J=11.4Hz,1H),4.56(d,J=6.0Hz,1H),4.34(s,2H),4.10–3.99(m,1H),3.73(s,2H),2.7 2(s,2H),2.30(s,3H),0.90–0.80(m,2H),0.75–0.62(m,J=3.8Hz,5H),0. 61–0.52(m,1H),0.51–0.46(m,1H),0.46–0.39(m,2H),0.32–0.21(m,4H).

[0413] Preparation of Example 33

[0414] To a solution of 3-ethylisoxazole-4-carboxylic acid (16.01 mg, 113.48 μmol) and DIPEA (44.00 mg, 340.44 μmol, 59.30 μL) in DMF (1 mL) were added HATU (51.75 mg, 136.17 μmol) and Intermediate 15-6. The mixture was stirred at room temperature for 1 hour. After the reaction, water (3 mL) was added to precipitate a large amount of white solid, which was filtered, washed with water, and dried to obtain Intermediate 33-1 (30 mg, 46.02 μmol, 40.56% yield). MS (ESI) m / z = 652 [M+1] + .

[0415] To a solution of Intermediate 33-1 (30 mg, 46.02 μmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to dryness and purified by MPLC to afford Example 33 (13 mg, 20.40 μmol, 44.33% yield). MS (ESI) m / z = 522 [M+1] + . 1 H NMR (600MHz, Methanol-d4) δ9.13 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 11. 3Hz,1H),5.01(dd,J=7.3,1.5Hz,1H),4.33(s,2H),3.78(s,2H),2.93(q,J=7.5 Hz,2H),2.73(s,2H),2.31(s,3H),1.28(t,J=7.6,1.5Hz,3H),0.98–0.84(m,2H ),0.83–0.76(m,1H),0.61–0.54(m,1H),0.54–0.40(m,3H),0.39–0.23(m,4H).

[0416] Preparation of Examples 34 to 36

[0417] Referring to the synthetic route of Example 33, in step 1, 3-ethylisoxazole-4-carboxylic acid was replaced with the corresponding isoxazole carboxylic acid in the following table. The remaining reagents and procedures were the same to obtain the corresponding example compound.

[0418] Preparation of Example 37a and Example 37b

[0419] Referring to the synthetic route of Examples 11a & 11b, intermediate 15-4 was used instead of intermediate 1-4 in step 1, and the remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-isopropanol, A / B=75 / 25; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 37a (P1, SFC t R =2.114), MS(ESI)m / z=545[M+1] + . 1H NMR (600MHz, Methanol-d4) δ7.98(d,J=7.9Hz,1H),7.50(d,J=2.1Hz,1H),7.19(d,J=11.2 Hz,1H),6.88(d,J=2.2Hz,1H),4.67(d,J=8.7Hz,1H),4.59–4.50(m,2H),4.32(s,2H),3.8 6–3.53 (m, 2H), 2.70 (s, 2H), 2.27 (s, 3H), 2.16–2.05 (m, 3H), 2.02–1.96 (m, 1H), 1.91 (d, J=13.6 Hz, 1H), 1.88–1.74 (m, 2H), 1.62–1.45 (m, 2H), 1.38 (t, J=7.2 Hz, 3H). Example 37b (P2, SFC t R =5.415), MS(ESI)m / z=545[M+1] + . 1 H NMR (600MHz, Methanol-d4) δ7.98(d,J=7.9Hz,1H),7.50(d,J=2.1Hz,1H),7.19(d,J=11.1 Hz,1H),6.88(d,J=2.1Hz,1H),4.68(dd,J=8.7,1.3Hz,1H),4.54(q,J=7.2Hz,2H),4.31(s, 2H),3.71(s,2H),2.69(s,2H),2.27(s,3H),2.15–2.04(m,3H),2.02–1.96(m,1H),1.93–1 .88(m,1H),1.80(ddd,J=33.2,14.1,8.3Hz,2H),1.63–1.45(m,2H),1.38(t,J=7.2Hz,3H).

[0420] Preparation of Example 38a and Example 38b

[0421] Referring to the synthetic route of Examples 11a & 11b, intermediate 15-4 was used instead of intermediate 1-4 in step 1, and 1-isopropylpyrazole-5-carboxylic acid was used instead of 1-ethylpyrazole-5-carboxylic acid in step 3. The remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-isopropanol, A / B=75 / 25; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 38a (P1, SFC tR =1.771), MS(ESI)m / z=559[M+1] + . 1 H NMR(600MHz,Methanol-d4)δ7.98(d,J=7.9Hz,1H),7.51(d,J=2.0Hz,1H),7.19(d,J=11.3H z,1H),6.81(d,J=2.0Hz,1H),5.45–5.35(m,1H),4.67(dd,J=8.6,1.4Hz,1H),4.30(s,2H), 3.72 (s, 2H), 2.69 (s, 2H), 2.27 (s, 3H), 2.16–2.04 (m, 3H), 1.99 (d, J = 13.6 Hz, 1H), 1.91 (d, J = 13.2 Hz, 1H), 1.88–1.75 (m, 2H), 1.63–1.49 (m, 2H), 1.45 (t, J = 6.7 Hz, 6H). Example 38b (P2, SFC t R =4.932), MS(ESI)m / z=559[M+1] + . 1 H NMR (600MHz, Methanol-d4) δ7.98 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 11. 3Hz,1H),6.81(d,J=2.1Hz,1H),5.45–5.35(m,1H),4.68(dd,J=8.5,1.1Hz,1H),4.30(s, 2H),3.92–3.52(m,2H),2.69(s,2H),2.27(s,3H),2.16–2.04(m,3H),2.02–1.96(m,1H), 1.91(d,J=13.5Hz,1H),1.81(d,J=32.3Hz,2H),1.63–1.49(m,2H),1.45(t,J=6.9Hz,6H).

[0422] Preparation of Example 39a and Example 39b

[0423] Referring to the synthetic route of Example 33, intermediate D-1 was used instead of 3-ethylisoxazole-4-carboxylic acid in step 1, and the remaining reagents and procedures were the same. In the final step, purification was performed by alkaline MPLC and then separated by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3 μm, 150 mm*3 mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=77 / 23; flow rate: 1 mL / min; column temperature: 40°C) to obtain Example 39a (P1, SFC t R =2.467), MS(ESI)m / z=571[M+1] + . 1 H NMR (600MHz, DMSO-d6) δ12.47(d,J=24.5Hz,1H),10.02(s,1H),8.63(d,J=8.8Hz,1H),7.93(d,J=8.2Hz,1H),7. 64(d,J=2.0Hz,1H),7.25(s,1H),7.11(d,J=2.0Hz,1H),6.24(td,J=55.8,5.2Hz,1H),5.83–5.72(m,1H),4.99( t, 1H), 4.34 (s, 2H), 3.61 (s, 2H), 2.61 (s, 2H), 2.21 (s, 3H), 1.53 (d, J = 6.9 Hz, 3H), 0.97–0.83 (m, 2H), 0.79 (td, J = 9.4, 7.8 Hz, 1H), 0.54–0.45 (m, 1H), 0.43–0.36 (m, 2H), 0.36–0.28 (m, 2H), 0.28–0.15 (m, 3H). Example 39b (P2, SFC t R =3.450), MS(ESI)m / z=571[M+1] + . 1H NMR (600MHz, DMSO-d6) δ12.40(s,1H),9.99(s,1H),8.53(d,J=8.7Hz,1H),7.90(d,J=8.2Hz,1H),7.60( d,J=2.0Hz,1H),7.21(d,J=11.6Hz,1H),7.09(d,J=2.0Hz,1H),6.23(td,J=55.9,5.0Hz,1H),5.82–5.7 0(m,1H),4.95(t,J=8.2Hz,1H),4.17(s,2H),3.57(s,2H),2.58(s,2H),2.17(s,3H),1.48(d,J=7.0Hz, 3H),0.93–0.80(m,2H),0.76(q,J=8.9Hz,1H),0.49–0.41(m,1H),0.38–0.23(m,4H),0.24–0.11(m,3H).

[0424] Preparation of Example 40a, Example 40b to Example 39a, Example 39b

[0425] Referring to the synthetic routes of Example 39a and Example 39b, the intermediate pyrazolecarboxylic acid shown in the table below was used instead of intermediate D-1 in step 1. The remaining reagents and operations were the same to obtain the corresponding example compounds.

[0426] Preparation of Example 43a, Example 43b and Example 43c

[0427] Referring to the synthetic route of Example 39a and Example 39a, intermediate D-51 was used instead of intermediate D-1 in step 1, and the remaining reagents and procedures were the same. In the final step, the product was purified by alkaline MPLC and then separated by SFC (chiral column model: Daicel CHIRALCEL OX-3; specification: 3 μm, 150 mm*3 mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=65 / 35; flow rate: 1 mL / min; column temperature: 40°C) to obtain Example 43a (P1, SFC t R =2.467), MS(ESI)m / z=597[M+1] + . 1¹H NMR (600 MHz, Methanol-d4) δ 7.98 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 10.7 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 5.90–5.78 (m, 1H), 5.03 (d, J = 6.1 Hz, 1H), 4.31 (s, 2H), 3.71 (s, 2H), 3.59 (dd, J = 13.3, 10.6 Hz, 1H), 3.16 (dd, J = 13.3, 4.2 Hz, 1H), 2.84–2.62 (m, 2H), 2.57 (s, 3H), 2.28 (s, 3H), 1.63 (d, J = 6.7 Hz, 3H), 0.96–0.84 (m, 3H), 0.61–0.42 (m, 4H), 0.37 (dq, J = 9.8, 5.0 Hz, 1H), 0.29 (dtq, J = 23.4, 9.4, 4.7 Hz, 3H). Example 43b (P2, mix, SFC t R = 3.110), MS (ESI) m / z = 597 [M+1] + . 1 ¹H NMR (600 MHz, Methanol-d4) δ 8.02 (dd, J = 13.4, 7.9 Hz, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 6.86 (dd, J = 15.8, 2.0 Hz, 1H), 5.88–5.80 (m, 1H), 5.00 (d, J = 7.1 Hz, 1H), 4.32 (s, 2H), 3.70 (d, J = 25.4 Hz, 2H), 3.56–3.46 (m, 1H), 3.41–3.32 (m, 1H), 2.63 (d, J = 44.0 Hz, 5H), 2.27 (d, J = 17.0 Hz, 3H), 1.62 (dd, J = 17.1, 6.7 Hz, 3H), 0.97–0.78 (m, 3H), 0.59–0.42 (m, 4H), 0.38 (dq, J = 9.6, 5.0 Hz, 1H), 0.29 (ddq, J = 22.2, 9.3, 4.8 Hz, 3H). Example 43c (P3, SFC t R = 3.762), MS (ESI) m / z = 597 [M+1] + . 1H NMR (600MHz, Methanol-d4) δ8.04(d,J=8.0Hz,1H),7.58(d,J=2.0Hz,1H),7.19(d,J=11.3Hz,1H),6 .89(d,J=2.0Hz,1H),5.90–5.83(m,1H),5.01(d,J=7.2Hz,1H),4.31(s,2H),3.68(dd,J=13.3,10.5 Hz,3H),3.15(dd,J=13.4,4.0Hz,1H),2.89–2.62(m,2H),2.58(s,3H),2.28(s,3H),1.60(d,J=6.7H z,3H),0.96–0.82(m,3H),0.58–0.43(m,4H),0.37(tdd,J=5.3,3.6,1.9Hz,1H),0.32–0.25(m,3H).

[0428] Preparation of Example 44a and Example 44b

[0429] Referring to the synthetic route of Example 15, intermediate C-5 was used instead of intermediate C-1 in step 5, and the remaining reagents and procedures were the same. In the final step, purification was performed by alkaline MPLC and then separated by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3 μm, 150 mm*3 mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=80 / 20; flow rate: 1 mL / min; column temperature: 40°C) to obtain Example 44a (P1, SFC t R =3.283), MS(ESI)m / z=581[M+1] + , 1 H NMR (600MHz, Methanol-d4) δ8.04(d,J=7.9Hz,1H),7.52(d,J=2.1Hz,1H),7.18(s,1H),6.80(d,J=2.0Hz,1H),5.43(h,J=6.7Hz,1H),4.94(t,J=6.0H z,1H),4.56–4.10(m,2H),4.04–3.95(m,2H),3.87–3.57(m,2H),2.70(s,2 H), 2.27 (d, J = 25.3Hz, 3H), 1.49–1.44 (m, 6H), 1.42 (s, 6H); Example 44b (P2, SFC t R =5.063), MS(ESI)m / z=581[M+1] + , 1H NMR (600MHz, Methanol-d4) δ8.04(d,J=7.9Hz,1H),7.52(d,J=2.1Hz,1H),7.19(s,1H),6.80(d,J=2.0Hz,1H),5.47–5.40(m,1H),4.94( t,J=6.0Hz,1H),4.30(s,2H),4.04–3.95(m,2H),3.84–3.56(m,2H),2.70(s,2H),2.29(s,3H),1.46(dd,J=6.6,4.2Hz,6H),1.42(s,6H).

[0430] Preparation of Examples 45 to 50

[0431] Referring to the synthetic route of Example 15, in step 5, the corresponding intermediate carboxylic acid in the table below is used instead of intermediate C-1. Meanwhile, in step 7, the corresponding pyrazolecarboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid or the same. The remaining reagents and operations are the same to obtain the corresponding example compounds.

[0432] Preparation of Example 51 and Example 52

[0433] Referring to the synthetic route of Example 1, in step 7, the corresponding pyrazole carboxylic acid in the table below was used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and procedures were the same to obtain the corresponding example compounds.

[0434] Preparation of Example 52 and Example 53

[0435] Referring to the synthetic route of Example 12, in step 8, 1-isopropylpyrazole-5-carboxylic acid was replaced with the corresponding pyrazole carboxylic acid in the table below. The remaining reagents and procedures were the same to obtain the corresponding example compounds.

[0436] Preparation of Examples 55 to 109

[0437] Referring to the synthetic route of Example 15, in step 7, 1-isopropylpyrazole-5-carboxylic acid was replaced with the corresponding pyrazole carboxylic acid in the table below. The remaining reagents and procedures were the same to obtain the corresponding example compounds.

[0438] Preparation of Example 110

[0439] To a solution of Intermediate 15-6 (1.0 g, 1.89 mmol) in DCM (5 mL) was added TFA (5 mL) in an ice-water bath. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The crude product was purified by MPLC (CH3CN / H2O, 0.05% NH4HCO3) to afford Intermediate 110-1 (534.36 mg, 1.34 mmol, 70.89% yield). MS (ESI) m / z = 399 [M+1] + .

[0440] To a solution of Intermediate D-46 (30.82 mg, 138.19 μmol) and Intermediate 110-1 (50 mg, 125.63 μmol) in DMF (1 mL) were added DIPEA (40.49 mg, 313.27 μmol, 54.56 μL) and HATU (42 mg, 110.46 μmol). The mixture was stirred at room temperature for 1 hour. After completion of the reaction, Example 110 (38.12 mg, 63.23 μmol, 50.33% yield) was obtained by preparative purification using MPLC. MS (ESI) m / z = 604 [M+1] + . 1 H NMR(400MHz,Methanol-d4)δ8.03(d,J=8.1Hz,1H),7.71(dd,J=16.7,2.0Hz,1H),7 .20(d,J=11.5Hz,1H),7.02(dd,J=12.6,2.0Hz,1H),6.07(p,J=8.0Hz,1H),4.98(d, J=6.8Hz,1H),4.83–4.70(m,2H),4.61(s,1H),4.51–4.15(m,3H),3.72(s,2H),2.7 0(s,2H),2.28(s,3H),1.38(d,J=2.6Hz,9H),1.01–0.79(m,3H),0.63–0.22(m,8H).

[0441] Preparation of Examples 111 to 115

[0442] Referring to the synthetic route of Example 110, in step 2, the corresponding pyrazole carboxylic acid in the table below is used instead of intermediate D-46. The remaining reagents and operations are the same to obtain the corresponding example compounds.

[0443] Preparation of Example 116

[0444] Methylmagnesium bromide (110.10 mmol, 37 mL) was added dropwise to a solution of Intermediate A-2 (10 g, 27.52 mmol) in dry THF (100 mL) in an ice-water bath at 0°C under nitrogen. The mixture was allowed to warm to room temperature and stirred for 3 hours. After the reaction, the reaction solution was poured into an icy aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC (CH3CN / H2O, 0.05% TFA) to afford Intermediate 116-1 (5.3 g, 14.59 mmol, 52.99% yield). MS (ESI) m / z = 363 [M+1] + .

[0445] To a single-necked eggplant-shaped flask were added Intermediate 116-1 (3.8 g, 10.46 mmol), Intermediate B-3 (3.39 g, 11.50 mmol), Pd2(dba)3 (478.82 mg, 522.89 μmol), Rac-BI-DIME (345.48 mg, 1.05 mmol), and 1,4-dioxane / water (38 mL / 7.6 mL). CS2CO3 (10.96 g, 20.92 mmol) was added while stirring. The mixture was evacuated and replaced with nitrogen three times. The temperature was raised to 100°C and stirred for 12 hours. After the reaction was complete, the mixture was filtered through hot celite, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to afford Intermediate 116-2 (913 mg, 2.02 mmol, 19.29% yield). MS (ESI) m / z = 452 [M+1] + .

[0446] To Intermediate 116-2 (913 mg, 2.02 mmol, 19.29%) in dry THF (10 mL) was added dropwise LiAlH4 (6.07 mmol, 6 mL, 1 M in THF) in an ice-water bath at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 2 hours. After completion of the reaction, ice water (0.23 mL), 15% aqueous NaOH (0.23 mL), and water (0.69 mL) were added sequentially at -10°C to quench the reaction. The reaction mixture was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure to afford Intermediate 116-3 (570 mg, 1.35 mmol, 66.56% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z = 424 [M+1] + .

[0447] Referring to the synthetic route of Example 1, intermediate 116-3 was used instead of intermediate 1-2. The remaining reagents and procedures were the same to obtain intermediate 116-5. MS (ESI) m / z = 406 [M+1] + .

[0448] Intermediate 116-5 (58 mg, 143.00 μmol), intermediate C-1 (43.38 mg, 143.00 μmol), EDCI (82.37 mg, 429.01 μmol), and pyridine (2.5 mL) were added to an eggplant-shaped flask and stirred at room temperature overnight. After the reaction, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC (CH3CN / H2O, 0.05% TFA) to obtain intermediate 116-6 (57 mg, 82.50 μmol, 57.69% yield). MS (ESI) m / z = 691 [M+1] + .

[0449] Referring to the synthetic route of Example 1, intermediate 116-6 was used instead of intermediate 1-5. The remaining reagents and procedures were the same to obtain Example 116. MS (ESI) m / z = 563 [M+1] + . 1 H NMR(600MHz,Methanol-d4)δ8.03(d,J=7.9Hz,1H),7.52(d,J=2.0Hz,1H),7.16 (s,1H),6.79(d,J=2.0Hz,1H),5.41(p,J=6.6Hz,1H),5.01(d,J=7.3Hz,1H),4. 26(s,2H),2.59(s,2H),2.29(s,3H),1.46(t,J=7.0Hz,6H),1.23(d,J=3.0Hz,6 H),0.95–0.80(m,3H),0.60–0.43(m,4H),0.42–0.35(m,1H),0.34–0.24(m,3H).

[0450] Preparation of Example 117

[0451] Referring to the synthetic route of Example 116, ethylpyrazole-5-carboxylic acid was used instead of isopropylpyrazole-5-carboxylic acid in step 8. The remaining reagents and procedures were the same to obtain Example 117. MS (ESI) m / z=549[M+1] + . 1H NMR(600MHz, Methanol-d4)δ8.03(d,J=8.0Hz,1H),7.51(d,J=2.1Hz,1H),7.16(d ,J=11.2Hz,1H),6.87(d,J=2.1Hz,1H),5.01(d,J=7.2Hz,1H),4.55(q,J=7.2Hz,2H ),4.26(s,2H),2.59(s,2H),2.29(s,3H),1.40(t,J=7.2Hz,3H),1.23(d,J=2.9Hz ,6H),0.95–0.81(m,3H),0.61–0.43(m,4H),0.42–0.36(m,1H),0.35–0.25(m,3H).

[0452] Preparation of Example 118a and Example 118b

[0453] To a single-necked flask, intermediate A-2 (30 g, 82.57 mmol) and methanol (240 mL) were added. A solution of NaOH (4.95 g, 123.86 mmol) in water (80 mL) was added under an ice-water bath. After addition, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the temperature was lowered to 0°C, the pH was adjusted to 4 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield intermediate 118-1 (28.7 g, 82.17 mmol, 99.51% yield). MS (ESI) m / z = 349 [M+1] + .

[0454] To a single-necked flask, intermediate 118-1 (28.7 g, 82.17 mmol), dimethylhydroxylamine hydrochloride (6.52 g, 106.82 mmol), and DMF (280 mL) were added. HATU (46.86 g, 123.25 mmol) and DIPEA (31.86 g, 246.50 mmol, 42.93 mL) were added in an ice-water bath. After addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC to afford intermediate 118-2 (20 g, 50.97 mmol, 62.04% yield). MS (ESI) m / z = 392 [M+1] + .

[0455] Methylmagnesium bromide (76.46 mmol, 26 mL) was added dropwise to a solution of Intermediate 118-2 (15 g, 38.23 mmol) in dry THF (150 mL) in an ice-water bath at 0°C under nitrogen. The mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction, the reaction mixture was poured into an icy aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC (CH3CN / H2O, 0.05% TFA) to afford Intermediate 118-3 (6.3 g, 18.14 mmol, 47.45% yield). MS (ESI) m / z = 347 [M+1] + .

[0456] To a single-necked flask, intermediate 118-3 (4 g, 11.52 mmol) and ethanol (40 mL) were added. Sodium borohydride (653.51 mg, 17.28 mmol) was added portionwise in an ice-water bath. After addition, the mixture was stirred and allowed to react for 1 hour. After completion of the reaction, the mixture was quenched by pouring into an icy aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude intermediate 118-4 (4.02 g, 11.51 mmol, 100.00% yield). MS (ESI) m / z = 349 [M+1] + .

[0457] Referring to the synthetic route of Example 116, intermediate 118-4 was used instead of intermediate 116-1. The remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=70 / 30; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 118a (P1, SFC t R =1.760), MS(ESI)m / z=549[M+1] + . 1H NMR (600MHz, Methanol-d4) δ8.04(d,J=7.9Hz,1H),7.53(d,J=2.0Hz,1H),7.18(s,1H),6.80(d,J=2.0Hz,1H),5.41(h ept,J=6.7Hz,1H),5.01(d,J=7.3Hz,1H),4.67(d,J=12.5Hz,1H),4.01(d,J=12.7Hz,1H),3.64(s,1H),2.86(d,J=15. 0 Hz, 1H), 2.28 (s, 4H), 1.46 (t, J = 6.8 Hz, 6H), 1.26 (d, J = 6.3 Hz, 3H), 0.95–0.85 (m, 2H), 0.82 (td, J = 9.3, 7.4 Hz, 1H), 0.63–0.54 (m, 1H), 0.54–0.42 (m, 3H), 0.38 (dq, J = 9.7, 4.9 Hz, 1H), 0.30 (ddt, J = 10.7, 8.8, 5.2 Hz, 3H). Example 118b (P2, SFC t R =1.880), MS(ESI)m / z=549[M+1] + . 1 H NMR(600MHz,Methanol-d4)δ8.02(d,J=7.9Hz,1H),7.53(d,J=2.0Hz,1H),7.18(s ,1H),6.80(d,J=2.0Hz,1H),5.41(hept,J=6.7Hz,1H),5.00(d,J=7.3Hz,1H),4.6 7(d,J=12.7Hz,1H),4.02(d,J=12.8Hz,1H),3.64(s,1H),2.85(d,J=14.9Hz,1H), 2.28(s,4H),1.46(t,J=7.0Hz,6H),1.25(d,J=6.3Hz,3H),0.97–0.85(m,2H),0.82 (td,J=9.2,7.2Hz,1H),0.57(tq,J=8.3,4.0Hz,1H),0.54–0.41(m,3H),0.38(dq,J=9.7,4.9Hz,1H),0.29(ddp,J=18.3,9.3,4.7Hz,3H).

[0458] Preparation of Example 119a and Example 119b

[0459] Referring to the synthetic route of Example 118, ethylpyrazole-5-carboxylic acid was used instead of isopropylpyrazole-5-carboxylic acid in step 11, and the remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=70 / 30; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 119a (P1, SFC t R =1.902), MS(ESI)m / z=535[M+1] + . 1 H NMR (600MHz, Methanol-d4) δ8.05(d,J=7.9Hz,1H),7.53(d,J=2.1Hz,1H),7.20(s,1H),6.89(d,J=2.1Hz,1H),5.03( d,J=7.3Hz,1H),4.69(d,J=12.4Hz,1H),4.57(q,J=7.2Hz,2H),4.03(d,J=12.7Hz,1H),3.66(s,1H),2.88(d,J=15.0 Hz, 1H), 2.30 (s, 4H), 1.42 (t, J = 7.2 Hz, 3H), 1.28 (d, J = 6.3 Hz, 3H), 1.01–0.87 (m, 2H), 0.84 (td, J = 9.2, 7.3 Hz, 1H), 0.59 (tdd, J = 8.0, 4.9, 3.6 Hz, 1H), 0.56–0.43 (m, 3H), 0.40 (dq, J = 9.7, 4.9 Hz, 1H), 0.36–0.22 (m, 3H). Example 119b (P2, SFC t R =2.145), MS(ESI)m / z=535[M+1] + . 1H NMR (600MHz, Methanol-d4) δ8.01(d,J=7.9Hz,1H),7.51(d,J=2.0Hz,1H),7.18(s,1H),6.87(d,J=2.1Hz,1H),5.00 (d,J=7.1Hz,1H),4.67(d,J=12.7Hz,1H),4.56(q,J=7.1Hz,2H),4.02(d,J=12.7Hz,1H),3.64(s,1H),2.85(d,J=15 .0Hz,1H),2.28(s,4H),1.40(t,J=7.2Hz,3H),1.25(d,J=6.3Hz,3H),0.95–0.85(m,2H),0.83(td,J=9.3,7.2Hz,1H ),0.57(tq,J=8.2,4.0Hz,1H),0.54–0.41(m,3H),0.38(dq,J=9.7,4.9Hz,1H),0.29(ddt,J=12.2,9.0,5.1Hz,3H).

[0460] Preparation of Example 120a and Example 120b

[0461] Referring to the synthetic route of Example 118, ethylmagnesium bromide was used instead of methylmagnesium bromide in step 3, and the remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AS-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=80 / 20; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 120a (P1, SFC t R =1.749), MS (ESI)m / z=563[M+1] + . 1¹H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 11.4 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 5.41 (p, J = 6.7 Hz, 1H), 5.01 (d, J = 7.1 Hz, 1H), 4.69 (d, J = 12.5 Hz, 1H), 4.00 (d, J = 12.5 Hz, 1H), 3.34 (s, 1H), 2.88 (d, J = 14.9 Hz, 1H), 2.27 (s, 4H), 1.65–1.52 (m, 2H), 1.46 (dd, J = 6.7, 4.8 Hz, 6H), 1.01 (t, J = 7.4 Hz, 3H), 0.96–0.77 (m, 3H), 0.62–0.53 (m, 1H), 0.48 (qdd, J = 9.0, 5.7, 3.1 Hz, 3H), 0.38 (dt, J = 9.4, 4.2 Hz, 1H), 0.35–0.21 (m, 3H). Example 120b (P2, SFC t R = 1.974), MS (ESI) m / z = 563 [M+1] + . 1 ¹H NMR (400 MHz, Methanol-d4) δ 8.03 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 11.4 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 5.50–5.31 (m, 1H), 5.01 (d, J = 7.0 Hz, 1H), 4.68 (d, J = 12.6 Hz, 1H), 4.00 (d, J = 12.6 Hz, 1H), 3.32 (s, 1H), 2.87 (d, J = 14.8 Hz, 1H), 2.27 (s, 4H), 1.63–1.52 (m, 2H), 1.46 (dd, J = 6.7, 4.9 Hz, 6H), 1.01 (d, J = 7.4 Hz, 3H), 0.96–0.79 (m, 3H), 0.61–0.53 (m, 1H), 0.48 (ddtd, J = 13.2, 9.3, 4.6, 4.2, 2.8 Hz, 3H), 0.42–0.35 (m, 1H), 0.35–0.25 (m, 3H). <000200​​​​To a single-necked flask, intermediate 15-6 (50 mg, 94.57 μmol) and dry dichloromethane (20 mL) were added, followed by DIPEA (24.44 mg, 189.13 μmol, 32.94 μL). Methyl chloroformate (9.83 mg, 104.02 μmol) was added dropwise in an ice-water bath, and the mixture was allowed to warm to room temperature and stirred for 30 minutes. After completion of the reaction, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield intermediate 121-1 (52 mg, 88.62 μmol, 93.71% yield). MS (ESI) m / z = 587 [M+1] + .

[0464] To a solution of Intermediate 121-1 (52 mg, 88.62 μmol) in DCM (1 mL) was added TFA (1 mL). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to dryness, dissolved in dichloromethane, and the pH was adjusted to 8 with triethylamine under ice-cold conditions. The residue was then concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC (H2O / CH3CN, 0.05% NH4HCO3) to afford Example 121 (17 mg, 37.24 μmol, 42.02% yield). MS (ESI) m / z = 457 [M+1] + . 1 H NMR (600MHz, DMSO-d6) δ12.43(d,J=29.0Hz,1H),9.74(s,1H),7.86(d,J=8.1Hz,1H),7.31( d,J=9.0Hz,1H),7.19(s,1H),4.45(dd,J=9.0,6.4Hz,1H),4.32–3.93(m,2H),3.71–3.55(m, 2H),3.54(s,3H),2.76–2.49(m,2H),2.17(s,3H),0.94–0.84(m,1H),0.81–0.73(m,1H),0.6 1–0.53(m,1H),0.47–0.38(m,1H),0.37–0.29(m,1H),0.29–0.21(m,2H),0.21–0.11(m,4H).

[0465] Preparation of Example 122

[0466] Referring to the synthetic route of Example 15, 1-fluorocyclopropanecarboxylic acid was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 7. The remaining reagents and procedures were the same to obtain Example 122. MS (ESI) m / z = 485 [M+1] + .

[0467] Preparation of Example 123a and Example 123b

[0468] Referring to the synthetic route of Example 33, intermediate D-8 was used instead of 3-ethylisoxazole-4-carboxylic acid in step 1. The remaining reagents and procedures were the same. In the final step, the product was purified by alkaline MPLC and then separated by SFC (chiral column model: Daicel CHIRALPAK IG; specifications: 3 μm, 150 mm*3 mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=75 / 25; flow rate: 1 mL / min; column temperature: 40°C) to obtain Example 123a (P1, SFC t R =3.993), MS(ESI)m / z=549[M+1] + . 1 H NMR (400MHz, Methanol-d4) δ8.04(d,J=8.0Hz,1H),7.55(d,J=2.1Hz,1H),7.19(d,J=11.4Hz,1H),6 .78(d,J=2.0Hz,1H),5.19(dp,J=9.1,6.5Hz,1H),5.00(d,J=7.1Hz,1H),4.31(s,2H),3.71(s,2H),2 .70 (s, 2H), 2.27 (s, 3H), 1.93 (ddq, J = 14.6, 9.1, 7.4 Hz, 1H), 1.81–1.70 (m, 1H), 1.47 (d, J = 6.7 Hz, 3H), 0.92–0.81 (m, 3H), 0.72 (t, J = 7.4 Hz, 3H), 0.60–0.36 (m, 5H), 0.34–0.23 (m, 3H). Example 123b (P2, SFC t R =4.966), MS(ESI)m / z=549[M+1] + . 1H NMR (400MHz, Methanol-d4) δ8.04(d,J=8.0Hz,1H),7.55(d,J=2.0Hz,1H),7.19(d,J=11.5Hz,1H ),6.81(d,J=2.0Hz,1H),5.22(dp,J=9.1,6.6Hz,1H),5.01(d,J=6.8Hz,1H),4.31(s,2H),3.72( s,2H),2.70(s,2H),2.28(s,3H),1.96(ddq,J=14.7,9.1,7.4Hz,1H),1.84–1.71(m,1H),1.46(d ,J=6.6Hz,3H),0.97–0.81(m,3H),0.74(t,J=7.4Hz,3H),0.61–0.34(m,5H),0.34–0.23(m,3H).

[0469] Preparation of Example 124

[0470] Referring to the synthetic route of Example 12, in step 8, intermediate D-21 was used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and procedures were the same to obtain Example 124. MS (ESI) m / z = 536 [M+1] + . 1 H NMR (600MHz, Methanol-d4) δ8.33(s,1H),8.18(s,1H),7.53(d,J=2.1Hz,1H),6.91(d,J=2.1Hz,1H ),4.98(d,J=6.6Hz,1H),4.65(td,J=6.9,2.1Hz,2H),4.45(td,J=6.0,1.6Hz,1H),4.37(td,J=5.9, 1.3Hz,1H),4.27(s,2H),3.76(s,2H),2.72(s,2H),2.30(s,3H),2.24–2.14(m,2H),0.98–0.81(m,3 H),0.59–0.53(m,1H),0.52–0.42(m,2H),0.41–0.32(m,2H),0.33–0.27(m,2H),0.26–0.21(m,1H).

[0471] Preparation of Example 125

[0472] Referring to the synthetic route of Example 12, in step 8, intermediate D-35 was used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and procedures were the same to obtain Example 125. MS (ESI) m / z = 548 [M+1] +. 1 H NMR (400MHz, Methanol-d4) δ8.33 (s, 1H), 8.21 (s, 1H), 7.54 (dd, J = 2.2, 1.0Hz ,1H),6.93(t,J=1.9Hz,1H),5.03–4.95(m,1H),4.61(dddt,J=64.0,8.7,6.3,2 .3Hz,1H),4.49–4.07(m,4H),3.75(s,2H),2.71(s,2H),2.30(s,3H),1.88–1. 65(m,1H),1.06–0.80(m,4H),0.71(dq,J=10.4,6.7Hz,1H),0.61–0.20(m,8H).

[0473] Preparation of Example 126 and Example 127

[0474] 6-Bromo-5-fluoro-2-pyridinecarboxylic acid (23.71 g, 107.77 mmol) and methanol (380 mL) were added to a single-necked flask. Concentrated sulfuric acid (71 mL) was then added dropwise at room temperature. The mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was quenched by pouring into ice water and extracted with dichloromethane. The organic phase was adjusted to pH 8 with sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate 126-1 (24.58 g, 105.03 mmol, 97.46% yield). MS (ESI) m / z = 234 [M+1] + .

[0475] To a single-necked flask, intermediate 126-1 (10 g, 42.73 mmol), aminoBoc (6.01 g, 51.28 mmol), Cs2CO3 (27.84 g, 85.46 mmol), Pd2(dba)3 (1.96 g, 2.14 mmol), Xantphos (2.47 g, 4.27 mmol), and toluene (150 mL) were added. The mixture was evacuated and replaced with nitrogen three times with stirring. The temperature was raised to 90°C and stirred overnight. After the reaction was complete, the mixture was filtered through hot celite, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to afford intermediate 126-2 (2.13 g, 12.52 mmol, 29.30% yield). MS (ESI) m / z = 171 [M+1] + .

[0476] To a single-necked flask, intermediate 126-2 (1.97 g, 11.58 mmol), glacial acetic acid (69.54 mg, 1.16 mmol), and acetonitrile (40 mL) were added. NBS (2.27 g, 12.74 mmol) was added at room temperature and stirred for 2 hours. After completion of the reaction, the reaction was quenched by addition of water and extracted with ethyl acetate. The organic phase was washed sequentially with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 126-3 (2.42 g, 9.73 mmol, 84.06% yield). MS (ESI) m / z = 249 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.82 (d, J = 10.2Hz, 1H), 6.84 (s, 2H), 3.82 (s, 3H).

[0477] To a single-necked flask, intermediate 126-3 (2.36 g, 9.48 mmol), intermediate A-3 (4.28 g, 10.42 mmol), CsF (2.88 g, 18.95 mmol), Pd(amphos)Cl2 (336.46 mg, 473.83 μmol), and dioxane / water (50 mL / 10 mL) were added. The atmosphere was evacuated and replaced with nitrogen three times with stirring. The temperature was raised to 100°C and stirred overnight. After the reaction, the mixture was filtered through hot celite, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to afford intermediate 126-4 (3.06 g, 6.76 mmol, 71.35% yield). MS (ESI) m / z = 453 [M+1] + .

[0478] Referring to the synthetic route of Example 1, intermediate 126-4 was used instead of intermediate 1-1. The remaining reagents and procedures were the same, except that when intermediate 126-8 was hydrogenated with palladium carbon and ammonium formate, about 1 / 3 of the raw materials lost fluorine and then went back separately to obtain Example 126. MS (ESI) m / z=536[M+1] + . 1H NMR (400MHz, Methanol-d4) δ7.69(d,J=10.1Hz,1H),7.52(d,J=2.0Hz,1H),6.79(d,J =2.0Hz,1H),5.41(p,J=6.7Hz,1H),5.07(s,1H),4.50(d,J=62.6Hz,2H),3.75(s,2H) , 2.79 (d, J = 51.4 Hz, 2H), 2.30 (s, 3H), 1.46 (dd, J = 6.6, 4.4 Hz, 6H), 0.90 (qd, J = 8.9, 8.3, 4.3 Hz, 3H), 0.64–0.41 (m, 5H), 0.36–0.27 (m, 3H). Example 127, MS (ESI) m / z = 518 [M+1] + . 1H NMR(400MHz,Methanol-d4)δ8.19(d,J=8.4Hz,1H),7.80(d,J=8.3Hz,1H),7.5 3(d,J=2.0Hz,1H),6.82(d,J=2.1Hz,1H),5.40(p,J=6.6Hz,1H),4.96(d,J=6.7 Hz,1H),4.40(s,2H),3.75(s,2H),2.79(d,J=58.1Hz,2H),2.28(s,3H),1.46(d d,J=6.6,5.5Hz,6H),1.02–0.76(m,3H),0.61–0.42(m,3H),0.42–0.21(m,5H).

[0479] Preparation of Example 128

[0480] To a single-necked flask, methyl 2-chloro-3-fluoroisonicotinate (9 g, 47.48 mmol), aminoBoc (8.34 g, 71.21 mmol), Cs2CO3 (30.94 g, 94.95 mmol), Pd(OAc)2 (532.94 mg, 2.37 mmol), Xantphos (2.75 g, 4.75 mmol), and dioxane (100 mL) were added. The atmosphere was evacuated and replaced with nitrogen three times with stirring. The temperature was raised to 100°C and stirred for 16 hours. After the reaction was complete, the mixture was filtered through hot celite, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to afford Intermediate 128-1 (1.6 g, 9.40 mmol, 19.81% yield). MS (ESI) m / z = 171 [M+1] + . 1H NMR (600MHz, Chloroform-d) δ7.92 (d, J = 5.2Hz, 1H), 7.03 (t, J = 4.9Hz, 1H), 3.95 (s, 3H).

[0481] Intermediate 128-1 (1.6 g, 9.40 mmol) and DMF (40 mL) were added to a single-necked flask. NBS (1.84 g, 10.34 mmol) was added at room temperature and stirred for 2 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed sequentially with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford Intermediate 128-2 (1.5 g, 6.02 mmol, 64.05% yield). MS (ESI) m / z = 249 [M+1] + . 1 H NMR(600MHz,Chloroform-d)δ8.01(s,1H),3.99(s,3H).

[0482] Referring to the synthetic route of Example 126, intermediate 128-2 was used instead of intermediate 126-3. The remaining reagents and procedures were the same to obtain Example 128. MS (ESI) m / z = 536 [M+1] + . 1 H NMR(600MHz,Chloroform-d)δ8.61(s,1H),8.25(s,1H),7.52(d,J=2.0Hz,1H),7.2 6(s,1H),7.18(d,J=8.3Hz,1H),6.58(d,J=2.1Hz,1H),5.49(p,J=6.7Hz,1H),5.04 (s,1H),3.65(d,J=191.7Hz,5H),2.81(s,1H),2.37(s,3H),1.50(dd,J=1 2.9,6.6Hz,6H),0.98–0.87(m,3H),0.70–0.50(m,4H),0.46–0.21(m,4H).

[0483] Preparation of Example 129

[0484] To a single-necked flask, intermediate E-1-2 (5.7 g, 17.80 mmol) and dichloromethane (50 mL) were added. Triphenylphosphine (7.00 g, 26.71 mmol) and carbon tetrabromide (7.68 g, 23.15 mmol) were then added at room temperature. The reaction was stirred and allowed to react overnight at room temperature. After completion of the reaction, water was added to quench the reaction and the product was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 129-1 (4.26 g, 11.12 mmol, 62.47% yield). MS (ESI) m / z = 382 [M+1] + .

[0485] Intermediate 129-1 (3.26 g, 8.51 mmol) and toluene (30 mL) were added to a three-necked flask. Cuprous iodide (162.08 mg, 851.06 μmol) and 2,2'-bipyridine (132.92 mg, 851.06 μmol) were added at room temperature, and the atmosphere was replaced with nitrogen three times under vacuum. The temperature was lowered to -70°C, and vinylmagnesium bromide (3.35 g, 25.53 mmol) was added dropwise. After addition, the temperature was gradually raised to room temperature and stirred overnight. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford Intermediate 129-2 (1.5 g, 4.54 mmol, 53.38% yield). MS (ESI) m / z = 328 [M-1]. + .

[0486] 3-Bromo-5-methyl-1H-pyrazole (20 g, 124.22 mmol) and tetrahydrofuran (200 mL) were added to a three-necked flask. The mixture was cooled to 0°C in an ice-water bath, and sodium hydroxide (5.96 g, 248.45 mmol) was added portionwise. After addition, the mixture was stirred at room temperature for 1 hour, followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (24.85 g, 149.07 mmol). The mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford Intermediate 129-3 (30 g, 103.00 mmol, 82.92% yield). MS (ESI) m / z = 291 [M+1]. + .

[0487] To a single-necked flask, intermediate 129-3 (6 g, 20.60 mmol), dioxane, and water (40 mL / 8 mL) were added. Allylboronic acid pinacol ester (9.52 g, 61.80 mmol), potassium carbonate (8.53 g, 61.80 mmol), and Pd(dppf)Cl2 (753.66 mg, 1.03 mmol) were then added. The atmosphere was evacuated and replaced with nitrogen three times. The temperature was raised to 100°C and stirred overnight. After the reaction, the mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 129-4 (4.67 g, 18.50 mmol, 89.81% yield). MS (ESI) m / z = 253 [M+1]. + .

[0488] To a single-necked flask, intermediate 129-4 (4.5 g, 17.83 mmol) and dichloromethane (40 mL) were added, followed by N-bromosuccinimide (3.49 g, 19.61 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 129-5 (5.2 g, 15.69 mmol, 88.04% yield). MS (ESI) m / z = 331 [M+1]. + .

[0489] To a three-necked flask, intermediate 129-5 (4.4 g, 13.28 mmol) and dioxane (60 mL) were added. Triethylamine (2.02 g, 19.92 mmol, 2.78 mL), Pd(OAc)2 (90.25 mg, 398.40 μmol), and CyJohnphos (279.26 mg, 796.81 μmol) were then added at room temperature. The atmosphere was evacuated and replaced with nitrogen three times. Pinacolborane (4.59 g, 35.86 mmol) was added via syringe. After addition, the temperature was gradually raised to 80°C and stirred overnight. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column to obtain intermediate 129-6 (5.2 g, 15.69 mmol, 88.04% yield). MS (ESI) m / z = 379 [M+1] + .

[0490] To a single-necked flask, intermediate 129-6 (1.32 g, 3.49 mmol), intermediate 129-2 (1.27 g, 3.84 mmol), dioxane, and water (10 mL / 2 mL) were added. Pd2(dba)3 (79.86 mg, 87.21 μmol), rac-BI-DIME (57.56 mg, 174.42 μmol), and potassium phosphate (1.48 g, 6.98 mmol) were added at room temperature. The atmosphere was evacuated and replaced with nitrogen three times. The temperature was gradually raised to 100°C and the reaction was stirred overnight. After completion of the reaction, water was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 129-7 (1.38 g, 2.74 mmol, 78.56% yield). MS (ESI) m / z = 502 [M+1]. + .

[0491] To a single-necked flask, intermediate 129-7 (1.38 g, 2.74 mmol) and dichloromethane (200 mL) were added. Grubbs' second-generation catalyst (116.34 mg, 137.03 μmol) was added at room temperature. The atmosphere was evacuated and replaced with nitrogen three times. The temperature was gradually raised to 45°C and stirred for 48 hours. After the reaction was complete, water was added to quench the reaction. The layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 129-8 (605 mg, 1.28 mmol, 46.61% yield). MS (ESI) m / z = 474 [M+1]. + .

[0492] To a single-necked flask, intermediate 129-8 (200 mg, 422.25 μmol) and ethyl acetate (1 mL) were added. 4 M HCl in ethyl acetate (16.89 mg, 4.22 mmol) was added under ice-water conditions. The mixture was gradually warmed to room temperature and stirred for 1 hour. After the reaction, the mixture was cooled in an ice-water bath, the pH was adjusted to 8 with triethylamine, and the mixture was concentrated to dryness under reduced pressure. The crude product was purified by MPLC (CH3CN / H2O, 0.05% NH4HCO3) to afford intermediate 129-9 (60 mg, 160.63 μmol, 38.04% yield). MS (ESI) m / z = 374 [M+1]. + .

[0493] Referring to the synthetic route of Example 1, intermediate 129-9 was used instead of intermediate 1-4 in step 5, and BOC-L-2-amino-3,3-dicyclopropylpropionic acid was used instead of intermediate C-1. The palladium carbon debenzylation carbonyl was changed to 4M HCl ethyl acetate solution for Boc removal. The Boc removal method was based on the synthetic method of intermediate 129-9. The remaining two synthetic methods were based on the synthetic route of Example 1. The remaining reagents and operations were the same to obtain Example 129. MS (ESI) m / z = 531 [M+1] + .

[0494] Preparation of Example 130

[0495] Example 129 (12 mg, 22.61 μmol) and methanol (2 mL) were added to a single-necked flask, followed by palladium on carbon (4.2 mg, 30% w / w). The atmosphere was replaced with hydrogen three times under vacuum, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by MPLC to afford Example 130 (240.00 μg, 4.51e-1 μmol, 1.99% yield). MS (ESI) m / z = 533 [M+1] + .

[0496] Preparation of Example 131

[0497] To a single-necked flask, intermediate A-2 (10.9 g, 30.00 mmol), methanol (1.35 g, 42.00 mmol), and tetrahydrofuran (110 mL) were added. Lithium borohydride (1.7 g, 78.05 mmol) was then added at room temperature. The mixture was then heated to 60°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled in an ice-water bath, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 131-1 (8.6 g, 25.65 mmol, 85.49% yield). MS (ESI) m / z = 335 [M+1] + .

[0498] To a three-necked flask, intermediate 131-1 (6.6 g, 19.68 mmol) and dichloromethane (60 mL) were added. Triethylamine (3.98 g, 39.37 mmol, 5.49 mL) was then added dropwise under an ice-water bath. Methanesulfonyl chloride (2.71 g, 23.62 mmol) was then added dropwise. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to quench the reaction and the product was extracted with dichloromethane. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate 131-2 (7.7 g, 18.63 mmol, 94.63% yield). MS (ESI) m / z = 413 [M+1] + .

[0499] Intermediate 131-2 (7.7 g, 18.63 mmol) and 33% methylamine methanol solution (60 mL) were added to a sealed tube and stirred at 60°C for 2.5 hours. After the reaction was complete, the mixture was cooled in an ice-water bath and concentrated to dryness under reduced pressure to obtain Intermediate 131-3 (6.29 g, 18.06 mmol, 96.94% yield), which was used directly in the next reaction without purification. MS (ESI) m / z = 348 [M+1] + .

[0500] To a single-necked flask, intermediate 131-3 (5.25 g, 15.07 mmol), tetrahydrofuran, and water (50 mL / 25 mL) were added. Sodium bicarbonate (3.95 g, 18.09 mmol) and (Boc)2O (3.95 g, 18.09 mmol) were then added at room temperature. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to yield intermediate 131-4 (5.57 g, 12.42 mmol, 82.41% yield). MS (ESI) m / z = 448 [M+1] + .

[0501] To a mixture of Intermediate B-3 (3.99 g, 13.52 mmol), Intermediate 131-4 (6.67 g, 14.87 mmol), and Cs2CO3 (8.81 g, 27.03 mmol) in 1,4-dioxane (80 mL) / water (16 mL) was added Pd(dtppf)Cl2 (881.18 mg, 1.35 mmol). Nitrogen was bubbled through the mixture to deoxygenate. The mixture was stirred at 80°C overnight. After completion of the reaction, the mixture was cooled, extracted with water and ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The mixture was purified by silica gel column chromatography to afford Intermediate 131-5 (4.1 g, 7.64 mmol, 56.50% yield). MS (ESI) m / z = 537 [M+1] + .

[0502] To a single-necked flask, intermediate 131-5 (196 mg, 365.19 μmol) was added tetrahydrofuran / methanol and water (2 mL / 2 mL / 2 mL). Sodium hydroxide (70.04 mg, 1.83 mmol) was then added at room temperature. The mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled in an ice-water bath and the pH was adjusted to 7 with 1N HCl. The mixture was then concentrated under reduced pressure to dryness to obtain the crude intermediate 131-6 (190 mg, 363.51 μmol). MS (ESI) m / z = 523 [M+1] + .

[0503] To a single-necked flask, intermediate 131-6 (190 mg, 363.51 μmol) and dichloromethane (3 mL) were added. Trifluoroacetic acid (414.47 mg, 3.64 mmol) was then added under an ice-water bath. The reaction was stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was cooled in an ice-water bath, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure to dryness to obtain the crude intermediate 131-7 (153 mg, 362.07 μmol). MS (ESI) m / z = 423 [M+1] + .

[0504] To a single-necked flask, intermediate 131-7 (153 mg, 362.07 μmol) and DMF (4 mL) were added, followed by DIPEA (187.18 mg, 1.45 mmol, 252.26 μL) and HATU (178.97 mg, 470.69 μmol). The reaction was stirred at room temperature for 1 hour, quenched by the addition of water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified on a silica gel column to afford intermediate 131-8 (121 mg, 299.10 μmol, 82.61% yield). MS (ESI) m / z = 405 [M+1] + .

[0505] To a single-necked flask, intermediate 131-8 (121 mg, 299.10 μmol) and pyridine (1.5 mL) were added, followed by intermediate C-1 (108.88 mg, 358.92 μmol) and EDCI (172.01 mg, 897.29 μmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC (CH3CN / H2O, 0.05% TFA) to afford intermediate 131-9 (128 mg, 185.54 μmol, 62.03% yield). MS (ESI) m / z = 690 [M+1] + .

[0506] Referring to the synthetic method of steps 6 to 8 of Example 1, intermediate 131-9 was used instead of intermediate 1-5. The remaining reagents and operations were the same to obtain Example 131. MS (ESI) m / z=562[M+1] + . 1 H NMR(400MHz, Methanol-d4)δ8.09(dd,J=14.7,7.8Hz,1H),7.51(t,J=2.6Hz,1H),7.18–7.10(m ,1H),6.78(dd,J=3.8,2.1Hz,1H),5.40(pd,J=6.7,2.3Hz,1H),5.01(dd,J=9.5,7.1Hz,1H),4. 01(tt,J=14.3,4.7Hz,1H),3.40(dt,J=14.4,5.5Hz,1H),3.35-3.24(m,1H),3.01(s,3H),2.92 –2.78(m,1H),2.17(s,3H),1.45(td,J=6.8,3.0Hz,6H),0.98–0.75(m,3H),0.63–0.16(m,8H).

[0507] Preparation of Examples 132 to 181

[0508] Referring to the synthetic route of Example 1, in step 5, intermediate 1-4 was replaced with the corresponding macrocyclic amine intermediate in the table below, and in step 7, 1-isopropylpyrazole-5-carboxylic acid was the same or replaced with the corresponding pyrazolecarboxylic acid in the table below. The remaining reagents and operations were the same to obtain the corresponding structural example compounds in the table.

[0509] Preparation of Example 182

[0510] Referring to the synthetic route of Example 12, intermediate E-31 was used instead of intermediate 12-5 in step 6. The remaining reagents and procedures were the same to obtain intermediate 182-1. MS (ESI) m / z = 749 [M+1] + .

[0511] To a single-necked flask, intermediate 182-1 (300 mg, 401.07 μmol) and dichloromethane (4 mL) were added, followed by palladium dichloride (14.12 mg, 80.21 μmol) and triethylamine (8.53 g, 280.75 μmol). Triethylsilane (232.62 mg, 2.01 mmol) was added dropwise in an ice-water bath. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was filtered over celite, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by reverse-phase MPLC to afford intermediate 182-2 (210.87 mg, 343.44 μmol, 85.63% yield). MS (ESI) m / z = 615 [M+1]. + .

[0512] Referring to the synthetic route of Example 12, in step 8, intermediate 182-2 was used instead of intermediate 12-7. The remaining reagents and procedures were the same to obtain intermediate Example 182. MS (ESI) m / z = 621 [M+1] + .

[0513] Preparation of Examples 183 to 185

[0514] Referring to the synthetic route of Example 182, in step 1, the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate E-31. The remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.

[0515] Preparation of Example 186a and Example 186b

[0516] Referring to the synthetic route of Example 118, intermediate E-11 was used instead of intermediate 118-8 in step 9, and the remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-0.1% DEA / ethanol, A / B=75 / 25; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 186a (P1, SFC t R =2.533), MS(ESI)m / z=644[M+1] + , 1H NMR (600MHz, Methanol-d4) δ8.24(d,J=7.7Hz,1H),7.52(d,J=2.0Hz,1H),7.25(d,J=10.8Hz,1H),6.79(d,J=2.0Hz, 1H),5.53(d,J=8.1Hz,1H),5.40(hept,J=6.6Hz,1H),5.00(d,J=7.4Hz,1H),4.21(t,J=12.8Hz,2H),3.72–3.51(m,2H ), 2.36 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H), 1.46 (dd, J = 11.3, 6.6 Hz, 6H), 0.96–0.86 (m, 2H), 0.82 (td, J = 9.3, 7.4 Hz, 1H), 0.61–0.55 (m, 1H), 0.54–0.41 (m, 3H), 0.37 (dt, J = 9.6, 4.7 Hz, 1H), 0.30 (dhept, J = 18.4, 4.8 Hz, 3H); Example 186b (P2, SFC t R =4.165), MS(ESI)m / z=644[M+1] + , 1 H NMR (600MHz, Methanol-d4) δ8.23(d,J=7.7Hz,1H),7.53(d,J=2.0Hz,1H),7.25(d,J=10.9Hz,1H),6.80(d,J=2.0Hz,1H),5.5 3(s,1H),5.41(hept,J=6.7Hz,1H),4.99(d,J=7.4Hz,1H),4.35–4.15(m,2H),3.76–3.49(m,2H),2.36(s,3H),1.54(d,J=7.2 Hz,3H),1.46(dd,J=10.4,6.7Hz,6H),0.90(dddt,J=22.6,13.0,8.0,5.0Hz,2H),0.81(td,J=9.3,7.4Hz,1H),0.57(tt,J=9. 0,4.3Hz,1H),0.54–0.40(m,3H),0.37(dq,J=9.7,4.9Hz,1H),0.31(ttd,J=7.2,5.0,2.6Hz,2H),0.25(dq,J=9.6,4.9Hz,1H).

[0517] Preparation of Example 187a and Example 187b

[0518] Referring to the synthetic route of Example 118, intermediate E-29 was used instead of intermediate 118-8 in step 9, and the remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=75 / 25; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 187a (P1, SFC t R =2.677), MS(ESI)m / z=562[M+1] + , 1 H NMR (600MHz, DMSO-d6) δ12.22(d,J=109.0Hz,1H),9.86(s,1H),8.21(d,J=8.6Hz,1H),7.86–7.58(m,2H),7.28(d,J=2.0Hz,1H),6.9 5(d,J=11.8Hz,1H),6.69(d,J=2.0Hz,1H),5.17(p,J=6.6Hz,1H),4.74(t,J=8.2Hz,1H),3.51(dddd,J=13.0,10.1,6.4,3.9Hz,1H),2 .64 (d, J = 32.0 Hz, 1H), 2.47 (dd, J = 16.4, 12.5 Hz, 1H), 1.85 (s, 3H), 1.14 (dd, J = 15.3, 6.6 Hz, 6H), 0.93 (d, J = 6.5 Hz, 3H), 0.76–0.69 (m, 1H), 0.68–0.62 (m, 1H), 0.55 (td, J = 9.4, 7.8 Hz, 1H), 0.30–0.22 (m, 1H), 0.19–0.03 (m, 6H), -0.04–0.09 (m, 1H); Example 187b (P2, SFC t R =4.627), MS(ESI)m / z=562[M+1] + , 1H NMR (600MHz, DMSO-d6) δ12.45(d,J=102.7Hz,1H),10.03(s,1H),8.45(d,J=8.6Hz,1H),7.88(t,J=11.6Hz,2H),7.51 (d,J=1.9Hz,1H),7.17(d,J=11.7Hz,1H),6.90(d,J=2.0Hz,1H),5.39(p,J=6.6Hz,1H),5.02–4.86(m,1H),3.74(dtd ,J=9.1,6.3,2.6Hz,1H),2.85(s,1H),2.69(dd,J=16.3,12.4Hz,1H),2.08(s,3H),1.37(dd,J=19.7,6.6Hz,6H),1.1 6(d,J=6.5Hz,3H),0.97–0.83(m,2H),0.79(td,J=9.4,7.6Hz,1H),0.49(dt,J=13.2,6.4Hz,1H),0.42–0.15(m,7H).

[0519] Preparation of Example 188a and Example 188b

[0520] Referring to the synthetic route of Example 12, intermediate D-41 was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 8. The remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-0.1% DEA / ethanol, A / B=60 / 40; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 188a (P1, SFC t R =2.850), MS(ESI)m / z=544[M+1] + , 1H NMR (600MHz, Methanol-d4) δ8.32(s,1H),8.22(s,1H),7.56(d,J=2.0Hz,1H),6.80(d,J=2.0Hz,1H),4.9 3(d,J=7.1Hz,1H),4.52(dq,J=9.6,6.7Hz,3H),3.68(d,J=96.4Hz,2H),2.68(d,J=35.9Hz,2H),2.30(s,3 H), 1.58 (d, J = 6.8 Hz, 3H), 1.33 (dddd, J = 12.9, 9.7, 8.0, 4.9 Hz, 1H), 0.94–0.80 (m, 3H), 0.62–0.53 (m, 2H), 0.53–0.43 (m, 2H), 0.40–0.32 (m, 3H), 0.32–0.27 (m, 4H), 0.24 (dt, J = 9.2, 4.7 Hz, 1H); Example 188b (P2, SFC t R =5.574), MS(ESI)m / z=544[M+1] + , 1 H NMR (600MHz, Methanol-d4) δ8.31(s,1H),8.22(s,1H),7.56(d,J=2.0Hz,1H),6.84(d,J=2.1Hz,1H),4.94(d,J=6.7Hz,1H),4.5 8(dq,J=9.5,6.7Hz,1H),4.35(s,2H),3.75(s,2H),2.71(s,2H),2.30(s,3H),1.56(d,J=6.8Hz,3H),1.38(dddd,J=12.8,9.8,8 .0,4.9Hz,1H),0.92(dtd,J=13.2,8.3,4.9Hz,1H),0.88–0.82(m,2H),0.62(tdd,J=8.8,5.4,3.6Hz,1H),0.56(dq,J=8.1,3.6H z,1H),0.52–0.43(m,2H),0.36(dddd,J=21.3,10.7,5.2,3.5Hz,4H),0.30(dt,J=9.2,4.9Hz,3H),0.24(dt,J=9.3,4.8Hz,1H).

[0521] Preparation of Example 189a and Example 189b

[0522] Referring to the synthetic route of Example 12, intermediate D-40 was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 8. The remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALCEL OX-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=80 / 20; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 189a (P1, SFC t R =3.813), MS(ESI)m / z=536[M+1] + , 1 H NMR (600MHz, Methanol-d4) δ8.33(d,J=29.6Hz,1H),8.22(s,1H),7.58(d,J=2.0Hz,1H),6.86(d,J=2.1Hz,1H),5.64(dddd,J= 13.1,8.0,6.7,4.6Hz,1H),4.98(d,J=7.1Hz,1H),4.69(ddd,J=47.7,9.4,8.1Hz,1H),4.61–4.59(m,0.5H),4.52(dd,J=9.4,4. 7Hz,0.5H),4.35(s,2H),3.69(d,J=72.1Hz,2H),2.74(d,J=35.5Hz,2H),2.31(s,3H),1.48(dd,J=6.9,1.6Hz,3H),0.94–0.81( m, 3H), 0.58–0.43 (m, 3H), 0.41–0.33 (m, 2H), 0.30 (dqt, J=9.3, 4.7, 2.9Hz, 2H), 0.24 (dqt, J=9.4, 4.9Hz, 1H).; Example 189b (P2, SFC t R =4.502), MS(ESI)m / z=536[M+1] + , 1H NMR (600MHz, Methanol-d4) δ8.32(s,1H),8.23(s,1H),7.57(d,J=2.0Hz,1H),6.88(d,J=2.0Hz,1H),5.66(dddd,J=13. 2,8.2,6.8,4.6Hz,1H),5.00(d,J=7.1Hz,1H),4.70(ddd,J=47.8,9.4,8.1Hz,1H),4.61(dd,J=9.3,4.6Hz,0.5H),4.53( dd,J=9.4,4.6Hz,0.5H),4.35(s,2H),3.94–3.57(m,2H),2.65(s,2H),2.30(s,3H),1.46(dd,J=6.9,1.6Hz,3H),0.94–0 .81(m,3H),0.55(tq,J=8.7,4.1Hz,1H),0.51–0.42(m,2H),0.37(dddd,J=9.3,7.5,5.2,4.0Hz,1H),0.34–0.22(m,4H).

[0523] Preparation of Example 190a and Example 190b

[0524] Referring to the synthetic route of Example 12, intermediate D-1 was used instead of 1-isopropylpyrazole-5-carboxylic acid in step 8. The remaining reagents and procedures were the same. The final step was to remove SEM, purify by MPLC (H2O / CH3CN, 0.05% NH4HCO3), and then separate by SFC (chiral column model: Daicel CHIRALPAK AD-3; specification: 3μm, 150mm*3mm; mobile phase: A-CO2, mobile phase: B-ethanol, A / B=80 / 20; flow rate: 1mL / min; column temperature: 40°C) to obtain Example 190a (P1, SFC t R =2.647), MS(ESI)m / z=554[M+1] + , 1H NMR (600MHz, Methanol-d4) δ8.35(d,J=33.5Hz,1H),8.23(s,1H),7.62(d,J=2.0Hz,1H),6.95(d,J=2.0Hz,1H),6 .10(td,J=56.2,5.3Hz,1H),5.70(ddd,J=10.6,5.3,1.7Hz,1H),5.01(d,J=7.2Hz,1H),4.36(s,2H),3.77(s,2H), 2.70 (d, J = 32.6 Hz, 2H), 2.33 (s, 3H), 1.62 (dd, J = 7.1, 1.2 Hz, 3H), 0.96–0.82 (m, 3H), 0.60–0.54 (m, 1H), 0.54–0.49 (m, 1H), 0.49–0.44 (m, 1H), 0.42–0.34 (m, 2H), 0.34–0.29 (m, 2H), 0.26 (dq, J = 9.3, 4.9 Hz, 1H); Example 190b (P2, SFC t R =5.788), MS(ESI)m / z=554[M+1] + , 1 HNMR(600MHz,Methanol-d4)δ8.33(s,1H),8.24(s,1H),7.62(d,J=2.0Hz,1H),6.97(d,J=2.0Hz,1H ),6.10(td,J=56.4,5.4Hz,1H),5.71(dd,J=7.1,5.4Hz,1H),5.02(d,J=7.1Hz,1H),4.36(s,2H),3. 77(s,2H),2.73(s,2H),2.32(s,3H),1.61(dd,J=7.0,1.2Hz,3H),0.96–0.83(m,3H),0.57(tq,J=8. 8,5.2,4.6Hz,1H),0.53–0.43(m,2H),0.42–0.36(m,1H),0.30(dddt,J=26.5,22.1,9.2,4.4Hz,4H).

[0525] Preparation of Example 191 and Example 213

[0526] Referring to the synthetic route of steps 6 to 9 of Example 12, in step 6, the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5. The remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.

[0527] Preparation of Example 214 and Example 233

[0528] Referring to the synthetic method of steps 6 to 9 of Example 12, in step 6, the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5, and in step 8, the corresponding carboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.

[0529] Preparation of Example 234 and Example 245

[0530] Referring to the synthesis method of Example 12, in step 8, 1-isopropylpyrazole-5-carboxylic acid was replaced with the corresponding carboxylic acid in the table below. The remaining reagents and operations were the same to obtain the corresponding structural example compounds in the table.

[0531] Preparation of Example 246

[0532] Referring to the synthetic method of steps 6 and 7 of Example 12, intermediate E-38 was used instead of intermediate 12-5 in step 6. The remaining reagents and procedures were the same to obtain intermediate 246-2. MS (ESI) m / z = 551 [M+1] + .

[0533] Referring to the synthetic route of Example 32, cyclobutanol was used instead of cyclopropanol in step 1, and intermediate 246-2 was used instead of intermediate 15-6. The remaining reagents and procedures were the same to obtain Example 246. MS (ESI) m / z = 519 [M+1] + . 1H NMR(600MHz, Methanol-d4)δ8.45(d,J=34.0Hz,2H),4.92(d,J=7.6Hz,2H),4.65–4.14(m,3H),3.55(s,2H), 3.17–2.84(m,2H),2.33(s,5H),2.11(dq,J=19.2,9.4Hz,2H),1.79(q,J=9.8,8.9Hz,1H),1.63(dtd,J=18.3 ,10.3,7.9Hz,1H),1.17(dt,J=20.8,4.5Hz,4H),0.93–0.82(m,2H),0.69(td,J=9.5,6.0Hz,1H),0.56(tt,J =9.0,4.7Hz,1H),0.49(tt,J=8.9,4.7Hz,1H),0.44–0.34(m,2H),0.25(dddt,J=38.0,14.0,9.2,4.7Hz,4H).

[0534] Preparation of Example 247

[0535] Referring to the synthetic route of Example 32, cyclobutanol was used instead of cyclopropanol in step 1, and intermediate 12-7 was used instead of intermediate 15-6. The remaining reagents and procedures were the same to obtain Example 247. MS (ESI) m / z = 480 [M+1] + . 1 H NMR(600MHz,Methanol-d4)δ8.34(s,1H),8.06(s,1H),4.96–4.89(m,1H),4.59–4.15(m,3H),3.78(s,2H),2. 80(d,J=66.9Hz,2H),2.32(s,5H),2.11(p,J=9.8Hz,2H),1.79(q,J=10.6Hz,1H),1.63(h,J=9.8Hz,1H),0.85 (dddd,J=13.2,9.9,8.1,4.9Hz,2H),0.70(q,J=8.9Hz,1H),0.57(dq,J=13.6,8.6,6.9Hz,1H),0.49(tt,J=8. 6,4.6Hz,1H),0.39(dtd,J=17.8,8.7,4.4Hz,2H),0.30(dq,J=9.9,5.0Hz,1H),0.24(dp,J=14.4,4.6Hz,3H).

[0536] Preparation of Example 248 and Example 257

[0537] Referring to the synthetic method of steps 6 to 9 of Example 12, in step 6, the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5, and in step 8, the corresponding carboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid. The remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.

[0538] In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples

[0539] Test Example 1, IL-17A enzyme-linked immunosorbent assay (ELISA) experiment

[0540] The inhibition of receptor-ligand binding by human IL17A inhibitors was quantitatively detected by competitive ELISA.

[0541] The specific steps of the IL-17A enzyme-linked immunosorbent assay (ELISA) experiment are as follows: (1) Coating of human IL-17A (Sino Biological lnc. Cat#12047-H07B): Human IL-17A was diluted into coating solution (50 mM PBS, pH 7.4) to obtain 0.2 μg / ml IL-17A. 100 μl per well of the 96-well plate was incubated at 37°C for 30 minutes. Note that the blank group was replaced with 100 μl of coating solution. (2) Elution: The plate was washed four times with 10 mM PBST (PBS, pH 7.4, 0.05% Tween-20), 200 μl per well each time, and the final wash was patted dry on absorbent paper. (3) Blocking: Prepare fresh 5% (w / v) skim milk solution before the start of the experiment. Prepare the appropriate volume according to the experimental needs. For example, dissolve 5 g of skim milk (Bio-Rad, 170-6404) in 100 mL of 10 mM PBST. Add 200 μl of 5% (w / v) skim milk solution to each well and incubate on a shaker at 25 degrees for 30 minutes. (4) Prepare 100X test compound. Prepare the test compound solution during the blocking period. Dissolve the powdered compound in DMSO to a stock concentration of 10 mM. Use DMSO to dilute the compound 4-fold to 9 concentrations, ranging from 0.61 μM to 4000 μM. (5) Elution: Repeat step (2). (6) Pre-incubation of IL17A with compound: Add 89 μl of PBST and 1 μl of 100X concentration of the test compound to the wells, mix well, and pre-incubate at 25°C for 10 minutes. Note: 1 μl of DMSO was added to both the blank and control groups instead of the compound. (7) Incubation of human IL17Ra: Add 10 μl of 16 nM human IL-17R (Sino Biological Inc., Cat#10895-H03H) and incubate at 25°C on a shaker for 30 minutes. The buffer is 10 mM PBST. (8) Elution: Repeat step (2). (9) HRP antibody incubation: Add 100 μl mouse anti-Fc tag HRP conjugated antibody (Sino Biological lnc., Cat#10702-MM01T-H) and incubate on a shaker at 25 degrees for 30 minutes. Mouse anti-Fc tag HRP conjugated antibody and 5% (w / v) skim milk solution are prepared at a volume ratio of 1:5000. (10) Elution, repeat step (2). (11) Add 100 μl TMB substrate (BD, Cat#555214, substrate A and substrate B are freshly prepared at a volume ratio of 1:1) solution and incubate at 25 degrees in the dark for 5-15 minutes. If the room temperature is low, the incubation time needs to be appropriately extended. Incubate until a significant color change appears in the control group. (12) Termination: Add 2.5 M HCl to terminate the color reaction. Use a microplate reader BMG PHERStar to measure the absorbance at a wavelength of 450 nm.(13) IC50 calculation: The relative percentage of residual activity at each concentration of the compound was calculated according to Equation 1. The IC50 of the test compound was calculated according to Equation 2: log (inhibitor) vs. normalized response--Variable slope in Graphpad6.

[0542] Equation 1: Relative percentage residual activity % = (sample absorbance - blank absorbance) / (control absorbance - blank absorbance) %

[0543] Equation 2: Y = 100 / (1 + 10^((LogIC50 - X) * HillSlope))

[0544] The compounds prepared in the examples were tested for IL-17A inhibitory activity according to the above method. The test results are shown in Table 1, where the IC 50 The categories are as follows according to the description.

[0545] “+” indicates IC 50 The measured value is less than or equal to 1 μM and greater than 150 nM;

[0546] “++” means IC 50 The measured value is less than or equal to 150nM and greater than 50nM;

[0547] "+++" means IC 50 The measured value was less than or equal to 50 nM.

[0548] Table 1. Inhibitory activity of compounds against human IL-17A

[0549] Test Example 2: IL17AF enzyme-linked immunosorbent assay (ELISA) experiment

[0550] The inhibition of receptor-ligand binding by human IL17AF inhibitors was quantitatively detected by competitive ELISA.

[0551] The specific steps of the IL17AF enzyme-linked immunosorbent assay (ELISA) experiment are as follows: (1) Coating of human IL17AF (Sino Biological lnc.Cat#CT047-H08H): Human IL17AF was diluted into coating solution (50mM PBS, pH 7.4) to obtain 0.625μg / ml IL17AF. 100μl per well of the 96-well plate was incubated at 37°C for 30 minutes. Note that the blank group was replaced with 100μl of coating solution. (2) Elution: The plate was washed four times with 10mM PBST (PBS, pH 7.4, 0.05% Tween-20), 200μl per well each time, and the final wash was patted dry on absorbent paper. (3) Blocking: Prepare fresh 5% (w / v) skim milk solution before the start of the experiment. Prepare the appropriate volume according to the experimental needs. For example, dissolve 5 g of skim milk (Bio-Rad, 170-6404) in 100 mL of 10 mM PBST. Add 200 μl of 5% (w / v) skim milk solution to each well and incubate on a shaker at 25 degrees for 30 minutes. (4) Prepare 100X test compound. Prepare the test compound solution during the blocking period. Dissolve the powdered compound in DMSO to a stock concentration of 10 mM. Use DMSO to dilute the compound 4-fold to 9 concentrations, ranging from 0.61 μM to 4000 μM. (5) Elution: Repeat step (2). (6) Pre-incubation of IL17AF with compound: Add 89 μl of PBST and 1 μl of 100X concentration of the test compound to the wells, mix well, and pre-incubate at 25°C for 10 minutes. Note: 1 μl of DMSO was added to both the blank and control groups instead of the compound. (7) Incubation of human IL17Ra: Add 10 μl of 100 nM human IL-17R (Sino Biological Inc., Cat#10895-H03H) and incubate at 25°C on a shaker for 30 minutes. The buffer is 10 mM PBST. (8) Elution: Repeat step (2). (9) HRP antibody incubation: Add 100 μl mouse anti-Fc tag HRP conjugated antibody (Sino Biological lnc., Cat#10702-MM01T-H) and incubate on a shaker at 25 degrees for 30 minutes. Mouse anti-Fc tag HRP conjugated antibody and 5% (w / v) skim milk solution are prepared at a volume ratio of 1:5000. (10) Elution, repeat step (2). (11) Add 100 μl TMB substrate (BD, Cat#555214, substrate A and substrate B are freshly prepared at a volume ratio of 1:1) solution and incubate at 25 degrees in the dark for 5-15 minutes. If the room temperature is low, the incubation time needs to be appropriately extended. Incubate until a significant color change appears in the control group. (12) Termination: Add 2.5 M HCl to terminate the color reaction. Use a microplate reader BMG PHERStar to measure the light absorbance at a wavelength of 450 nm.(13) IC50 calculation: The relative percentage of residual activity at each concentration of the compound was calculated according to Equation 1. The IC50 of the test compound was calculated according to Equation 2: log (inhibitor) vs. normalized response--Variable slope in Graphpad6.

[0552] Equation 1: Relative percentage residual activity % = (sample absorbance - blank absorbance) / (control absorbance - blank absorbance) %

[0553] Equation 2: Y = 100 / (1 + 10^((LogIC50 - X) * HillSlope))

[0554] The IL17AF inhibitory activity of the compounds prepared in the examples was tested according to the above method. The test results are shown in Table 2, where the IC 50 The categories are as follows according to the description.

[0555] “+” indicates IC 50 The measured value is less than or equal to 1 μM and greater than 500 nM;

[0556] “++” means IC 50 The measured value is less than or equal to 500nM and greater than 100nM;

[0557] "+++" means IC 50 The measured value was less than or equal to 100 nM.

[0558] Table 2. Inhibitory activity of compounds against human IL17AF

[0559] Experimental Example 3: Compounds inhibit human IL17A protein from inducing HT-29 cells to produce chemokine GROα / CXCL1

[0560] 5x 10 4 Human colorectal cancer epithelial cells HT-29 (Chengdu Zhongyuan Gongchuang Technology Co., Ltd.) were added to 96-well plates and cultured overnight at 37°C. A mixture of 30 ng / mL human IL17A protein (R&D, #317-ILB) and a gradient of IL17A small molecule inhibitors or 0.3 μg / mL positive control IL17A antibody (R&D, #AF-317-NA) was incubated at 37°C for 1 hour and then added to the above 96-well plates. The cells were co-incubated with HT-29 cells at 37°C for 48 hours, and then the GROα level in the cell culture supernatant was detected using a GROα ELISA kit (Cisbio, #62HCXC1PEG).

[0561] The compounds prepared in the examples were subjected to the experiment of inhibiting the production of chemokine GROα / CXCL1 by HT-29 cells induced by human IL17A protein according to the methods of Experimental Examples 1 and 2. The results are shown in Table 3. The IC values ​​of each compound for inhibiting GROα / CXCL1 in HT-29 cells are shown in Table 3. 50 Inhibitory activity. The IC of each compound was determined 50 The categories are as follows according to the description.

[0562] “+” indicates IC 50 The measured value is less than or equal to 1 μM and greater than 500 nM;

[0563] “++” means IC 50 The measured value is less than or equal to 500nM and greater than 100nM;

[0564] "+++" means IC 50 The measured value was less than or equal to 100 nM.

[0565] Table 3. IC of compounds against GROα / CXCL1 in HT-29 cells 50

[0566] The experiments show that the compounds of the examples of the present invention have good human IL-17A inhibitory activity and can be effectively used to treat diseases with abnormal hIL-17A activity.

Claims

1. A compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, represents a single bond or a double bond; X 1 Selected from C or N; X 2 , X 3 are independently selected from O, N, NR X or CR X ; X 4 , X 5 are independently selected from C or N; Each R X are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, -OC 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -O(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -O(4- to 10-membered heterocycloalkyl), deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl; Y 1 , Y 2 , Y 3 Each independently selected from N or CR Y ; Each R Y are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-OC 1～6 Alkyl, -C 0～2 Alkylene-O (halogen substituted C 1～6 Alkyl), -C 0～2 Alkylene-O (3-10 membered cycloalkyl), -C 0～2 Alkylene-O(4- to 10-membered heterocycloalkyl); Z is selected from C(O), S(O) or S(O)2; R 1 Selected from -C 1～6 Alkyl, deuterium substituted C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 2～6 Alkenyl, halogen-substituted C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted C 2～6 Alkynyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-OR 11 , -C 0～2 Alkylene-NR 11 R 12 ; wherein alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 1a replace; R 11 , R 12 are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 1a replace; Each R 1a are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR 1b , -C 0～4 Alkylene-SR 1b , -C 0～2 Alkylene-C(O)R 1b , -C 0～2 Alkylene-C(O)NR 1b R 1c , -C 0～4 Alkylene-NR 1b R 1c , -C 0～2 Alkylene-NR 1b C(O)R 1c , -C 0～4 Alkylene-S(O)2R 1b , -C 0～4 Alkylene-NHS(O)2R 1b , -C 0～4 Alkylene-S(O)R 1b , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 1d replace; R 1b , R 1c , R 1d are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -SH, -S(C 1～6 Alkyl), -C 0～2 Alkylene-O(C 1～6 alkyl), -C(O)NH2, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); Alternatively, two R attached to the same carbon atom 1a , and the carbon atoms connected thereto together form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group; wherein the cycloalkyl group or heterocycloalkyl group is optionally replaced by one, two or three independent R 1e replace; R 1e are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -SH, -S(C 1～6 Alkyl), -C 0～2 Alkylene-O(C 1～6 alkyl), -C(O)NH2, -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); R 2 Selected from -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5- to 12-membered bridged cycloalkyl), -C 0～2 Alkylene-(5- to 12-membered heterocyclic alkyl), -C 0～2 Alkylene-(5- to 12-membered spirocycloalkyl), -C 0～2 Alkylene-(5- to 12-membered spiroheterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-OR 21 , -C 0～2 Alkylene-NR 21 R 22 , -C 0～2 Alkylene-CN; wherein alkylene, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two, three or four independent R 2a replace; R 21 , R 22 are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 2a replace; Each R 2a are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR 2b , -C 0～2 Alkylene-C(O)R 2b , -C 0～2 Alkylene -C(O)NR 2b R 2c , -C 0～2 Alkylene-NR 2b R 2c , -C 0～2 Alkylene-NR 2b C(O)R 2c , -C 0～4 Alkylene-S(O)2R 2b , -C 0～4 Alkylene -CN, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5- to 12-membered bridged cycloalkyl), -C 0～2 Alkylene-(5- to 12-membered heterocyclic alkyl), -C 0～2 Alkylene-(5- to 12-membered spirocycloalkyl), -C 0～2 Alkylene-(5- to 12-membered spiroheterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 2d replace; or, Two R's attached to the same carbon atom 2a , together with the carbon atom to which it is connected, form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group; R 2b , R 2c are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally replaced by one, two or three independent R 2d replace; Each R 2d are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, halogen, cyano, =O, =S, nitro, -OH, -O(C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl); R 3 Selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～2 Alkylene-OR 31 , -C 0～2 Alkylene-NR 31 R 32 wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 3a replace; R 31 , R 32 are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); Each R 3a are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl; L is selected from C 2～6 Alkylene, C 2～6 wherein, 1) One, two or three methylene groups in an alkylene or alkenylene group may be optionally replaced by O, NR L1 , C(O), S(O) or S(O)2; and / or 2) Alkylene and alkenylene are optionally substituted by one, two, three or four independent R L replace; Each R L1 Selected from hydrogen, deuterium, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 0～2 Alkane Base-OC 1～6 Alkyl, -C 0～2 Alkylene -CN, -C 0～2 Alkylene-C(O)(C 1～6 Alkyl), -C 0～2 Alkylene-O (3-10 membered cycloalkyl), -C 0～2 Alkylene-O(4- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(5-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle), -C 0～4 Alkylene-N(C 1～6 Alkyl)(C 1～6 wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R L2 replace; Each R L2 are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl; Each R L are independently selected from hydrogen, deuterium, halogen, cyano, =O, =S, nitro, -C 1～6 Alkyl, deuterium-substituted-C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OC 1～6 Alkyl, -C 0～2 Alkylene-O (3-10 membered cycloalkyl), -C 0～2 Alkylene-O(4- to 10-membered heterocycloalkyl); or, Two R's attached to the same carbon atom L , and the carbon atom to which it is connected together form a 3- to 10-membered cycloalkyl or a 4- to 10-membered heterocycloalkyl.

2. The compound according to claim 1, characterized in that: X 1 C, X 2 NR X , X 3 N, X 4 C, X 5 is C; Or, X 1 C, X 2 N, X 3 N, X 4 C, X 5 is N; Or, X 1 C, X 2 N, X 3 CR X , X 4 N, X 5 is C; Or, X 1 N, X 2 N, X 3 CR X , X 4 C, X 5 is C; Or, X 1 C, X 2 O, X 3 N, X 4 C, X 5 For C.

3. The compound according to any one of claims 1 to 2, characterized in that: The compound shown in formula I is shown below: Among them, R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Z, L are defined as described in claim 1.

4. The compound according to any one of claims 1 to 3, characterized in that: Y 1 , Y 2 , Y 3 Each independently selected from N or CR Y ; Each R Y are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy; Z is selected from C(O) or S(O)2.

5. The compound according to any one of claims 1 to 4, characterized in that: R 3 Selected from methyl, deuterated methyl, ethyl, perdeuterated ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxymethyl, methoxymethyl, deuterated methoxymethyl, amino, methylamino, dimethylamino, deuterated methylamino.

6. The compound according to any one of claims 1 to 5, characterized in that: The R 1 Selected from 7. The compound according to any one of claims 1 to 6, characterized in that: The R 2 Selected from 8. The compound according to any one of claims 1 to 7, characterized in that: L is selected from Among them, the aa end and X 4 connected.

9. The compound according to any one of claims 1 to 8, characterized in that: The compound is specifically:

10. Use of the compound according to any one of claims 1 to 9, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an IL-17A-mediated disease.

11. The use according to claim 10, characterized in that: The IL-17A-mediated disease is one or more of diseases associated with inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndrome.

12. A pharmaceutical composition, characterized in that: The invention relates to a preparation prepared by adding a pharmaceutically acceptable auxiliary material to the compound described in any one of claims 1 to 9, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 9, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition of psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma and / or COPD.

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